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The objectives of this retrospective observational study were to investigate the association between BCS at 21 d before calving with prepartum and postpartum DMI, energy balance (EB), and milk yield. Data from 427 multigravid cows from 11 different experiments conducted at the University of Florida (Gainesville, FL) were used. Cows were classified according to their BCS at 21 d before calving as fat (BCS ≥ 4.00; n = 83), moderate (BCS = 3.25–3.75; n = 287), and thin (BCS ≤ 3.00; n = 57). Daily DMI from −21 to −1 and from +1 to +28 DIM was individually recorded. Energy balance was calculated as the difference between net energy for lactation consumed and required. Dry matter intake in fat cows was lower than that in moderate and thin cows both prepartum (fat = 9.97 ± 0.21, moderate = 11.15 ± 0.14, and thin = 11.92 ± 0.22 kg/d) and postpartum (fat = 14.35 ± 0.49, moderate = 15.47 ± 0.38, and thin = 16.09 ± 0.47 kg/d). Dry matter intake was also lower for moderate cows compared with thin cows prepartum, but not postpartum. Energy balance in fat cows was lower than in moderate and thin cows both prepartum (fat = −4.16 ± 0.61, moderate = −1.20 ± 0.56, and thin = 0.88 ± 0.62 Mcal/d) and postpartum (fat = −12.77 ± 0.50, moderate = −10.13 ± 0.29, and thin = −6.14 ± 0.51 Mcal/d). Energy balance was also lower for moderate cows compared with thin cows both prepartum and postpartum. There was a quadratic association between BCS at 21 d before calving and milk yield. Increasing BCS from 2.5 to 3.5 was associated with an increase in daily milk yield of 6.0 kg and 28 d cumulative milk of 147 kg. Increasing BCS from 3.5 to 4.5 was associated with a decrease in daily milk yield of 4.4 kg and 28 d cumulative milk of 116 kg. In summary, a moderate BCS at 21 d before calving was associated with intermediate DMI and EB pre- and postpartum but greater milk yield compared with thinner and fatter cows. Our findings indicate that a moderate BCS is ideal for ensuring a successful lactation. [ABSTRACT FROM AUTHOR]

Dairy cows with clinical ketosis (CK) exhibit excessive adipose tissue (AT) lipolysis and systemic inflammation. Lipolysis in cows can be induced by the canonical (hormonally induced) and inflammatory lipolytic pathways. Currently, the most common treatment for CK is oral propylene glycol (PG); however, PG does not reduce lipolysis or inflammation. Niacin (NIA) can reduce the activation of canonical lipolysis, whereas cyclooxygenase inhibitors such as flunixin meglumine (FM) can limit inflammation and inhibit the inflammatory lipolytic pathway. The objective of this study was to determine the effects of including NIA and FM in the standard PG treatment for postpartum CK on AT function. Multiparous Jersey cows (n = 18; 7.1 ± 3.8 DIM) were selected from a commercial dairy. Inclusion criteria were CK symptoms (lethargy, depressed appetite, and drop in milk yield) and high blood levels of BHB (≥1.2 mmol/L). Cows with CK were randomly assigned to one of 3 treatments: (1) PG: 310 g administered orally once per day for 5 d, (2) PG+NIA: 24 g administered orally once per day for 3 d, and (3) PG+NIA+FM: 1.1 mg/kg administered IV once per day for 3 d. Healthy control cows (HC; n = 6) matched by lactation and DIM (±2 d) were sampled. Subcutaneous AT explants were collected at d 0 and d 7 relative to enrollment. To assess AT insulin sensitivity, explants were treated with insulin (1 µL/L) during lipolysis stimulation with a β-adrenergic receptor agonist (isoproterenol, 1 µM). Lipolysis was quantified by glycerol release in the media. Lipid mobilization and inflammatory gene networks were evaluated using quantitative PCR. Protein biomarkers of lipolysis, insulin signaling, and AT inflammation, including hormone-sensitive lipase, protein kinase B (Akt), and ERK1/2, were quantified by capillary immunoassays. Flow cytometry of AT cellular components was used to characterize macrophage inflammatory phenotypes. Statistical significance was determined by a nonparametric t -test when 2 groups (HC vs. CK) were analyzed and an ANOVA test with Tukey adjustment when 3 treatment groups (PG vs. PG+NIA vs. PG+NIA+FM) were evaluated. At d 0, AT from CK cows showed higher mRNA expression of lipolytic enzymes ABHD5 , LIPE , and LPL , as well as increased phosphorylation of hormone-sensitive lipase compared with HC. At d 0, insulin reduced lipolysis by 41% ± 8% in AT from HC, but CK cows were unresponsive (−2.9 ± 4%). Adipose tissue from CK cows exhibited reduced Akt phosphorylation compared with HC. Cows with CK had increased AT expression of inflammatory gene markers, including CCL2 , IL8 , IL10 , TLR4 , and TNF, along with ERK1/2 phosphorylation. Adipose tissue from CK cows showed increased macrophage infiltration compared with HC. By d 7, AT from PG+NIA+FM cows had a more robust response to insulin, as evidenced by reduced glycerol release (36.5% ± 8% compared with PG at 26.9% ± 7% and PG+NIA at 7.4% ± 8%) and enhanced phosphorylation of Akt. By d 7, PG+NIA+FM cows presented lower inflammatory markers, including ERK1/2 phosphorylation, and reduced macrophage infiltration, compared with PG and PG+NIA. These data suggest that including NIA and FM in CK treatment improves AT insulin sensitivity and reduces AT inflammation and macrophage infiltration. [Display omitted] [ABSTRACT FROM AUTHOR]

Many patients diagnosed with rheumatoid arthritis (RA) report relief of symptoms after consuming certain foods. Diet plays a vital role in rheumatoid arthritis-related inflammation regulation. This study investigates the relationship between dietary inflammation index (DII) scores and RA disease activity. Forty-one RA patients were enrolled in the study. The general inflammatory index of the diet was analyzed by recording the 24-h food consumption of the patients, and the nutrients were analyzed using the Nutrition Information Systems Package Program. Dietary inflammatory indices were calculated for each patient using the patients' macro and micronutrient intake levels. RA disease activity was assessed using the Disease Activity Score-28 (DAS-28). The DAS-28 score was lower in the anti-inflammatory diet group compared to the pro-inflammatory diet group (p = 0.163). A weak but significant relationship was found between diet inflammation index score and DAS-28 (r = 0.3468, p = 0.0263). The effect of the dietary inflammatory index on the DAS-28 was 12.02%. Dietary iron, vitamin C, niacin, and magnesium intakes were statistically significantly higher in the quartile group that received an anti-inflammatory diet than in the quartile group that received a pro-inflammatory diet. The intake of some micronutrients, such as iron, zinc, magnesium, and folic acid, was significantly lower than the recommended values in all RA quartile groups. Our results suggest that reducing inflammation through the diet may have a weak but significant effect in controlling disease activity in RA patients. [ABSTRACT FROM AUTHOR]

Nicotinamide mononucleotide (NMN) is a precursor of NAD+, its efficient bio-production through microbial fermentation has rarely been reported. Bacillus subtilis was postulated to lack the inherent ability of NMN biosynthesis, however, certain level of NMN (53.67 mg/L) was detected in the fermentation broth containing nicotinamide. An endogenous enzyme (PncB) previously annotated as a nicotinic acid phosphotransferase was identified to be involved in the key synthetic reaction, since the deletion of pncB revoked the production of NMN, while the enhanced expression of PncB significantly increased the titer of NMN (110.0 mg/L). The structural simulation of PncB revealed the possible catalytic mechanisms of NMN forming. The NMN synthesis was further boosted by removing a possible deamidase (CinA), the yield of extracellular NMN reached 202.9 mg/L. After introducing the NMN transporter PnuC into the host cell, the fermentation level of NMN increased by another 65.34 %. And, with 20 g/L glucose and 10 g/L NAM supplemented in the medium, a maximal of 1.21 g/L of NMN was accumulated, signifying the potential of biological production of NMN using food-grade Bacillus subtilis. [Display omitted] • Bacillus subtilis synthesizes NMN from nicotinamide using its native enzymes. • The nicotinate phosphoribosyltransferase is pivotal for the production of NMN in Bacillus subtilis. • Deletion of an uncharacterized deamidase (CinA) led to a higher titer of NMN. [ABSTRACT FROM AUTHOR]

Amine-based molecules are frequently utilized for defect passivation in perovskite films. However, the passivation effect can vary considerably depending on the structural differences of the amine molecules. In this study, we selected small-sized formamidine iodide (FAI), long-chain octylammonium iodide (OAI), and aromatic nicotinic acid (NA) to passivate surface defects in perovskite films. The charge transport in perovskite solar cells (PSCs) was inhibited by the excessively long alkyl chain of OAI but was enhanced by the π-conjugated structure of NA. Consequently, the power conversion efficiency (PCE) of OAI and NA-passivated PSCs decreased by 0.91% and increased by 0.23%, respectively. Interestingly, FAI was found to react preferentially with the PbI 2 at the grain boundary of perovskite films, promoting secondary grain growth and resulting in a 21% increase in grain size. Due to the reduction in grain boundaries and the combined passivation of MA+ and I− vacancies, the PCE of FAI-passivated PSCs increased from 18.63% to 19.35% in ambient air and maintained 91% of their initial values after 76 days of storage under conditions of 20 ± 5 °C and <5% RH. This study introduces a promising strategy for selecting an appropriate amine molecule for surface passivation in efficient and stable fully-ambient air processed PSCs. [ABSTRACT FROM AUTHOR]

Depressive disorder in adolescents is a major health problem with inadequate treatment. Omega-3 (ω3) polyunsaturated fatty acids are a promising adjuvant therapy in adult depression. The primary objective of this study was to investigate the efficacy of adjuvant ω3 treatment on depressive symptoms in adolescent depression. Secondarily, we explored the effects of ω3 on cognitive function and memory and niacin skin flushing response (NSFR), as their robust associations with adolescent depression. A total of 71 adolescents with depression (aged 13–24; 59.2 % female) were randomly assigned to receive ω3 plus Paxil (n = 34) or Paxil alone (n = 37) for 12 weeks. Primary outcome was depression severity according to scores on Montgomery-Asberg Depression Rating Scale (MADRS). Secondary outcomes were cognitive function and memory, and NSFR. Significant improvements in depressive symptoms over time (p = 0.00027 at week 12) were observed in the ω3 + Paxil group compared with Paxil group. Additionally, in the ω3 + Paxil group, significant improvements in memory over time, and greater cognitive function and NSFR were also observed compared with the Paxil group; the NSFR was negatively correlated with MADRS scores at baseline. The trial was open label; thus, the outcome measures should be viewed as preliminary since inherent bias in outcomes due to the potential of a placebo effect. Our results demonstrate that adjuvant ω3 treatment is effective for reducing depressive symptoms as well as improving cognitive function, memory and the NSFR; these results suggest ω3 is a promising adjuvant treatment for adolescent depression. • This study has evaluated the efficacy of omega-3 treatment in adolescent depression. • Adjuvant omega-3 treatment was efficacious for reducing depressive symptoms. • Omega-3 improved cognitive function, memory and niacin skin flushing response (NSFR). • Omega-3 may be a promising adjuvant treatment for adolescent depression. [ABSTRACT FROM AUTHOR]

Geotrichum candidum is a dimorphic yeast used in cheese processing. To our knowledge, no major metabolites have been identified to date in G. candidum except for some amino acid and fatty acid metabolites. This has limited research on the commercial use of G. candidum. In this study, we aimed to analyze temporal changes in the intra- and extra-cellular metabolites of G. candidum and Saccharomyces cerevisiae cultured in YM medium as reference. As a result of metabolite analysis, it was observed that G. candidum tends to accumulate pentose phosphate pathway compounds, which are involved in nucleic acid synthesis, after 48 h of cultivation when compared to S. cerevisiae. In addition, G. candidum accumulated higher amounts of the antioxidant glutathione in the medium than did S. cerevisiae. In addition, G. candidum accumulated large amounts of B vitamins such as pantothenic acid and nicotinic acid in the medium. Finally, we examined the potential of G. candidum as a host for the production of useful compounds such as pantothenic acid. When cultured in medium supplemented with the pantothenic acid precursor β-alanine, G. candidum produced 12-fold higher amounts of pantothenic acid (30 μM) than that by S. cerevisiae. This study indicates that G. candidum accumulates various useful compounds that are dissimilar to those produced by S. cerevisiae. Furthermore, G. candidum has the potential to produce useful chemicals under appropriate culture conditions. [ABSTRACT FROM AUTHOR]

Excessive and protracted lipolysis in adipose tissues of dairy cows is a major risk factor for clinical ketosis (CK). This metabolic disease is common in postpartum cows when lipolysis provides fatty acids as an energy substrate to offset negative energy balance. Lipolysis in cows can be induced by the canonical (hormonally induced) and inflammatory pathways. Current treatments for CK focus on improving glucose in blood (i.e., oral propylene glycol [PG], or i.v. dextrose). However, these therapies do not inhibit the canonical and inflammatory lipolytic pathways. Niacin (NIA) can reduce activation of the canonical pathway. Blocking inflammatory responses with cyclooxygenase inhibitors such as flunixin meglumine (FM) can inhibit inflammatory lipolytic activity. The objective of this study was to determine the effects of including NIA and FM in the standard PG treatment for postpartum CK on circulating concentrations of ketone bodies. A 4-group, parallel, individually randomized trial was conducted in multiparous Jersey cows (n = 80) from a commercial dairy in Michigan during a 7-mo period. Eligible cows had CK symptoms (lethargy, depressed appetite, and milk yield) and hyperketonemia (blood β-hydroxybutyrate [BHB] ≥1.2 mmol/L). Cows with CK were randomly assigned to 1 of 3 groups where the first group received 310 g of oral PG once per day for 5 d; the second group received PG for 5 d + 24 g of oral NIA once per day for 3 d (PGNIA); and the third group received PG for 5 d + NIA for 3 d + 1.1 mg/kg i.v. FM once per day for 3 d (PGNIAFM). The control group consisted of cows that were clinically healthy (HC; untreated; BHB <1.2 mmol/L, n = 27) matching for parity and DIM with all 3 groups. Animals were sampled at enrollment (d 0), and d 3, 7, and 14 to evaluate ketone bodies and circulating metabolic and inflammatory biomarkers. Effects of treatment, sampling day, and their interactions were evaluated using mixed effects models. Logistic regression was used to calculate the odds ratio (OR) of returning to normoketonemia (BHB <1.2 mmol/L). Compared with HC, enrolled CK cows exhibited higher blood concentrations of dyslipidemia markers, including nonesterified fatty acids (NEFA) and BHB, and lower glucose and insulin levels. Cows with CK also had increased levels of biomarkers of pain (substance P), inflammation, including lipopolysaccharide-binding protein, haptoglobin, and serum amyloid A, and proinflammatory cytokines IL-4, MCP-1, MIP-1α, and TNFα. Importantly, 72.2% of CK cows presented endotoxemia and had higher circulating bacterial DNA compared with HC. By d 7, the percentage of cows with normoketonemia were higher in PGNIAFM = 87.5%, compared with PG = 58.33%, and PGNIA = 62.5%. At d 7 the OR for normoketonemia in PGNIAFM cows were 1.5 (95% CI, 1.03–2.17) and 1.4 (95% CI, 0.99–1.97) relative to PG and PGNIA, respectively. At d 3, 7, and 14, PGNIAFM cows presented the lowest values of BHB (PG = 1.36; PGNIA = 1.24; PGNIAFM = 0.89 ± 0.13 mmol/L), NEFA (PG = 0.58; PGNIA = 0.59; PGNIAFM = 0.45 ± 0.02 mmol/L), and acute phase proteins. Cows in PGNIAFM also presented the highest blood glucose increment across time points and insulin by d 7. These data provide evidence that bacteremia or endotoxemia, systemic inflammation, and pain may play a crucial role in CK pathogenesis. Additionally, targeting lipolysis and inflammation with NIA and FM during CK effectively reduces dyslipidemia biomarkers, improves glycemia, and improves overall clinical recovery. [ABSTRACT FROM AUTHOR]

Rumen-protected choline (RPC) supplementation in the periparturient period has in some instances prevented and alleviated fatty liver disease in dairy cows. Mechanistically, however, it is unclear how choline prevents the accumulation of lipid droplets (LD) in liver cells. In this study, primary liver cells isolated from liver tissue obtained via puncture biopsy from 3 nonpregnant mid-lactation multiparous Holstein cows (∼160 d postpartum) were used. Analyses of LD via oil red O staining, protein abundance via Western blotting, and phospholipid content and composition measured by thin-layer chromatography and HPLC/mass spectrometry were performed in liver cells cultured in choline-deficient medium containing 150 μmol/L linoleic acid for 24 h. In a subsequent experiment, lipophagy was assessed in liver cells cultured with 30, 60, or 90 µmol/L choline-chloride. All data were analyzed statistically using SPSS 20.0 via t -tests or one-way ANOVA. Compared with liver cells cultured in Dulbecco's Modified Eagle Medium alone, choline deficiency increased the average diameter of LD (1.59 vs. 2.10 µm), decreased the proportion of small LD (<2 µm) from 75.3% to 56.6%, and increased the proportion of large LD (>4 µm) from 5.6% to 15.0%. In addition, the speed of LD fusion was enhanced by the absence of choline. Among phospholipid species, the phosphatidylcholine (PC) content of liver cells decreased by 34.5%. Seventeen species of PC (PC [18:2_22:6], PC [15:0_16:1], PC [14:0_20:4], and so on) and 6 species of lysophosphatidylcholine (LPC; LPC [15:0/0:0]), PC (22:2/0:0), LPC (20:2/0:0), and so on] were decreased, while PC (14:1_16:1) and LPC (0:0/20:1) were increased. Choline deficiency increased the triglyceride (TAG) content (0.57 vs. 0.39 μmol/mg) in liver cells and increased the protein abundance of sterol regulatory element binding protein 1, sterol regulatory element binding protein cleavage activation protein, and fatty acid synthase by 23.5%, 17%, and 36.1%, respectively. Upon re-supplementation with choline, the phenotype of LD (TAG content, size, proportion, and phospholipid profile) was reversed, and the ratio of autophagy marker LC3II/LC3I protein was significantly upregulated in a dose-dependent manner. Overall, at least in vitro in mid-lactation cows, these data demonstrated that PC synthesis is necessary for normal LD formation, and both rely on choline availability. According to the limitation of the source of liver cells used, further work should be conducted to ascertain that these effects are applicable to liver cells from postpartum cows, the physiological stage where the use of RPC has been implemented for the prevention and treatment of fatty liver. [ABSTRACT FROM AUTHOR]

We examined the effects of a supplement of plant polyphenols extracts of green tea, capsicum, and fenugreek, and electrolytes ([Na+, K+]; AXT, Axion ThermoPlus, CCPA, France] during summer heat load on production, welfare, and oxidative stress proteins in adipose tissue (AT) of dairy cows. A total of 42 multiparous mid-lactation cows were divided into 3 groups during summer, and were fed for 2 wk either a standard milking cow diet (CTL, n = 14) or diets supplemented with 100 g/d of AXT (100AXT, n = 14), or 150 g/d of AXT (150AXT, n = 14), while being cooled 5 times a day. Then, half of the cows from each dietary treatment were cooled (CL) or not cooled (NCL) for 2 wk, after which the cooled and uncooled groups were switched for additional 2 wk. Cows were milked 3 times a day, and milk composition was analyzed at the end of each 2-wk period. Vaginal temperature (VT) was measured for 3 consecutive days in each period. Biopsies of subcutaneous AT were taken from 10 NCL cows (5 each of CTL and 150AXT) at the end of the period and examined by liquid chromatography-tandem mass spectrometry proteomics analysis. Data were analyzed with PROC MIXED of SAS (version 9.2, SAS Institute Inc.). The model included the effects of dietary treatment, cooling regimen, period, and their interactions. Protein and mRNA abundances and proteomic data (P ≤ 0.05 and fold change [FC] ± 1.5) were analyzed by t -test. Milk yields and 4% fat-corrected milk (FCM) were higher in 100AXT than in CTL; milk components were not different. Dry matter intake (DMI) was higher in 100AXT than in CTL. The effect of cooling and the interactions of period × cooling were significant for DMI, 4% FCM, energy-corrected milk, and milk/DMI. The proportion of time that VT was >39°C was lower in 100AXT and in 150AXT than in CTL. Daily rumination time was greater in 150AXT than in CTL, and lying time was greater in 100AXT and 150AXT than in CTL. Proteomics of AT demonstrated that 150AXT had increased abundances of peroxidasin (FC = 1.6), microsomal glutathione S-transferase 2 (FC = 2.5), and heme oxygenase 1 (FC = 3.6) compared with CTL. Top enriched canonical pathways included acute phase response signaling, Nrf2-mediated oxidative stress response, and lipopolysaccharide (LPS)/IL-1-mediated inhibition of RXR function. Immunoblots of AT showed a higher abundance of the transient receptor potential vanilloid 1 and of LPS binding protein in AT of 150AXT compared with CTL. Supplementation of AXT increased DMI, milk, and 4% FCM, lowered VT, improved welfare indices, and enriched the AT with Nrf2-oxidative stress response and acute phase response proteins in heat-stressed dairy cows. [ABSTRACT FROM AUTHOR]

The current study was conducted to examine the effect of l -carnitine (LC) supplementation on telomere length and mitochondrial DNA copy number (mtDNAcn) per cell in mid-lactation cows challenged by lipopolysaccharide (LPS) in blood and liver. The mRNA abundance of 31 genes related to inflammation, oxidative stress, and the corresponding stress response mechanisms, the mitochondrial quality control and the protein import system, as well as the phosphatidylinositol 3-kinase/protein kinase B pathway, were assessed using microfluidics integrated fluidic circuit chips (96.96 dynamic arrays). In addition to comparing the responses in cows with or without LC, our objectives were to characterize the oxidative and inflammatory status by assessing the circulating concentration of lactoferrin (Lf), haptoglobin (Hp), fibrinogen, derivates of reactive oxygen metabolites (dROM), and arylesterase activity (AEA), and to extend the measurement of Lf and Hp to milk. Pluriparous Holstein cows were assigned to either a control group (CON, n = 26) or an LC-supplemented group (CAR; 25 g LC/cow per day; d 42 ante partum to d 126 postpartum (PP), n = 27). On d 111 PP, each cow was injected intravenously with LPS (Escherichia coli O111:B4, 0.5 µg/kg). The mRNA abundance was examined in liver biopsies of d −11 and +1 relative to LPS administration. Plasma and milk samples were frequently collected before and after the challenge. After LPS administration, circulating plasma fibrinogen and serum dROM concentrations increased, whereas AEA decreased. Moreover, serum P4 initially increased by 3 h after LPS administration and declined thereafter irrespective of grouping. The Lf concentrations increased in both groups after LPS administration, with the CAR group showing greater concentrations in serum and milk than the CON group. After LPS administration, telomere length in blood increased, whereas mtDNAcn per cell decreased; however, both remained unaffected in liver. For mitochondrial protein import genes, the hepatic mRNA abundance of the translocase of the mitochondrial inner membrane (TIM)- 17B was increased in CAR cows. Moreover, TIM23 increased in both groups after LPS administration. Regarding the mRNA abundance of genes related to stress response mechanisms, 7 out of 14 genes showed group × time interactions, indicating a (local) protective effect due to the dietary LC supplementation against oxidative stress in mid-lactating dairy cows. For mtDNAcn and telomere length, the effects of the LPS-induced inflammation were more pronounced than the dietary supplementation of LC. Dietary LC supplementation affected the response to LPS primarily by altering mitochondrial dynamics. Regarding mRNA abundance of genes related to the mitochondrial protein import system, the inner mitochondrial membrane translocase (TIM complex) seemed to be more sensitive to dietary LC than the outer mitochondrial membrane translocase (TOM complex). [ABSTRACT FROM AUTHOR]

Inadequate exposure to estradiol (E 2) and progesterone (P 4) may be the main causes of altered endometrial epidermal growth factor (EGF) profile, leading to reduced fertility in dairy cows. We hypothesized that PGF 2α administration at different timings of the estrous cycle and stages of follicular development could change the profile of steroid hormones between luteolysis and estrus. This results in reduction in the peak concentration of endometrial EGF on day 3 (day 0 = estrus) in the next estrous cycle. In study 1, lactating Holstein cows were treated with PGF 2α either on days 12–14 (selection phase group, n = 20) or on days 16–17 (control group, n = 24) of the estrous cycle. Blood samples were obtained before PGF 2α treatment, 24 and 48 h after treatment, and on the day of estrus and ovulation for E 2 and P 4 assays. Endometrial tissues were collected by biopsy on day 3 for EGF assays. The duration from PGF 2α treatment to both estrus and ovulation was longer in the selection phase group than in the control group (P < 0.05). The time between estrus and ovulation was longer in the selection phase group (P < 0.05). E 2 concentrations were higher in the control group on the day of estrus (P < 0.05). P 4 concentrations were not different between the groups. Endometrial EGF concentrations were lower in the selection phase group than in the control group (P < 0.05). In study 2, lactating Holstein cows were treated with PGF 2α either on day 12 (selection phase group, n = 76) or day 16 (control group, n = 80). They were subjected to artificial insemination (AI) at estrus, and those that failed to ovulate by 24h after the first AI were subjected to second AI. On day 3, endometrial EGF concentration was determined. At estrus and on days 3 and 7, blood was collected for E 2 and P 4 assay from 20 randomly selected cows in each group before PGF 2α treatment. The cows in the selection phase group exhibited lower EGF concentration, proportion of cows with normal EGF profile, and conception rate than cows in the control group (P < 0.05). On the day of estrus, E 2 concentrations tended to be lower in the selection phase group than in the control group (P = 0.08). P 4 concentrations were not different between the groups. These findings suggest that low E 2 concentrations at estrus and low P 4 concentrations for a prolonged period due to premature termination of CL in the absence of a dominant follicle are potential causes of altered endometrial EGF profile in dairy cows. • Treatment using PGF2α during follicle selection of the second follicle wave. • Extended the time from treatment to estrus and ovulation. • Reduced the proportion of cows ovulating within 24 h after AI. • Reduced the endometrial EGF concentrations on the next cycle and conception rate. [ABSTRACT FROM AUTHOR]

Riboflavin is a precursor of the essential coenzymes flavin mononucleotide and flavin adenine dinucleotide. Both possess antioxidant properties and are involved in oxidation-reduction reactions, which have a significant impact on energy metabolism. Also, the coenzymes participate in metabolism of pyridoxine, niacin, folate, and iron. Humans must obtain riboflavin through their daily diet because of the lack of programmed enzymatic machineries for de novo riboflavin synthesis. Because of its physiological nature and fast elimination from the human body when in excess, riboflavin consumed is unlikely to induce any negative effects or develop toxicity in humans. The use of riboflavin in pharmaceutical and clinical contexts has been previously explored, including for preventing and treating oxidative stress and reperfusion oxidative damage, creating synergistic compounds to mitigate colorectal cancer, modulating blood pressure, improving diabetes mellitus comorbidities, as well as neuroprotective agents and potent photosensitizer in killing bloodborne pathogens. Thus, the goal of this review is to provide a comprehensive understanding of riboflavin's biological applications in medicine, key considerations of riboflavin safety and toxicity, and a brief overview on the nanoencapsulation of riboflavin for various functions including the treatment of a range of diseases, photodynamic therapy, and cellular imaging. Riboflavin (Vitamin B 2) is an essential nutrient and important in the prevention and treatment of a wide range of diseases. This review provides an overview on the role of riboflavin in the regulation of human health and metabolic processes and discusses the key points of riboflavin (RF) safety and toxicity, and potential of RF nanoparticles as photoactivatable agents in photodynamic therapy (PDT) and molecular cell imaging applications. The graphical abstract was created using BioRender illustration tool, accessed at https://www.biorender.com. [Display omitted] [ABSTRACT FROM AUTHOR]

The objective of this experiment was to investigate the effects of an essential oil (EO) blend on lactational performance, rumen fermentation, nutrient utilization, blood variables, enteric methane emissions and manure greenhouse gas-emitting potential in dairy cows. A randomized complete block design experiment was conducted with 26 primiparous and 22 multiparous Holstein cows. A 2-wk covariate and a 2-wk adaptation periods preceded a 10-wk experimental period used for data and sample collection. Treatments were: (1) basal diet supplemented with placebo (CON); and (2) basal diet supplemented with a blend of EO containing eugenol and geranyl acetate as main compounds. Supplementation with EO did not affect dry matter intake, milk and energy-corrected milk yields, and feed efficiency of cows, compared with CON. Milk fat and lactose concentrations were increased, and milk total solids (TS) concentration and milk fat yield tended to be increased by EO. Multiparous cows supplemented with EO tended to have slightly decreased dry matter and crude protein digestibility compared with CON multiparous cows. There was a tendency for increased ruminal pH by EO, whereas other rumen fermentation variables did not differ between treatments. Daily methane emission was not affected by EO supplementation, but methane emission intensity per kg of milk fat was decreased by 8.5% by EO. Methane emission intensity per kg of milk lactose and milk TS were decreased and methane emission intensity per kg of milk yield tended to be decreased by up to 10% in EO multiparous cows, but not in primiparous cows. The greenhouse gas-emitting potential of manure was not affected by EO supplementation. Compared with CON, fecal nitrogen excretion was increased by EO supplementation in multiparous, but not in primiparous cows, and milk nitrogen secretion (as a % of nitrogen intake) tended to be increased in EO supplemented cows. Blood variables were not affected by EO supplementation in the current study. Overall, dietary supplementation of EO did not affect lactational performance of the cows, although milk fat and lactose concentrations were increased. Most enteric methane emission metrics were not affected, but EO decreased methane intensity per kg of milk fat by 8.5%, compared with the control. [ABSTRACT FROM AUTHOR]

The association between dietary intake and depression is receiving increasing attention. However, the relationship between depressive symptoms and niacin intake is still unclear. The purpose of this study was to explore the association between niacin intake and depressive symptoms. We used univariate analysis and multivariate logistic regression equations to explore the association between covariates or niacin intake and depression. Generalized additive models and smoothing fitted curves were used to examine the presence of nonlinear relationships. Upon finding a nonlinear relationship, a recursive algorithm was used to calculate the inflection point. Population differences were also explored through stratified analysis. In the model adjusted for all covariates，the ORs (95 % CI) for the association between niacin intake and depression were 0.94 (0.87, 1.01), which was no statistical significance. However, the result of the linear trend test with quartiles of niacin intake indicated the association between niacin intake and depression may be U-shaped. The generalized additive model confirmed this U-shaped relationship, finding an inflection point (26.6 mg/d). An opposite relationship was observed before and after the inflection point, with ORs (95 % CI) of 0.77 (0.68, 0.87) before the inflection point and 1.13 (1.01, 1.28) after the inflection point. The association in men, Mexican American, White, adults aged<40, and BMI <30 was consistent with the overall tendency. We found a U-shaped association between niacin intake and depression in the general American population, and the same association was observed in men, Mexican American, White, adults aged < 40, and BMI < 30. • Our study highlighted a U-shaped association between niacin intake and depression with an inflection point of 26.6 mg/d in the general US adults. • The relationship was negative before the inflection point and positive after the inflection point. • The U-shaped association was also observed in men, Mexican American, White, adults aged<40, and BMI <30. [ABSTRACT FROM AUTHOR]

Axonal degeneration is a hallmark feature of neurodegenerative diseases. Activation of the NAD(P)ase sterile alpha and toll-interleukin receptor motif containing protein 1 (SARM1) is critical for this process. In resting neurons, SARM1 activity is inhibited, but upon damage, SARM1 is activated and catalyzes one of three NAD(P)+ dependent reactions: (1) NAD(P)+hydrolysis to form ADP-ribose (ADPR[P]) and nicotinamide; (2) the formation of cyclic-ADPR (cADPR[P]); or (3) a base exchange reaction with nicotinic acid (NA) and NADP+ to form NA adenine dinucleotide phosphate. Production of these metabolites triggers axonal death. Two activation mechanisms have been proposed: (1) an increase in the nicotinamide mononucleotide (NMN) concentration, which leads to the allosteric activation of SARM1, and (2) a phase transition, which stabilizes the active conformation of the enzyme. However, neither of these mechanisms have been shown to occur at the same time. Using in vitro assay systems, we show that the liquid-to-solid phase transition lowers the NMN concentration required to activate the catalytic activity of SARM1 by up to 140-fold. These results unify the proposed activation mechanisms and show for the first time that a phase transition reduces the threshold for NMN-based SARM1 activation to physiologically relevant levels. These results further our understanding of SARM1 activation and will be important for the future development of therapeutics targeting SARM1. [ABSTRACT FROM AUTHOR]

The objective of this study was to quantify the effects of supplementing transition dairy cows with a low inclusion dry glycerol product in the pre- and postpartum periods on feed intake, metabolic markers, and milk yield and components. Multiparous Holstein dairy cows (n = 60) were enrolled in a 2-by-2 factorial design study. Starting 21 d before expected parturition, cows individually received a dry cow diet with (1) 250 g/d glycerol product supplementation [66% pure glycerol (United States Pharmacopeia grade); GLY], or (2) no supplementation (CON) mixed to their total mixed ration. After parturition, cows, again, were individually assigned to either GLY, or (2) no supplementation (CON) to their partial mixed ration for the first 21 d in milk (DIM). Cows were milked by an automated milking system and offered a target of 5.4 kg DM/d pellet (23% of target total dry matter intake, DMI) in the automated milking system and followed for 42 d into lactation. Blood samples were collected 6.3 ± 3.47 d before calving for all blood measures and 3, 7, 10, and 14 DIM for analysis of glucose and β-hydroxybutyrate, as well as 3 and 7 DIM for nonesterified fatty acids (NEFA) and haptoglobin. Initial dry cow body weight (BW), calf birth weight, previous 305-d milk, and month of parturition were used as covariates in the statistical model. Cows supplemented with GLY prepartum lost less BW and consumed more DMI pre- and postpartum, as well as had lower postpartum blood β-hydroxybutyrate and NEFA concentrations compared with those fed the CON treatment prepartum. Cows supplemented with GLY postpartum had lesser DMI in the first 42 DIM than cows fed CON postpartum, but also had reduced blood NEFA concentrations, odds of a high haptoglobin test, odds of a low blood glucose test, and lesser preformed fatty acid concentrations and yields in their milk. Cows supplemented glycerol both pre- and postpartum lost the least total BW from −21 to 21 DIM. No treatment effects were detected for milk yield; however, cows receiving GLY postpartum had lower milk fat. Overall, glycerol supplementation during the transition period, particularly during the 21 d before calving, was associated with markers of improved metabolic status. [ABSTRACT FROM AUTHOR]

Previous studies have shown niacin has neuroprotective effects on the central nervous system. However, its specific effect on spinal cord ischemia/reperfusion injury has not yet been explored. This study aims to evaluate whether niacin can contribute neuroprotective effects on spinal cord ischemia/reperfusion injury. Rabbits were randomized into 4 groups of 8 animals: group I (control), group II (ischemia), group III (30 mg/kg methylprednisolone, intraperitoneal), and group IV (500 mg/kg niacin, intraperitoneal). The rabbits in group IV were premedicated with niacin for 7 days prior to inducing ischemia/reperfusion injury. The control group was subjected only to a laparotomy, while the remaining groups underwent spinal cord ischemia through a 20-minute occlusion of the aorta caudal to the left renal artery. Following the procedure, levels of catalase, malondialdehyde, xanthine oxidase, myeloperoxidase, and caspase-3 were analyzed. Ultrastructural, histopathological, and neurological evaluations were also performed. Spinal cord ischemia/reperfusion injury resulted in increased levels of xanthine oxidase, malondialdehyde, myeloperoxidase, and caspase-3, with a concomitant decrease in catalase levels. Treatment with methylprednisolone and niacin led to decreased levels of xanthine oxidase, malondialdehyde, myeloperoxidase, and caspase-3 and an increase in catalase. Both methylprednisolone and niacin treatments demonstrated improvements in histopathological, ultrastructural, and neurological assessments. Our findings suggest that niacin has antiapoptotic, anti-inflammatory, antioxidant, and neuroprotective effects at least equal to methylprednisolone in ischemia/reperfusion injury of the spinal cord. This study is the first to report the neuroprotective impact of niacin on spinal cord ischemia/reperfusion injury. Further research is warranted to elucidate the role of niacin in this context. [ABSTRACT FROM AUTHOR]

Increased diet fermentability may decrease ruminal pH and fiber digestibility, and increase the flow of trans fatty acids (FA) to the lower tract ultimately leading to milk fat depression. We recently showed that feeding super-conditioned corn, a new method of corn processing (95°C for 6 min in super-conditioner) for ruminants has potential to the reduction in milk fat yield caused by changes in ruminal pH and increased trans FA in milk fat. Supplementing yeast culture (YC) and replacing starch with sugar sources in diet can counteract the negative effects of high fermentable diets by improving ruminal pH and milk fat output. This study aimed to evaluate the effect of feeding beet liquid molasses (LM) and YC on intake and total-tract digestibility of nutrients, milk yield and composition, ruminal fermentation, milk FA profile, and plasma concentrations of glucose, nonesterified FA, β-hydroxybutyric acid, and urea N in early-lactation dairy cows fed high-starch diets containing super-conditioned corn. Twelve primiparous and 18 multiparous Holstein cows (mean ± SD; 67 ± 12 d in milk and 42 ± 2.1 kg of milk at the beginning of the experiment) were blocked by parity, pre-experimental milk yield, and DIM. Cows were used in a randomized complete block design experiment with 14 d as covariate period and 37 d for the experimental period. The following dietary treatments were fed as total mixed rations: (1) control diet (CTRL = no YC or LM supplementation), (2) LM supplementation at 5% of the diet dry matter (MOL diet), and (3) CTRL supplemented with 10 g/d of YC (YST diet). Diets were formulated to be isonitrogenous and isoenergetic. Intake of nutrients and apparent total-tract digestibility of crude protein and starch did not change across treatments. In contrast, cows fed the YST diet had the greatest apparent total-tract digestibility of dry matter, organic matter and neutral detergent fiber. Compared with the CTRL diet, yield of 4% FCM increased by 2.4 and 1.8 kg in cows fed MOL or YST, respectively. The ruminal molar proportions of acetate and butyrate increased in cows fed the YST or MOL diets, respectively, but the proportion of ruminal propionate was not affected by treatments. Milk fat concentration increased by supplementing both LM and YC and the milk yield of total trans -18:1 dropped by 45% and 18% relative to CTRL with MOL or YST diets, respectively. While the MOL diet increased the milk proportion and yield of de novo FA, no treatment effects were observed for the proportion and yield of preformed FA in the milk fat. Apart from β-hydroxybutyric acid concentration in plasma, which was greatest in cows fed MOL, remaining blood metabolites were not affected by treatments. Overall, MOL and YST diets increased 4% FCM and milk fat concentration and reduced the proportion of total trans- 18:1 FA in milk fat in cows fed a concentrate based on super-conditioned corn. These responses were associated with increased ruminal pH and the molar proportions of acetate and butyrate with feeding the MOL and YST diets. [ABSTRACT FROM AUTHOR]

Peripartum rumen-protected choline (RPC) supplementation is beneficial for cow health and production, yet the optimal dose is unknown. In vivo and in vitro supplementation of choline modulates hepatic lipid, glucose, and methyl donor metabolism. The objective of this experiment was to determine the effects of increasing the dose of prepartum RPC supplementation on milk production and blood biomarkers. Pregnant multiparous Holstein cows (n = 116) were randomly assigned to one of 4 prepartum choline treatments that were fed from −21 d relative to calving (DRTC) until calving. From calving until +21 DRTC, cows were fed diets targeting 0 g/d choline ion (control, CTL) or the recommended dose (15 g/d choline ion; RD) of the same RPC product that they were fed prepartum. The resulting treatments targeted: (1) 0 g/d pre- and postpartum [0.0 ± 0.000 choline ion, percent of dry matter (%DM); CTL]; (2) 15 g/d pre- and postpartum of choline ion from an established product (prepartum: 0.10 ± 0.004 choline ion, %DM; postpartum: 0.05 ± 0.004 choline ion, %DM; ReaShure, Balchem Corp.; RPC1 RD▸RD); (3) 15 g/d pre- and postpartum of choline ion from a concentrated RPC prototype (prepartum: 0.09 ± 0.004 choline ion, %DM; postpartum: 0.05 ± 0.003 choline ion, %DM; RPC2, Balchem Corp.; RPC2 RD▸RD); or (4) 22 g/d prepartum and 15 g/d postpartum from RPC2 [prepartum: 0.13 ± 0.005 choline ion, %DM; postpartum: 0.05 ± 0.003 choline ion, %DM; high prepartum dose (HD), RPC2 HD▸RD ]. Treatments were mixed into a total mixed ration, and cows had ad libitum access via a roughage intake control system (Hokofarm Group). From calving to +21 DRTC, all cows were fed a common base diet and treatments were mixed into the total mixed ration (supplementation period, SP). Thereafter, all cows were fed a common diet (0 g/d choline ion) until +100 DRTC (postsupplementation period, postSP). Milk yield was recorded daily and composition analyzed weekly. Blood samples were obtained via tail vessel upon enrollment, approximately every other day from −7 to +21 DRTC, and at +56 and +100 DRTC. Feeding any RPC treatment reduced prepartum dry matter intake compared with CTL. During the SP, no evidence for a treatment effect on energy-corrected milk (ECM) yield was found, but during the postSP, RPC1 RD▸RD and RPC2 RD▸RD treatments tended to increase ECM, protein, and fat yields. During the postSP, the RPC1 RD▸RD and RPC2 RD▸RD treatments tended to increase, and RPC2 HD▸RD increased, the de novo proportion of total milk fatty acids. During the early lactation SP, RPC2 HD▸RD tended to increase plasma fatty acids and β-hydroxybutyrate concentrations, and RPC1 RD▸RD and RPC2 RD▸RD reduced blood urea nitrogen concentrations compared with CTL. The RPC2 HD▸RD treatment reduced early lactation serum lipopolysaccharide binding protein compared with CTL. Overall, peripartum RPC supplementation at the recommended dose tended to increase ECM yield postSP, but no evidence was seen of an additional benefit on milk production with an increased prepartum dose of choline ion. The effects of RPC on metabolic and inflammatory biomarkers support the potential for RPC supplementation to affect transition cow metabolism and health and may support the production gains observed. [ABSTRACT FROM AUTHOR]

Acute liver failure (ALF) is associated with high mortality. Alterations in albumin structure and function have been shown to correlate with outcomes in cirrhosis. We undertook a biomolecular analysis of albumin to determine its correlation with hepatocellular injury and early mortality in ALF. Altogether, 225 participants (200 patients with ALF and 25 healthy controls [HC]) were enrolled. Albumin was purified from the baseline plasma of the training cohort (ALF, n = 40; survivors, n = 8; non-survivors, n = 32; and HC, n = 5); analysed for modifications, functionality, and bound multi-omics signatures; and validated in a test cohort (ALF, n = 160; survivors, n = 53; non-survivors, n = 107; and HC, n = 20). In patients with ALF, albumin is more oxidised and glycosylated with a distinct multi-omics profile than that in HC, more so in non-survivors (p <0.05). In non-survivors, albumin was more often bound (p <0.05, false discovery rate <0.01) to proteins associated with inflammation, advanced glycation end product, metabolites linked to arginine, proline metabolism, bile acid, and mitochondrial breakdown products. Increased bacterial taxa (Listeria , Clostridium , etc.) correlated with lipids (triglycerides [4:0/12:0/12:0] and phosphatidylserine [39:0]) and metabolites (porphobilinogen and nicotinic acid) in non-survivors (r2 >0.7). Multi-omics signature-based probability of detection for non-survival was >90% and showed direct correlation with albumin functionality and clinical parameters (r2 >0.85). Probability-of-detection metabolites built on the top five metabolites, namely, nicotinic acid, l -acetyl carnitine, l -carnitine, pregnenolone sulfate, and N -(3-hydroxybutanoyl)- l -homoserine lactone, showed diagnostic accuracy of 98% (AUC 0.98, 95% CI 0.95–1.0) and distinguish patients with ALF predisposed to early mortality (log-rank <0.05). On validation using high-resolution mass spectrometry and five machine learning algorithms in test cohort 1 (plasma and paired one-drop blood), the metabolome panel showed >92% accuracy/sensitivity and specificity for prediction of mortality. In ALF, albumin is hyperoxidised and substantially dysfunctional. Our study outlines distinct 'albuminome' signatures capable of distinguishing patients with ALF predisposed to early mortality or requiring emergency liver transplantation. Here, we report that the biomolecular map of albumin is distinct and linked to severity and outcome in patients with acute liver failure (ALF). Detailed structural, functional, and albumin-omics analysis in patients with ALF led to the identification and classification of albumin-bound biomolecules, which could segregate patients with ALF predisposed to early mortality. More importantly, we found albumin-bound metabolites indicative of mitochondrial damage and hyperinflammation as a putative indicator of <30-day mortality in patients with ALF. This preclinical study validates the utility of albuminome analysis for understanding the pathophysiology and development of poor outcome indicators in patients with ALF. [Display omitted] • Albumin is hyperoxidised and hyperglycated and shows reduced (60%) binding capacity in ALF. • Albumin biomolecular composition (bound multi-omics profile) is severely deranged and correlates with severity in ALF. • Albumin biomolecular integration highlights hyperinflammation and mitochondrial failure linked to non-survival in ALF. • Albumin-bound metabolome showed the highest diagnostic accuracy for the prediction of early mortality in ALF. [ABSTRACT FROM AUTHOR]

NAD+ and glutathione precursors are currently used as metabolic modulators for improving the metabolic conditions associated with various human diseases, including non-alcoholic fatty liver disease, neurodegenerative diseases, mitochondrial myopathy, and age-induced diabetes. Here, we performed a one-day double blinded, placebo-controlled human clinical study to assess the safety and acute effects of six different Combined Metabolic Activators (CMAs) with 1 g of different NAD+ precursors based on global metabolomics analysis. Our integrative analysis showed that the NAD+ salvage pathway is the main source for boosting the NAD+ levels with the administration of CMAs without NAD+ precursors. We observed that incorporation of nicotinamide (Nam) in the CMAs can boost the NAD+ products, followed by niacin (NA), nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), but not flush free niacin (FFN). In addition, the NA administration led to a flushing reaction, accompanied by decreased phospholipids and increased bilirubin and bilirubin derivatives, which could be potentially risky. In conclusion, this study provided a plasma metabolomic landscape of different CMA formulations, and proposed that CMAs with Nam, NMN as well as NR can be administered for boosting NAD+ levels to improve altered metabolic conditions. [Display omitted] • The administration of serine, NAC and LCAT with NAD precursor is safe and well tolerated. • NAD salvage pathway is the main source of NAD when orally taking serine, NAC and LCAT. • Nam in the CMAs showed the best ability to boost plasma NAD+ products. • NA in the CMAs led to flushing reaction, decreased phospholipids and increased bilirubin. • Nam, NMN as well as NR are good candidates for boosting NAD level. [ABSTRACT FROM AUTHOR]

Growing evidence suggests that the depletion of plasma NAD+ and glutathione (GSH) may play an important role in the development of metabolic disorders. The administration of Combined Metabolic Activators (CMA), consisting of GSH and NAD+ precursors, has been explored as a promising therapeutic strategy to target multiple altered pathways associated with the pathogenesis of the diseases. Although studies have examined the therapeutic effect of CMA that contains N-acetyl- l -cysteine (NAC) as a metabolic activator, a system-wide comparison of the metabolic response to the administration of CMA with NAC and cysteine remains lacking. In this placebo-controlled study, we studied the acute effect of the CMA administration with different metabolic activators, including NAC or cysteine with/without nicotinamide or flush free niacin, and performed longitudinal untargeted-metabolomics profiling of plasma obtained from 70 well-characterized healthy volunteers. The time-series metabolomics data revealed the metabolic pathways affected after the administration of CMAs showed high similarity between CMA containing nicotinamide and NAC or cysteine as metabolic activators. Our analysis also showed that CMA with cysteine is well-tolerated and safe in healthy individuals throughout the study. Last, our study systematically provided insights into a complex and dynamics landscape involved in amino acid, lipid and nicotinamide metabolism, reflecting the metabolic responses to CMA administration containing different metabolic activators. [Display omitted] • The administration of different CMA formulas was safe and no toxic effect was seen in the healthy subjects participated in the study. • Similar plasma cysteine kinetics were observed between CMA formulas with NAC and cysteine. • Longitudinal untargeted-metabolomics profiling reveals the acute metabolic response is similar between CMA formulas with NAC and cysteine. [ABSTRACT FROM AUTHOR]

• New norfloxacin cocrystals synthesized by a mechanochemical method. • The apparent aqueous solubility in the cocrystals is higher compared to pure drug. • Establishment of scale-up conditions from solution crystallization. Cocrystals are recognized as one of the most efficient approaches to improve aqueous solubility of Biopharmaceutical Classification System, BCS, classes II and IV drugs. Cocrystal discovery and the establishment of experimental conditions suitable for scale-up purposes are some of the main challenges in cocrystal investigation. In this work, the investigation of mechanochemical synthesis of norfloxacin cocrystals with picolinic and isonicotinic acids is performed, leading to the discovery of two new cocrystals of this important BCS class IV antibiotic, which were characterized through thermal, spectral and diffractometric analysis. Norfloxacin apparent aqueous solubility using the cocrystals is also presented, with higher values being obtained for all the investigated systems when compared to the pure drug. Norfloxacin has 3 polymorphs and several solvents/hydrates, which represents a challenge for obtaining pure cocrystal forms from solvent crystallization. This challenge was successfully overcome in this work, as experimental conditions to obtain the pure cocrystals (the new ones and also norfloxacin-nicotinic acid and norfloxacin-saccharin) were established using Crystal16 equipment. This is a crucial step to envisage future scale-up procedures and therefore a valuable information for the pharmaceutical industry. [Display omitted] [ABSTRACT FROM AUTHOR]

Coenzymes are important for all classes of enzymatic reactions and essential for cellular metabolism. Most coenzymes are synthesized from dedicated precursors, also referred to as vitamins, which prototrophic bacteria can either produce themselves from simpler substrates or take up from the environment. The extent to which prototrophs use supplied vitamins and whether externally available vitamins affect the size of intracellular coenzyme pools and control endogenous vitamin synthesis is currently largely unknown. Here, we studied coenzyme pool sizes and vitamin incorporation into coenzymes during growth on different carbon sources and vitamin supplementation regimes using metabolomics approaches. We found that the model bacterium Escherichia coli incorporated pyridoxal, niacin, and pantothenate into pyridoxal 50-phosphate, NAD, and coenzyme A (CoA), respectively. In contrast, riboflavin was not taken up and was produced exclusively endogenously. Coenzyme pools were mostly homeostatic and not affected by externally supplied precursors. Remarkably, we found that pantothenate is not incorporated into CoA as such but is first degraded to pantoate and β- alanine and then rebuilt. This pattern was conserved in various bacterial isolates, suggesting a preference for β-alanine over pantothenate utilization in CoA synthesis. Finally, we found that the endogenous synthesis of coenzyme precursors remains active when vitamins are supplied, which is consistent with described expression data of genes for enzymes involved in coenzyme biosynthesis under these conditions. Continued production of endogenous coenzymes may ensure rapid synthesis of the mature coenzyme under changing environmental conditions, protect against coenzyme limitation, and explain vitamin availability in naturally oligotrophic environments. [ABSTRACT FROM AUTHOR]

Studies reveal increased incidences of cardiovascular events such as heart attacks and strokes in patients with elevated lipoprotein(a) levels. Niacin-ER has shown to lower lipoprotein(a) levels by approximately 30% though unknown if niacin-ER reduces cardiovascular events in this population. This single center study evaluates 129 patients with a personal or family history of a premature cardiovascular event whose lipoprotein(a) levels were greater than 75nmol/L and prescribed niacin-ER. Identify patients with personal or family history of premature cardiovascular events through history and screen patients for baseline serum lipoprotein(a); levels greater than or equal to 75nmol/L were included. Patients were monitored for incidences of cardiovascular events, elevation of liver enzymes, and side-effects of niacin-ER. The study is an effort to determine if niacin-ER can reduce cardiovascular events. While current ASO-RNA and siRNA studies are undergoing trials, niacin-ER may be a less costly alternative. The study followed 129 adult patients seen by a Board Certified Lipidologist/Cardiologist from 2014-2024 with baseline lipoprotein(a) greater than 75 nmol/L. Patients were started on 1000 mg-2000 mg (mean 1713 mg) of niacin-ER and a high intensity statin. In the study, 118 patients were prescribed niacin-ER, while 11 were a better fit for PCSK-9 therapy. Of the 118 patients, 36 could not tolerate the flushing, despite mitigating strategies. Patients' hospital and outpatient records were reviewed for cardiovascular events. The average baseline value of lipoprotein(a) was 221.59 nmol/L, higher than 35-70 nmol/L in AIM-HIGH and HPS2-THRIVE trials. Current trials with siRNA and ASO-RNA therapies set inclusion criteria at >150 nmol/L. The average lipoprotein(a) after starting niacin-ER amounted to 157.71 nmol/L, a 33.68% reduction. Fifteen patients laboratory tests resulted in non-prohibitive mildly elevated liver function tests (LFTs), with maximum ALT and AST of 85 U/L and 68 U/L, respectively, after starting niacin. All patients were on high-intensity statin. Niacin-ER reduced lipoprotein(a) levels by 33.68%, comparable to published data of 30%. Niacin-ER continues to be shown as safe and well-tolerated with no incidences of strokes, infections, gastrointestinal symptoms, or rhabdomyolysis; there was a non-significant elevation in LFTs. In the 83 patients taking niacin-ER, there were no subsequent cardiovascular events up to ten years follow up. Reduction in cardiovascular events could not be observed with the low sample size. The study reinforces the need to further assess the effectiveness of niacin-ER on cardiovascular events while prospective therapies continue through trials. [ABSTRACT FROM AUTHOR]

Depressive disorder (DD) affects approximately 20 % of adolescents worldwide, but it is underdiagnosed due to the lack of objective biomarkers. Niacin skin flushing response (NSFR) is an objective and noninvasive biomarker of adult depression; however, its effectiveness has not been assessed in adolescents. This study included 198 adolescents with 50 % healthy controls (HC). Linear mixed-effects model and multiple linear regression analyses were performed to assess differences in NSFR between the DD and HC groups. Logistic regression models based on NSFR were constructed, and the area under curve (AUC) was calculated to evaluate the performance of models. Spearman correlations were calculated to assess the relationships between NSFR and disease duration and hormone levels associated with puberty. Adolescents with DD displayed significantly attenuated and delayed NSFR compared to HC. NSFR effectively distinguished DD patients from HC with AUC values of 0.719 (sensitivity = 0.844) and 0.721 (sensitivity = 0.829) determined in the discovery and validation sets, respectively. Within the DD group, the maximum degree of NSFR was negatively correlated with the disease duration (r = −0.28, p = 0.011), and the overall degree of NSFR was positively associated with prolactin (r = 0.29, p = 0.039) and thyroxine (r = 0.29, p = 0.027) levels. Future investigations will be necessary to confirm our results in an independent sample set. This study provides the first evidence of the utility of NSFR as an objective auxiliary diagnostic biomarker for adolescent depression. It provides new clues to understand the pathophysiology of the disease, and helps promote precise diagnosis, treatment, and prognostic evaluation of adolescent depression. • A relatively large cohort of adolescents with or without depression was used. • Niacin skin flushing response (NSFR) was attenuated and delayed in patients. • Diagnostic model based on NSFR showed fair predictive power in two sample sets. • NSFR was positively associated with thyroxine and prolactin levels in patients. • Our results supported the value of NSFR as a biomarker for adolescent depression. [ABSTRACT FROM AUTHOR]

Experimental investigations of dust explosions in standard industrial testing equipment such as the MIKE3 minimum ignition energy (MIE) testing device are promising ways of producing fundamental insights into dust cloud ignitability. However, advanced experimental methods must be developed to characterize the dust cloud ignition and combustion behavior of various types of dust. In this work, high-speed broadband and species-specific chemiluminescence imaging diagnostics are implemented to explore similarities and differences between organic and metal powder ignition kernel development. A selected set of 600-mg niacin (ϕ = 2.9) and aluminum (ϕ = 1.6) powder samples were dispersed in the air and ignited using a high-voltage spark inside a standard MIKE3 device. The resulting broadband flame emission was recorded at 4 kHz using a high-speed camera for the first 10 ms after the spark. For the niacin sample, species-specific chemiluminescence emissions from excited-state hydroxyl (OH*) and methylidyne (CH*) radicals were also recorded at 4 kHz and 1 kHz, respectively. The flame kernel in each image frame was detected using an intensity thresholding algorithm and tracked throughout the video sequence, yielding quantitative size, position, and velocity measurements of the evolving flame kernel during the first 10 ms after the ignition spark. For the niacin sample, a continuous and non-uniform reaction zone composed of burning particle clusters and excited-state radicals was observed. The niacin flame kernels grew from 5 mm to 17 mm with an initial velocity of 5 m/s. Conversely, an intensely bright reaction zone and discrete burning particles near the flame kernel boundary were observed in the aluminum sample. The aluminum flame kernels grew from 7 mm to 10 mm with an initial velocity of 3 m/s. The niacin and aluminum flame kernels traveled 7–11 mm away from the central spark gap and slowed down to 1 m/s by the end of the 10-ms period. This time-resolved imaging study, when coupled with previously reported three-dimensional particle and flow field data prior to the arrival of the ignition spark, sets the foundation for an improved multi-physics understanding of the initiation of dust cloud ignition and explosion processes. [ABSTRACT FROM AUTHOR]

NAD+ is a cellular redox cofactor involved in many essential processes. The regulation of NAD+ metabolism and the signaling networks reciprocally interacting with NAD+-producing metabolic pathways are not yet fully understood. The NAD+-dependent histone deacetylase (HDAC) Hst1 has been shown to inhibit de novo NAD+ synthesis by repressing biosynthesis of nicotinic acid (BNA) gene expression. Here, we alternatively identify HDAC Rpd3 as a positive regulator of de novo NAD+ metabolism in the budding yeast Saccharomyces cerevisiae. We reveal that deletion of RPD3 causes marked decreases in the production of de novo pathway metabolites, in direct contrast to deletion of HST1. We determined the BNA expression profiles of rpd3Δ and hst1Δ cells to be similarly opposed, suggesting the two HDACs may regulate the BNA genes in an antagonistic fashion. Our chromatin immunoprecipitation analysis revealed that Rpd3 and Hst1 mutually influence each other's binding distribution at the BNA2 promoter. We demonstrate Hst1 to be the main deacetylase active at the BNA2 promoter, with hst1A cells displaying increased acetylation of the N-terminal tail lysine residues of histone H4, H4K5, and H4K12. Conversely, we show that deletion of RPD3 reduces the acetylation of these residues in an Hst1-dependent manner. This suggests that Rpd3 may function to oppose spreading of Hst1-dependent heterochromatin and represents a unique form of antagonism between HDACs in regulating gene expression. Moreover, we found that Rpd3 and Hst1 also coregulate additional targets involved in other branches of NAD+ metabolism. These findings help elucidate the complex interconnections involved in effecting the regulation of NAD+ metabolism. [ABSTRACT FROM AUTHOR]

Niacin was found in the lysolecithin model of multiple sclerosis (MS) to promote the phagocytic clearance of debris and enhance remyelination. Lysolecithin lesions have prominent microglia/macrophages but lack lymphocytes that populate plaques of MS or its experimental autoimmune encephalomyelitis (EAE) model. Thus, the current study assessed the efficacy of niacin in EAE. We found that niacin inconsistently affects EAE clinical score, and largely does not ameliorate neuropathology. In culture, niacin enhances phagocytosis by macrophages, but does not reduce T cell proliferation. We suggest that studies of niacin for potential remyelination in MS should include a therapeutic that targets adaptive immunity. [Display omitted] • Niacin inconsistently ameliorates clinical disability in EAE mice. • Niacin does not promote remyelination in EAE unlike that reported in lysolecithin. • Niacin enhances phagocytosis of myelin debris but does not affect T cell mitosis. • Niacin for potential repair in MS should be accompanied by drugs targeting T cells. [ABSTRACT FROM AUTHOR]

• Cobalt/niacin MOF presented as nano-catalyst. • An efficient catalytic synthesis of some new benzothiazoles and benzimidazoles. • Validation as acetylcholine esterase inhibitors (AChE inhibitors). • In vitro anti-Alzheimer's activity of the prepared compounds. Metal-organic frameworks (MOFs) presented as an efficient, economic, sustainable and green stable catalyst. Co/Niacin-MOF in nano shape was prepared by hydrothermal method and illustrated by IR, SEM and XRD. The prepared Co/Niacin-MOF used in the synthesis of some new benzothiazoles and benzimidazoles (3a - 3f, 4a - 4f). The prepared benzo heterocyclic compounds were checked as acetylcholine esterase inhibitors (AChE inhibitors) and the data obtained from in vitro and molecular docking explained that there two promised values for compounds 4-(benzo[ d ]thiazol-2-yl)phenyl benzoate (3e) and 4-(1 H -benzo[ d ]imidazol-2-yl)phenyl 4-methylbenzenesulfonate (4f) compared with Donepezil as a reference Alzheimer drug. [Display omitted] [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by progressive memory loss and behavioral disorders. The excessive accumulation of amyloid β (Aβ) and the formation of neurofibrillary tangles (NFTs) damage synaptic connections and the death of neurons. However, the underlying mechanisms of pathogenesis of AD remain unclear. Growing evidence indicates that impaired mitochondrial function may play a crucial role in the development of AD. In the current study, we investigated whether nicotinic acid (NA) could protect against amyloid β 1-42 -induced cytotoxicity in differentiated SH-SY5Y cells. Our results revealed the neuroprotective effects of NA on the differentiated SH-SY5Y cells treated with Aβ 1-42. In detail, the 1-h pre-incubation with NA increased cell viability and lowered LDH levels. NA pre-incubation abolished Aβ 1-42 treatment-associated alterations of mRNA levels of synaptic genes and enhanced the relative β3 Tubulin fluorescence intensity. NA eliminated the Aβ 1-42 -induced mitochondrial dysfunction by increasing the potential of mitochondrial membranes and maintaining a balance between the fusion and fission of mitochondria. Moreover, Aβ 1-42 decreased mRNA levels of anti-apoptotic bcl2 and increased mRNA levels of pro-apoptotic: bim , bak , cytochrome c, and caspase 9. At the same time, the NA pre-treatment reduced Aβ 1-42 -dependent apoptotic death of differentiated SH-SY5Y cells. The above data suggest that NA presents a protective activity against Aβ 1-42 -induced cytotoxicity in differentiated SH-SY5Y cells by inhibiting the mitochondrial pathway of apoptosis and restoring the proper function of mitochondria. • Nicotinic acid (NA) abrogated the toxic effects of Amyloid β 1-42 (Aβ 1-42) on the differentiated SH-SY5Y cells. • NA abolished the negative effect of Aβ 1-42 on mRNA levels of synaptic markers in differentiated SH-SY5Y cells. • NA restored the Aβ 1-42 -induced mitochondrial membrane depolarization (ΔΨm) in differentiated SH-SY5Y cells. • NA restored the mitochondrial dynamic function in Aβ 1-42 treated differentiated SH-SY5Y cells. • NA reduced Aβ 1-42 -dependent apoptotic death of differentiated SH-SY5Y cells. [ABSTRACT FROM AUTHOR]

Phenolic compounds (PCs) are diverse in nature and undergo complex migration and transformations in the environment, making it challenging to use techniques such as chromatography and other traditional methods to determine the concentration of PCs by separation, individual monitoring and subsequent addition. To address this issue, a facile and on-site strategy was developed to measure the concentration of PCs using a novel nanozyme with polyphenol oxidase-like activity. First, the nanozyme was designed by coordinating the asymmetric ligand nicotinic acid with copper to mimic the structure of mononuclear and trinuclear copper clusters of natural laccases. Subsequently, by introducing 2-mercaptonicotinic acid to regulate the valence state of copper, the composite nanozyme CuNA10S was obtained with significantly enhanced activity. Interestingly, CuNA10S was shown to have a broad substrate spectrum capable of catalyzing common PCs. Building upon the superior performance of this nanozyme, a method was developed to determine the concentration of PCs. To enable rapid on-site sensing, we designed and prepared CuNA10S-based test strips and developed a tailored smartphone sensing platform. Using paper strip sensors combined with a smartphone sensing platform with RGB streamlined the sensing process, facilitating rapid on-site analysis of PCs within a range of 0–100 μM. Our method offers a solution for the quick screening of phenolic wastewater at contaminated sites, allowing sensitive and quick monitoring of PCs without the need for standard samples. This significantly simplifies the monitoring procedure compared to more cumbersome large-scale instrumental methods. [Display omitted] • A novel nanozyme mimicking the laccase structure. • A facile and on-site sensing strategy for phenolic compounds. • The test paper strip-based smartphone-assisted sensing platform. [ABSTRACT FROM AUTHOR]

Marine heatwaves (MHWs) have become more frequent, intense and extreme in oceanic systems in the past decade, resulting in mass mortality events of marine invertebrates and devastating coastal marine ecosystems. While metabolic homeostasis is a fundamental requirement in stress tolerance, little is known about its role under intensifying MHWs conditions. Here, we investigated impacts of MHWs on the metabolism in pearl oysters (Pinctada maxima) – an ecologically and economically significant bivalve species in tropical ecosystems. Activities of digestive enzymes (gastric proteases, lipases, and amylases) did not significantly respond to various scenario of recurrent MHWs varying from 24 °C to 28 °C (moderate) and 32 °C (severe). The metabolomics analysis revealed nine and five key metabolism pathways under both MHWs scenarios. Specifically, pathways associated with energy metabolism were impaired by moderate MHWs, manifesting in downregulation of differential metabolite (The nicotinic acid and N-acetyl-glutamic acid). The content of CDP-ethanolamine was significantly decrease, and the perturbations of oxidative stress caused by the decreased of content of D-glutamine. Metabolites related to a suite of body functions (e.g., the lipid metabolism, biomineralization, and antioxidant defenses) showed significantly negative responses by severe MHWs. These findings reveal the metabolic impairments of marine bivalves when subjected to MHWs varying in intensity and frequency, implying cascading consequences which deserve further investigation. • The physiological systems of pearl oysters were significantly disturbed following recurrent MHWs. • Dysfunctions of biochemical functions were observed following recurrent MHWs. • With increasing intensity of MHWs, metabolic perturbations increased strikingly. [ABSTRACT FROM AUTHOR]

[Display omitted] • Niacin deficiency decreased the growth performance of fish. • Niacin deficiency affected muscle amino acid and fatty acid compositions of fish. • Niacin deficiency exerted negative impacts on flesh physicochemical properties. • Niacin deficiency may quicken flesh pH drop by promoting glycolysis. • Niacin deficiency impaired mitochondrial homeostasis. Energy metabolism exerts profound impacts on flesh quality. Niacin can be transformed into nicotinamide adenine dinucleotide (NAD), which is indispensable to energy metabolism. To investigate whether niacin deficiency could affect energy metabolism and flesh quality, six diets with graded levels of 0.49, 9.30, 21.30, 33.30, 45.30 and 57.30 mg/kg niacin were fed to grass carp (Ctenopharyngodon idella) for 63 days. The results showed that niacin deficiency declined flesh quality by changing amino acid and fatty acid profiles, decreasing shear force, increasing cooking loss and accelerating pH decline. The accelerated pH decline might be associated with enhanced glycolysis as evident by increased hexokinase (HK), pyruvate kinase (PK) and lactic dehydrogenase (LDH) activities, and mitochondrial dysfunction as evident by destroyed mitochondrial morphology, impaired respiratory chain complex I and antioxidant ability. Based on PWG and cooking loss, the niacin requirements for sub-adult grass carp were 31.95 mg/kg and 29.66 mg/kg diet, respectively. [ABSTRACT FROM AUTHOR]

• Innovative solvate Formulations: three pioneering salt solvates of paliperidone (PLPT) were crafted, boasting 40 K higher thermal stability and strengthened by charge-assisted hydrogen bonds. • Remarkable solubility Upgrade: PLPT·NA·2H 2 O·2MeOH exhibited an astounding solubility increase—883.78 times—across pH levels from 1.2 to pure water, promising revolutionary enhancements in drug delivery. • Precise molecular Design: intricate hydrogen bonding networks within these salt solvates, exemplified by N+-H···O− interactions, underpin their exceptional structural integrity and improved properties. Paliperidone (PLPT) is a pharmaceutical compound widely used in the treatment of psychiatric disorders. However, its limited solubility poses challenges for its formulation and bioavailability.In this study, three previously unreported salt solvates of PLPT were successfully synthesized: PLPT·PCBA·H 2 O (PCBA, para-chlorobenzoic acid), PLPT·NA·2H 2 O·2MeOH (NA, niacin acid), and PLPT·GA·2EtOH (GA, gallic acid). Considering the requirement of drying in actual production, the test samples were dried in a 333.15 K overnight and then used for TGA-DSC (thermogravimetric analysis-differential scanning calorimetry) testing. The results indicate that the thermal stability of PLPT·NA·2H 2 O·2MeOH was enhanced by approximately 40 K. The salt-like nature of these compounds was confirmed through ΔpKa calculations and single-crystal structure analysis, which revealed the formation of charge-assisted hydrogen bonds (N+-H···O−). Significant hydrogen bonding and π-π interactions were observed, as evidenced by 3D d norm Hirshfeld surfaces and 2D fingerprint plots. They were characterized by predominant H···H, O···H, and N···H interactions, contributing to their structural stability. PXRD (powder X-ray diffraction) and IR (infrared spectroscopy) characterization provided further confirmation of the solvate formation. Notably, solubility experiments demonstrated a remarkable increase in the solubility of PLPT·NA·2H 2 O·2MeOH in simulated human body environments, exhibiting solubility enhancements of approximately 883.78 times, 166.57 times, 5.18 times, and 6.37 times across the range from pure water to pH 1.2. The remaining two salt solvates exhibit a notable enhancement in solubility under different pH conditions. An anomaly is observed only at pH 4, which is associated with the degree of protonation of PLPT and the intrinsic solubility of GA and PCBA. Dissolution rates indicate a significant improvement in all three salt solvates under various simulated human physiological environments, particularly at pH 6.8.These findings highlight the potential of these solvates as promising candidates for enhanced PLPT formulations. Dissolution rate experiments also indicate that the formation of salts significantly enhances the drug's dissolution rate. This study represents the first report on salt solvates of PLPT and provides valuable insights for the improvement of PLPT and other poorly soluble drug formulations. Three previously unreported salt solvates of PLPT were successfully synthesized: (a)PLPT·PCBA·H 2 O, (b)PLPT·NA·2H 2 O·2MeOH, and (c)PLPT·GA·2EtOH. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] In this work, multicomponent trimethoprim-based pharmaceutical solid systems were developed by mechanochemistry, using coformers from the GRAS list and other active pharmaceutical ingredients. The choice of coformers took into account their potential to increase the aqueous solubility/dissolution rate of TMP or its antibacterial activity. All the binary systems were characterized by thermal analysis, powder X-ray diffraction and infrared spectroscopy, and 3 equimolar systems with FTIR pointing to salts, and 4 eutectic mixtures were identified. The intrinsic dissolution rate of TMP in combination with nicotinic acid (a salt) and with paracetamol (eutectic mixture) were 25% and 5% higher than for pure TMP, respectively. For both Gram-positive and −negative strains, the antibacterial activity of TMP with some of the coformers was improved, since the dosage used was lower than the TMP control. A significant increase in antibacterial activity against E. coli was found for the eutectic mixture with curcumin, with the best results being obtained for the eutectic and equimolar mixtures with ciprofloxacin. Combining trimethoprim with coformers offers an interesting alternative to using trimethoprim alone: multicomponent forms with enhanced TMP dissolution rates were identified, as well as combinations showing enhanced antibacterial activity relatively to the pure drug. [ABSTRACT FROM AUTHOR]

Wilson disease (WD) is an inherited disorder characterized by abnormal copper metabolism with complex pathological features. Currently, this mechanism of copper overload-induced hepatic injury remains unclear. In this study, male toxic milk (TX) mice were selected as experimental subjects. Copper levels and biochemical indices were measured by atomic absorption spectroscopy (AAS) and kits. Liver tissue ultrastructure was observed by hematoxylin-eosin (H&E), sirius red staining and transmission electron microscopy. Plasma and liver metabolic profiles of TX mice were characterized by untargeted metabolomics. In addition, the expression of enzymes related to arachidonic acid metabolism in liver tissue was detected by Western blotting. The results showed the excessive copper content, concomitant oxidative stress, and hepatic tissue structural damage in TX mice. Seventy-eight metabolites were significantly different in WD, mainly involved in the metabolism of arachidonic acid, glycerophospholipids, sphingolipids, niacin and nicotinamide, and phenylalanine. Furthermore, the arachidonic acid metabolic pathway is an important pathway involved in WD metabolism. The level of arachidonic acid in the liver of TX mice was significantly lower (p < 0.01) compared to the control group. The expression of cytoplasmic phospholipase A2 (cPLA2) and arachidonic acid 12-lipoxygenase (ALOX12), related to the arachidonic acid metabolic pathway, was significantly different in the liver of TX mice (p < 0.01). Modulation of the arachidonic acid metabolic pathway could be a potential therapeutic strategy to alleviate WD symptoms. • Copper accumulation and excretion disorders occurs in the WD. • Oxidative stress and inflammatory response are important factors in liver injury • The reduction of arachidonic acid in the liver is a hallmark dysregulation in WD. • The cPLA2 and ALOX12 co-regulate arachidonic acid levels. [ABSTRACT FROM AUTHOR]

Niacin (NIA) supplementation showed effectiveness against Parkinson's disease (PD) in clinical trials. The depletion of NAD and endoplasmic reticulum stress response (ERSR) are implicated in the pathogenesis of PD, but the potential role for NAD precursors on ERSR is not yet established. This study was undertaken to decipher NIA molecular mechanisms against PD-accompanied ERSR, especially in relation to PKC. Alternate-day-low-dose-21 day-subcutaneous exposure to rotenone (ROT) in rats induced PD. Following the 5th ROT injection, rats received daily doses of either NIA alone or preceded by the PKC inhibitor tamoxifen (TAM). Extent of disease progression was assessed by behavioral, striatal biochemical and striatal/nigral histopathological/immunohistochemical analysis. Via activating PKC/LKB1/AMPK stream, NIA post-treatment attenuated the ERSR reflected by the decline in ATF4, ATF6 and XBP1s to downregulate the apoptotic markers, CHOP/GADD153, p -JNK and active caspase-3. Such amendments congregated in motor activity/coordination improvements in open field and rotarod tasks, enhanced grid test latency and reduced overall PD scores, while boosting nigral/striatal tyrosine hydroxylase immunoreactivity and increasing intact neurons (Nissl stain) in both SNpc and striatum that showed less neurodegeneration (H&E stain). To different extents, TAM reverted all the NIA-related actions to prove PKC as a fulcrum in conveying the drug neurotherapeutic potential. PKC activation is a pioneer mechanism in the drug ERSR inhibitory anti-apoptotic modality to clarify NIA promising clinical and potent preclinical anti-PD efficacy. This kinase can be tagged as a druggable target for future add-on treatments that can assist dopaminergic neuronal aptitude against this devastating neurodegenerative disease. Effect of post-treatment with NIA alone or preceded by TAM on ER-stress response in PD rats. The UPR arms; PERK, IRE1α, and ATF6 are engaged by the GRP78/BiP bond in the ER under normal conditions; however, under ER-stress, the three transducers are liberated to start the UPR sequalae. PERK constrains the global protein synthesis by phosphorylating eIF2α, permitting ATF4 translation. IRE1α cleaves XBP1 mRNA to generate the unconventional spliced segment, XBP1s, whereas ATF6 departs to the Golgi apparatus to be processed to ATF6(N). The three nascent factors, ATF4, XBP1s and ATF6(N) orchestrate CHOP transcription that initiates the Casp-3-induced execution, in synchrony with the recruited JNK after IRE1α activation. Pan PKC inhibition by TAM hindered the NIA-mediated ERSR relief by suppressing the downstream AMPK/LKB1 trajectory. AMPK, adenosine monophosphate-activated protein kinase; ATF4, activating transcription factor 4; ATF6, activating transcription factor 6; ATF6(N), N-terminal cytosolic fragment of ATF6; Casp-3, caspase-3; CHOP, C/EBP-homologous protein; eIF2α, eukaryotic translation initiation factor 2α; ER, endoplasmic reticulum; GRP78/BiP, glucose-regulated protein 78; IRE1α, inositol-requiring transmembrane kinase endoribonuclease-1α; JNK, c-Jun N-terminal kinase; LKB1, liver kinase B1; NIA, niacin; PD, parkinson's disease; PERK, protein kinase RNA-like endoplasmic reticulum kinase; PKC, protein kinase C; TAM, tamoxifen; UPR, unfolded protein response; XBP1, X-box binding protein-1; XBP1s, spliced X-box binding protein 1 (XBP1). [Display omitted] [ABSTRACT FROM AUTHOR]

• Novel half-sandwich Ru(II) nicotinic hydrazone complexes. • N-alkylation of amine using benzyl alcohol through transfer hydrogen mechanism. • Effective N-alkylation of amine against a wide range of substrates that includes anilines bearing electron withdrawing/electron donating group, fused aromatic, heteroaromatic, alicyclic and aliphatic amines. • Efficient antibacterial activity against both gram positive (S. aureus and E. faecalis) and gram negative bacteria (E. coli and K. pneumoniae). A new series of half sandwich ruthenium(II) complexes supported by nicotinic acid hydrazone derivatives of general formula [Ru(ɳ6-p-cymene)(Cl)(L)], where L represents N'-benzylidenenicotinohydrazide (HL1), N'-(naphthalen-1-ylmethylene)nicotinohydrazide (HL2) or N'-(pyren-1-ylmethylene)nicotinohydrazide (HL3) were synthesized and fully characterized. The solid-state molecular structures of ligands and complexes were elucidated with single-crystal X-ray diffraction. The ligands HL1 and HL2 possess monoclinic crystal system with P 2 1 /c and C 2 /c space groups respectively, whereas all the three Ru(II) complexes C1–3 are typical three-legged piano-stool geometries with orthorhombic(Aba2) (C1) and triclinic(P- 1) (C2–3) systems respectively. The catalytic activities of these ruthenium complexes in the synthesis of N-alkylated amines were explored. Under optimal reaction condition, the complex C3 was found to be the most efficient catalyst for the N-alkylation of primary to secondary amines using benzyl alcohol. A wide range of substrates have been studied that includes anilines bearing electron withdrawing/electron donating group, fused aromatic, heteroaromatic, alicyclic and aliphatic amines with good to excellent yield. In addition, the antibacterial activity of the complexes were tested against different human pathogenic bacteria, among them C2 complex with naphthyl moiety was found to be the most active one against both Gram-positive (S. aureus and E. faecalis) and Gram-negative (E. coli and K. pneumoniae) bacteria. These two different studies demonstrate the catalytic and biological importance of our newly prepared Ruthenium complex. Novel Ruthenium nicotinic hydrazone series of complexes were successfully prepared. [Ru(ɳ6-p-cymene)(Cl)(L)](C3) complex has showed excellent catalytic activity in N-alkylation of amines through transfer hydrogenation. In addition, these complexes have also demonstrates good antibacterial activities against gram positive and gram negative bacteria. [Display omitted] [ABSTRACT FROM AUTHOR]

• ADE and ADE+ B supplementation increased oxymyoglobin proportion at different periods of ageing. • MFI increased in ADE and ADE+ B treatments when compared with the control. • ADE and ADE+ B supplementation decreased MDA content at different periods of aging. • ADE and ADE+ B supplementation increased FRAP at 24 and 192 h post mortem. • The B-vitamin blend (biotin, niacin, and thiamine) supplementation did not improve meat quality. This study was conducted to investigate the effects of supplementation of B vitamins, fat-soluble vitamins (ADE), and combination of B +ADE on beef quality parameters and antioxidant status. Forty young Nellore bulls were allocated randomly across four treatments: no vitamin supplementation (Control); B vitamins supplementation (B); fat-soluble vitamins supplementation (ADE); and ADE + B supplementation. At the end of a 140-day trial, samples were collected to perform analysis of meat quality parameters and status activity of antioxidant enzymes at 1 h, 24 h, 192 h and 360 h post mortem. Treatments had no significant on pH24h, sarcomere length, meat color (L*, b*, chroma) or fat color (L*, a*, b*) of the longissimus lumborum muscle at 24 h, 192 h and 360 h post mortem between treatments B, ADE or ADE+ B in relation to the control treatment. Furthermore, no significant changes were observed in the redox form of myoglobin (OMb, DMb, MMb) 24 h post mortem. However, the ADE and ADE+ B treatments resulted in a higher percentage of intramuscular fat in the longissimus lumborum muscle when compared to the control treatment. Greater myofibrillar fragmentation index at 24 h, 192 h and 360 h, higher levels of oxymyoglobin at 192 h and 360 h, lower levels of metmyoglobin at 360 h were detected in the ADE and ADE+ B treatments when compared to the control treatment. Furthermore, ADE increased superoxide dismutase (SOD) at 192 h and ferric reducing antioxidant power (FRAP) at 360 h compared to the control treatment, while ADE and ADE+ B treatments increased FRAP at 24 h and 192 h, and catalase (CAT) at 192 h Moreover, ADE and ADE+ B treatments decreased glutathione peroxidase (GPx) at 24 h and decreased malondialdehyde (MDA) content at 24 h and 360 h when compared to the control treatment. The use of ADE and ADE+ B favored the formation of oxymyoglobin, prevented the oxidation of myoglobin, increased the ferric reducing antioxidant power and impaired lipid oxidation at different periods of ageing. [ABSTRACT FROM AUTHOR]

[Display omitted] • Isomeric configurations lead to varied binding energies and adsorption affinities. • Meta-substitution to COOH enhances nucleophilic reaction for favorable adsorption. • Substitution at Ortho/Para positions causes difference due to steric hindrance. • Adsorption affinity mirrors corrosion inhibition efficiency during CMP process. • Nicotinic acid, meta-substitution, attained the highest anti-corrosion at 88.57 %. We systematically investigate the adsorption behavior and corrosion inhibition efficacy of pyridine carboxylic acid isomers (Picolinic, Nicotinic, Isonicotinic acids) on Cu films in alkaline conditions. By integrating theoretical analyses, density functional theory (DFT) calculations, and experimental techniques, we demonstrate the underlying mechanisms governing the adsorption affinities and corrosion inhibition properties of these isomers. Our results show that Nicotinic acid exhibits the highest adsorption affinity and corrosion inhibition efficiency on Cu films, attributed to its favorable electronic and steric properties that enhance nucleophilic interaction and electron donation capabilities. On the other hand, Picolinic acid hindered by steric effects shows the lowest adsorption affinity and inhibition efficiency. The electrochemical studies confirm that Nicotinic acid significantly lowers the corrosion current density and enhances the polarization resistance, offering superior protection against corrosion. Furthermore, the chemical and electrochemical interactions between the inhibitors and Cu films are detailed, with insights into the modification of the Cu surface's electric structure and the formation of protective layers against oxidation. Our research contributes important insights for the development and use of effective corrosion inhibitors for Cu, especially in semiconductor manufacturing and other industries, highlighting the importance of an isomer's molecular structure in its ability to adsorb and prevent corrosion. [ABSTRACT FROM AUTHOR]

This study comprehensively evaluated the effects of Lactiplantibacillus plantarum T1 and CSK (ropy and non-ropy phenotypes), on flavour, and nutrient metabolites of fermented milks using gas chromatography-mass spectrometry and non-targeted metabolomics. The microrheological analysis showed that the protein gelation time of CSK fermented milk was earlier (5.2 h) than that of T1 (7.0 h), while the fermented milk by T1 had higher elastic modulus. Fermentation by both strains significantly enhanced the antioxidant activity of the fermented milk, including scavenging capabilities against ABTS, DPPH, and hydroxyl radicals. Meanwhile, fermentation by two strains produced various volatile flavor compounds (hexanoic acid, caprylic acid, capric acid, nonanal, decanal, 2-heptanone and 2-nonanone, etc.), and L. plantarum CSK displayed more stronger acid production capacity. In addition, a total of 397 shared metabolites and 81 unique metabolites were identified by untargeted metabolomics analysis of the two groups of fermented milks, mainly including lipids and lipid-like molecules (66, 27.27%), organic heterocyclic compounds (40, 16.53%), phenylketones and polyketones (23, 9.5%), and organic acids and their derivatives (49, 20.25%). Furthermore, both strains significantly elevated the amino acid nutritional levels in the fermented milk, conferred an abundance of active metabolites such as niacin and nicotinamide. During the fermentation, L. plantarum CSK notably produced antioxidant fumaric acid and exhibited higher fatty acid metabolism compared to L. plantarum T1. Overall, this study provides some practical basis for the development of fermented cow's milk with good antioxidant activity and high nutritional quality using different phenotypes of L. plantarum. [Display omitted] • Two L. plantarum exhibited good cow's milk fermentation viability. • Fermented milk by two L. plantarum showed good antioxidant activity. • L. plantarum fermentation effectively increased the amino acid nutrient levels. • L. plantarum CSK could produce abundant fumaric acid during milk fermentation. • Fermented milk enriched with active metabolites such as niacin and nicotinamide. [ABSTRACT FROM AUTHOR]

• CCFM 1266 possesses crucial genes for fermenting dairy and utilizing fructooligosaccharides and mannan oligosaccharides. • CCFM 1266 maintains high viable cell counts during fermentation and storage. • Fermented milk by CCFM 1266 improves flavor compounds and metabolic nutrients. • CCFM 1266 significantly elevates niacin levels in yogurt. • The authors declare no conflict of interest. Previous studies have demonstrated that Ligilactobacillus salivarius CCFM 1266 exhibits anti-inflammatory properties and the capability to synthesize niacin. This study aimed to investigate the fermentative abilities of L. salivarius CCFM 1266 in fermented milk. Metabonomic analysis revealed that fermentation by L. salivarius CCFM 1266 altered volatile flavor compounds and metabolite profiles, including heptanal, nonanal, and increased niacin production. Genomic investigations confirmed that L. salivarius CCFM 1266 possess essential genes for the metabolism of fructose and mannose, affirming its proficiency in utilizing fructooligosaccharides and mannan oligosaccharides. The addition of fructooligosaccharides and mannan oligosaccharides during the fermentation process significantly facilitated the proliferation of L. salivarius CCFM 1266 in fermented milk, with growth exceeding 107 colony-forming units (CFU)/mL. This intervention not only augmented the microbial density but also modified the metabolite composition of fermented milk, resulting in an elevated presence of advantageous flavor compounds such as nonanal, 2,3-pentanedione, and 3-methyl-2-butanone. However, its influence on improving the texture of fermented milk was observed to be minimal. Co-fermentation of L. salivarius CCFM 1266 with commercial fermentation starters indicated that L. salivarius CCFM 1266 was compatible, similarly altering metabolite composition and increasing niacin content in fermented milk. In summary, the findings suggest that L. salivarius CCFM 1266 holds substantial promise as an adjunctive fermentation starter, capable of enhancing the nutritional diversity of fermented milk products. [ABSTRACT FROM AUTHOR]

Four rare earth metal complexes have been synthesized based on Pr3+, Gd3+ and Er3+ and two polyacid ligands. Fluorescence test show that fluorescence intensity of complex 1 , 2 , 3 and 4 is weaker than that of its corresponding ligand. Magnetic test show that complex 1 has ferromagentic behavior and complexes 2 , 3 and 4 have weak antiferromagentic behavior. [Display omitted] • Complexes 1 and 2 have the same spatial configuration, they are undulating wave surfaces structure. • Compared to ligand fluorescence of complexes 1 and 2 undergoes a red shift, while 3 and 4 undergo a blue shift. • Complex 1 exhibits ferromagnetic behavior, complex 2, 3 and 4 exhibits antiferromagnetic behavior. In order to further enrich the research on the synthesis of complexes with polycarboxylic acid ligands and rare earth metal ion. In this study, four rare earth complexes, namely, [Gd(cpia)] n (1), [Er(cpia)] n (2), [Pr(cpna) 2 ·2H 2 O] n (3) and [Gd(Hcpna)(cpna)•3H 2 O] n (4) have been synthesized by solvothermal method based on 5-(2-carboxyphenoxy)isophthalic acid (H 3 cpia) and 5-(4-carboxyphenoxy)nicotinic acid ligand (H 2 cpna) with rare earth metal ions Pr3+, Gd3+ and Er3+. Single crystal X-ray diffraction analyses reveal that complexes 1 , 2 and 3 are two-dimensional network structure, 4 is one-dimensional chain structures. The fluorescence test results show that the fluorescence intensity of complexes 1 and 2 were lower than that of the H 3 cpia ligand, the fluorescence intensity of complexes 3 and 4 were lower than that of the H 2 cpna ligand. Magnetic results indicate complex 1 has ferromagentic behavior and weak antiferromagentic behavior in the complexes 2, 3 and 4. [ABSTRACT FROM AUTHOR]

[Display omitted] • In the heading molecules the optical properties get enhanced with the addition of solvents. • Electron-hole transfer occurs in both of these compounds. • The UV–Vis analysis shows the maximum absorbance in the gas phase with n → π* transition. • Topographical study demonstrates the localised electron zones in the compounds. • Thermochemical studies reveal the stability of the compounds. • The NBO study shows the presence of π → π* transitions in the compounds. 6-Chloro-3-fluoro-2-(trifluoromethyl) isonicotinic acid (6C3F2TINA) and 6-Chloro-5-fluoronicotinic acid (6C5FNA) are currently being studied using the DFT method for the detailed examination of structural and molecular character alterations in gas as well as in several organic solvent media. Implementing electrostatic potential maps and Fukui functions analyses the reactive environment of compounds. The occurrence of the transfer of electrons and holes within the molecule is reported by a charge transfer study along with the heat maps. The orbital study investigates the electronic density and interactions within the molecules. Optical examination of compounds revealed an enhancement with the solvents. The bonding type found in molecules is determined by topographical investigation, which examines the concentration and localisation of electrons present in them. The UV–Vis spectra exhibit the absorption characteristics of these compounds. The thermodynamic investigation reveals the compound's stability at various temperatures at 1 atm pressure. [ABSTRACT FROM AUTHOR]

A sensitive and rapid liquid chromatography-tandem mass spectrometry (LC–MS/MS) method was developed and validated for the simultaneous determination of tryptophan (Trp) and ten metabolites of kynurenine pathway, including kynurenine (Kyn), 3-hydroxy-kynurenine (3-HK), kynurenic acid (KA), xanthurenic acid (XA), 3-Hydroxy-anthranilic acid (3-HANA), quinolinic acid (QA), nicotinic acid mononucleotide (NaMN), picolinic acid (Pic), nicotinamide (NAM) and nicotinic acid (NA) in both plasma and urine. This LC-MS/MS method was used to predict the occurrence of acute kidney injury (AKI) in a cohort of patients with cardiac surgery under cardiopulmonary bypass (CPB). Urinary concentrations of Pic, as well as Pic to Trp and Pic to 3-HANA ratios were highly predictive of an AKI episode the week after CPB, indicating that Pic could be a predictive biomarker of AKI. Thus, monitoring the kynurenine pathway activity with this LC–MS/MS method is a clinically relevant tool to identify new biomarkers of kidney injury. [ABSTRACT FROM AUTHOR]

Sulfur-insertion reactions are essential for the biosynthesis of several cellular metabolites, including enzyme cofactors. In Lactobacillus plantarum, a sulfur-containing nickel-pincer nucleotide (NPN) cofactor is used as a coenzyme of lactic acid racemase, LarA. During NPN biosynthesis in L. plantarum, sulfur is transferred to a nicotinic acid-derived substrate by LarE, which sacrifices the sulfur atom of its single cysteinyl side chain, forming a dehydroalanine residue. Most LarE homologs contain three conserved cysteine residues that are predicted to cluster at the active site; however, the function of this cysteine cluster is unclear. In this study, we characterized LarE from Thermotoga maritima (LarETm) and show that it uses these three conserved cysteine residues to bind a [4Fe-4S] cluster that is required for sulfur transfer. Notably, we found LarETm retains all side chain sulfur atoms, in contrast to LarELp. We also demonstrate that when provided with L-cysteine and cysteine desulfurase from Escherichia coli (IscSEc), LarETm functions catalytically with IscSEc transferring sulfane sulfur atoms to LarETm. Native mass spectrometry results are consistent with a model wherein the enzyme coordinates sulfide at the nonligated iron atom of the [4Fe-4S] cluster, forming a [4Fe-5S] species, and transferring the noncore sulfide to the activated substrate. This proposed mechanism is like that of TtuA that catalyzes sulfur transfer during 2-thiouridine synthesis. In conclusion, we found that LarE sulfur insertases associated with NPN biosynthesis function either by sacrificial sulfur transfer from the protein or by transfer of a noncore sulfide bound to a [4Fe-4S] cluster. [ABSTRACT FROM AUTHOR]

Trace elements and vitamins, named together micronutrients (MNs), are essential for human metabolism. Recent research has shown the importance of MNs in common pathologies, with significant deficiencies impacting the outcome. This guideline aims to provide information for daily clinical nutrition practice regarding assessment of MN status, monitoring, and prescription. It proposes a consensus terminology, since many words are used imprecisely, resulting in confusion. This is particularly true for the words "deficiency", "repletion", "complement", and "supplement". The expert group attempted to apply the 2015 standard operating procedures (SOP) for ESPEN which focuses on disease. However, this approach could not be applied due to the multiple diseases requiring clinical nutrition resulting in one text for each MN, rather than for diseases. An extensive search of the literature was conducted in the databases Medline, PubMed, Cochrane, Google Scholar, and CINAHL. The search focused on physiological data, historical evidence (published before PubMed release in 1996), and observational and/or randomized trials. For each MN, the main functions, optimal analytical methods, impact of inflammation, potential toxicity, and provision during enteral or parenteral nutrition were addressed. The SOP wording was applied for strength of recommendations. There was a limited number of interventional trials, preventing meta-analysis and leading to a low level of evidence. The recommendations underwent a consensus process, which resulted in a percentage of agreement (%): strong consensus required of >90% of votes. Altogether the guideline proposes sets of recommendations for 26 MNs, resulting in 170 single recommendations. Critical MNs were identified with deficiencies being present in numerous acute and chronic diseases. Monitoring and management strategies are proposed. This guideline should enable addressing suboptimal and deficient status of a bundle of MNs in at-risk diseases. In particular, it offers practical advice on MN provision and monitoring during nutritional support. [ABSTRACT FROM AUTHOR]

The lack of objective diagnostic markers has long been a challenge in the clinical management of schizophrenia (SZ). The current bivariate cut-offs method is an objective quantification of niacin skin flush abnormality (NFA) for identifying the SZ subgroup. However, the sensitivity of approximately 30% limits the application of NFA as a marker for detecting SZ. A laser Doppler flowmeter was employed to test the niacin skin-flushing response in 123 patients with first-episode psychosis including first-episode SZ (FES, n = 82) and psychotic bipolar disorders (PBP, n = 41), and non-psychiatric comparisons (NPC, n = 80). We modified the bivariate cut-offs using a combination of the niacin concentration corresponding to the half-maximal blood flow response (EC50) and a new quantitative indicator called the overall trend area (OTA). The NFA used this study method predicted FES in the NPC group with 57% sensitivity, 89% specificity, and 73% accuracy compared to the 28% sensitivity, 91% specificity, and 59% accuracy of the existing method. This novel method could discern FES from the PBP group with an accuracy of 62%, compared with the 45% of the old method. In addition, we also discuss whether the bivariate cut-offs were occasional by adjusting the cut-offs threshold. The experimental results showed that the sensitivity and specificity were most stable when using the study method. The study indicates that NFA using modified bivariate cut-offs may be a potential objective marker in FES, and the niacin skin test could be feasible for early diagnosis and treatment of SZ. [ABSTRACT FROM AUTHOR]