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Endothelial cells of mammalian blood vessels have multiple levels of heterogeneity along the vascular tree and among different organs. Further heterogeneity results from blood flow turbulence and variations in shear stress. In the aorta, vascular endothelial protein tyrosine phosphatase (VE-PTP), which dephosphorylates tyrosine kinase receptor Tie2 in the plasma membrane, undergoes downstream polarization and endocytosis in endothelial cells exposed to laminar flow and high shear stress. VE-PTP sequestration promotes Tie2 phosphorylation at tyrosine992 and endothelial barrier tightening. The present study characterized the heterogeneity of VE-PTP polarization, Tie2-pY992 and total Tie2, and claudin-5 in anatomically defined regions of endothelial cells in the mouse descending thoracic aorta, where laminar flow is variable and IgG extravasation is patchy. We discovered that VE-PTP and Tie2-pY992 had mosaic patterns, unlike the uniform distribution of total Tie2. Claudin-5 at tight junctions also had a mosaic pattern, whereas VE-cadherin at adherens junctions bordered all endothelial cells. Importantly, the amounts of Tie2-pY992 and claudin-5 in aortic endothelial cells correlated with downstream polarization of VE-PTP. VE-PTP and Tie2-pY992 also had mosaic patterns in the vena cava, but claudin-5 was nearly absent and extravasated IgG was ubiquitous. Correlation of Tie2-pY992 and claudin-5 with VE-PTP polarization supports their collective interaction in the regulation of endothelial barrier function in the aorta, yet differences between the aorta and vena cava indicate additional flow-related determinants of permeability. Together, the results highlight new levels of endothelial cell functional mosaicism in the aorta and vena cava, where blood flow dynamics are well known to be heterogeneous.

The regulation of the mammalian circadian clock is largely dependent on heredity. In model animals for circadian rhythm studies, C57BL/6 and BALB/c mice exhibit considerable differences in their adaptation to circadian disruption, yet deeper comparisons remain unexplored. Here, we have established embryonic fibroblast cells derived from C57BL/6 mice (MEF) and BALB/c (BALB/3T3) mice, which have been transfected with the Bmal1 promoter-driven luciferase (Bmal1-Luc) reporter gene. Next, dexamethasone was applied for various cyclic stimulations, which revealed that Bmal1 bioluminescence of MEF cells was entrained to 24 to 26 h cycles, whereas BALB/3T3 cells have a wider range (22 to 28 h) with lower amplitudes. Behaviorally, BALB/c mice swiftly adapted to a 6-h advance light/dark cycle, unlike C57BL/6 mice. Furthermore, we found the expression of the circadian rhythm gene Npas2 in BALB/c mice is significantly lower than that in C57BL/6 mice. This observation is consistent with the differentially expressed genes (DEGs) in the intestine and lung tissues of C57BL/6 and BALB/c mice, based on the RNA-seq datasets downloaded from the Gene Expression Omnibus (GEO). In summary, our study uncovers that BALB/c mice possess greater resilience in circadian rhythm than C57BL/6 mice, both cellular and behaviorally, identifying potential genes underlying this difference. [ABSTRACT FROM AUTHOR]

With the escalating prevalence of hair loss, the demand for effective hair loss treatment has surged. This study evaluated the effects of hot water extract of Hydrangea serrata (Thunb.) Ser. leaf (WHS) on hair growth, employing cell cultures, mice, and human skin organoid models. Both WHS and hydrangenol were found to enhance 5α-reductase inhibitory activity. WHS and hydrangenol have been shown to stimulate dermal papilla cell (DPC) growth, potentially through factors like keratinocyte growth factor (KGF), fibroblast growth factor 10 (FGF10), and transforming growth factor-β1 (TGF-β1). They also elevated the expression levels of keratin genes (K31 and K85) and the ceramide synthase (CerS3) gene, crucial clinical indicators of hair health. Furthermore, they exhibited notable anti-inflammatory and anti-androgenic properties by reducing the levels of tumor necrosis factor-α (TNF-α) and androgen signaling molecules, including androgen receptor (AR) and dickkopf-1 (DKK-1) gene expression. Oral administration of WHS to C57BL/6 mice for 3 weeks confirmed its hair growth-promoting effects, improving hair growth parameters and gene expression without significant changes in hair weight. Additionally, in a human skin organoid model, WHS was found to stimulate hair formation and augment the expression of follicle markers. These findings position WHS as a promising nutraceutical for promoting hair health, as evidenced by its efficacy in both in vitro and in vivo models. [ABSTRACT FROM AUTHOR]

We studied psychoemotional characteristics and the blood level of corticosterone in sexually mature male C57BL/6 mice (n=40): intact (control), after simulating preoperative stress and surgery, after surgery, and after anesthesia alone. It was found that the anxiety index calculated on the basis of testing in the elevated plus maze was significantly higher in both groups of operated animals. The mice of both operated groups and animals exposed to anesthesia alone showed increased anxiety. Symptoms indicating a high probability of transition of anxiety into a psychoemotional disorder have been recorded. [ABSTRACT FROM AUTHOR]

Bisphenol A (BPA) is a component of polycarbonate plastics that has been implicated in memory impairment. The present study investigated the effect of carnosic acid (CA) on memory deficit induced by BPA and the role of Akt in this mechanism. First, SH-SY5Y cells were treated with 20 nM BPA and 1 μM CA for 12 h. The results showed that treatment of CA with BPA improved the alternation of IRS-1/Akt/GSK-3β as well as the induction of ApoE and Ser396p-tau. Moreover, treatment of CA with BPA restored the signaling involved in long-term potentiation (LTP) effect, leading to induction of synaptic-related proteins, such as PSD-95, synapsin1a, and pro-BDNF. Wortmannin treatment alleviated the reversal by CA. Then, C57BL/6 J male mice were orally administered with CA to test the memory function in BPA treatment. The results showed that CA and RE can improve BPA-induced impairment of motor, recognition, and spatial memory by using open-field test (OFT), novel objective recognition test (NOR), and Y-maze test, respectively. Moreover, CA and RE improved the phosphorylation of tau and the reduction of PSD-95, synapsin1a, and pro-BDNF proteins induced by BPA. Therefore, the results indicated that CA decreased the phosphorylated tau and memory impairment induced by BPA through Akt pathway. [ABSTRACT FROM AUTHOR]

Abstract Bilharzia is a parasitic flatworm that causes schistosomiasis, a neglected tropical illness worldwide. Praziquantel (PZQ) is a commercial single treatment of schistosomiasis so alternative drugs are needed to get rid of its side effects on the liver. The current study aimed to estimate the effective role of Ficus carica nanoparticles (Fc-NPCs), silver nanoparticles (Ag-NPCs) and Ficus carica nanoparticles loaded on silver nanoparticles (Fc-Ag NPCs) on C57BL/6 black female mice infected by Schistosoma mansoni and treated with PZQ treatment. It was proved that schistosomiasis causes liver damage in addition to the PZQ is ineffective as an anti-schistosomiasis; it is recorded in the infected mice group and PZQ treated group as in liver function tests, oxidative stress markers & anti-oxidants, pro-inflammatory markers, pro-apoptotic and anti-apoptotic markers also in liver cells’ DNA damage. The amelioration in all tested parameters has been clarified in nanoparticle-protected mice groups. The Fc-Ag NPCs + PZQ group recorded the best preemptive effects as anti-schistosomiasis. Fc-NPCs, Ag-NPCs and Fc-Ag NPCs could antagonize PZQ effects that were observed in amelioration of all tested parameters. The study showed the phytochemicals’ nanoparticles groups have an ameliorated effect on the health of infected mice.

Introduction: α-amylase inhibitors are an important class of second-line antihyperglycemic drugs. They slow down the breakdown and absorption of carbohydrates, reducing peak glucose concentration with meals. Recent reports have also shown other beneficial effects of α-amylase inhibitors on type 2 diabetes mellitus (T2DM). Materials and Methods: T2DM was modeled by keeping C57BL/6 mice on a high-fat diet for 21 weeks. Starting at week 18, the animals were orally administered acarbose at a dose of 24 mg/kg or the comparative drug metformin at a dose of 200 mg/kg for 4 weeks. Body weight gain, visceral fat mass, and adipocyte diameter were monitored during the period of test substances administration. At weeks 17, 19 and 21 of the study, glucose tolerance starch test and insulin resistance test were performed, and fasting blood glucose was measured. Results: Administration of acarbose for 2 and 4 weeks resulted in a significant reduction of postprandial glucose concentration in the starch test; glucose AUC was significantly lower after administration of acarbose at a dose of 24 mg/kg on the background of T2DM modeling. Acarbose at a dose of 24 mg/kg effectively reduced fasting glucose concentration after 2 and 4 weeks of daily treatment on par with metformin. Administration of acarbose at a dose of 24 mg/kg for 2 and 4 weeks resulted in a significant decrease in the glucose AUC in the insulin resistance test. Acarbose promoted a significant decrease in adipocyte diameter and body weight gain against the background of T2DM modeling. Conclusion: Long-term acarbose administration at a daily dose of 24 mg/kg is effective in reducing postprandial glucose concentration in mice with T2DM due to its α-amylase inhibitory activity. Additionally, it can alleviate insulin resistance, lower fasting glucose concentration, and prevent obesity development by stimulating GLP-1 secretion.

Bilharzia is a parasitic flatworm that causes schistosomiasis, a neglected tropical illness worldwide. Praziquantel (PZQ) is a commercial single treatment of schistosomiasis so alternative drugs are needed to get rid of its side effects on the liver. The current study aimed to estimate the effective role of Ficus carica nanoparticles (Fc-NPCs), silver nanoparticles (Ag-NPCs) and Ficus carica nanoparticles loaded on silver nanoparticles (Fc-Ag NPCs) on C57BL/6 black female mice infected by Schistosoma mansoni and treated with PZQ treatment. It was proved that schistosomiasis causes liver damage in addition to the PZQ is ineffective as an anti-schistosomiasis; it is recorded in the infected mice group and PZQ treated group as in liver function tests, oxidative stress markers & anti-oxidants, pro-inflammatory markers, pro-apoptotic and anti-apoptotic markers also in liver cells' DNA damage. The amelioration in all tested parameters has been clarified in nanoparticle-protected mice groups. The Fc-Ag NPCs + PZQ group recorded the best preemptive effects as anti-schistosomiasis. Fc-NPCs, Ag-NPCs and Fc-Ag NPCs could antagonize PZQ effects that were observed in amelioration of all tested parameters. The study showed the phytochemicals' nanoparticles groups have an ameliorated effect on the health of infected mice. [ABSTRACT FROM AUTHOR]

Three hyperimmune egg-based formulations rich in immunoglobulin Y (IgY) were orally administered (daily, for up to 90 days) to C57BL/6 mice that were not microbially challenged. The serum levels of 32 cytokines were quantified every 30 days. Histopathology, hematology, and serum biochemistry investigations were also performed. As a sign of increased immune activity, lymphohistiocytic infiltrates were detected in the digestive tract and the liver after 30, 60, and 90 days of treatment. These infiltrates were also present in the lungs after 30 and 60 days, but not at 90 days. Blood analysis indicated systemic inflammation after 30 days of treatment: increases in pro-inflammatory cytokines, glycemia, total serum proteins, ALT, and ALP. After 60 and 90 days of treatment, the analyzed blood parameters showed mixed signs of both increased and decreased inflammation. The increased cytokines, which varied with formulation and time of exposure, indicated a combination of mostly Th17- and Th2-type immune responses. As the mice were healthy and housed in standardized sanitary conditions, and were not microbially challenged, the data were consistent with an interaction of IgY with the gut-associated lymphoid tissue as the main mechanism of action. This interaction generated a local immune response, which subsequently induced a systemic response. [ABSTRACT FROM AUTHOR]

Colonization resistance, conferred by the host's microbiota through both direct and indirect protective actions, serves to protect the host from enteric infections. Here, we identified the specific members of the gut microbiota that impact gastrointestinal colonization by Citrobacter rodentium, a murine pathogen causing colonic crypt hyperplasia. The gut colonization levels of C. rodentium in C57BL/6 mice varied among breeding facilities, probably due to differences in microbiota composition. A comprehensive analysis of the microbiota revealed that specific members of the microbiota may influence gut colonization by C. rodentium, thus providing a potential link between the two. [ABSTRACT FROM AUTHOR]

Abstract C57BL/6 mice are frequently utilized as murine models with the desired genetic background for altertion in multiple research contexts. So far, there is still a lack of comprehensive kidney morphology and single-cell transcriptome atlas at all stages of growth of C57BL/6 mice. To provide an interactive set of reference standards for the scientific community, we performed the current study to investigate the kidney’s development throughout the capillary-loop stage until senescence. Eight groups, with five to six mice each, represented embryonic stage (embryos 18.5 days), suckling period (1 day after birth), juvenile stage (1 month old), adulthood (containing 3 months old, 6 months old and 10 months old), reproductive senescence stage (20 months old), and post-senescence stage (30 months old), respectively. With age, the thickness of the glomerular basement membrane (GBM) was increased. Notably, GBM knobs appeared at three months and became frequent with age. Using single-cell transcriptome data, we evaluated how various biological process appear in particular cell types and investigated the potential mechanism of formation of GBM konbs. In conclusion, having access to detailed kidney morphology and single-cell transcriptome maps from C57BL/6 mice at various developmental stages of C57BL/6 mice would be a novel and major resource for biological research and testing of prospective therapeutic approaches.

C57BL/6 mice are frequently utilized as murine models with the desired genetic background for altertion in multiple research contexts. So far, there is still a lack of comprehensive kidney morphology and single-cell transcriptome atlas at all stages of growth of C57BL/6 mice. To provide an interactive set of reference standards for the scientific community, we performed the current study to investigate the kidney's development throughout the capillary-loop stage until senescence. Eight groups, with five to six mice each, represented embryonic stage (embryos 18.5 days), suckling period (1 day after birth), juvenile stage (1 month old), adulthood (containing 3 months old, 6 months old and 10 months old), reproductive senescence stage (20 months old), and post-senescence stage (30 months old), respectively. With age, the thickness of the glomerular basement membrane (GBM) was increased. Notably, GBM knobs appeared at three months and became frequent with age. Using single-cell transcriptome data, we evaluated how various biological process appear in particular cell types and investigated the potential mechanism of formation of GBM konbs. In conclusion, having access to detailed kidney morphology and single-cell transcriptome maps from C57BL/6 mice at various developmental stages of C57BL/6 mice would be a novel and major resource for biological research and testing of prospective therapeutic approaches. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is the most common chronic inflammatory demyelinating disease of the central nervous system. Oxidative stress via distinct pathobiological pathways plays a pivotal role in the formation and persistence of MS lesions. Acetyl-L-carnitine (ALC) facilitates the uptake of acetyl coenzyme-A into the mitochondria by a fatty acid oxidation process. ALC could be a therapeutic antioxidant in the myelin repair process. This study explored the potential neuroprotective effects of ALC in cuprizone (CPZ) intoxicated mice. Thirty male C57BL/6 mice were divided into three groups. The control animals received a normal diet. The CPZ and CPZ + ALC groups were fed with a 0.2% cuprizone diet for 12 weeks. In the CPZ + ALC group, animals received ALC (300 mg/kg/day) from the 10th -12th weeks. Animals were evaluated functionally by beam walking test (BWT) weekly. Eventually, the corpus callosum (CC) was extracted for histological, biochemical, and molecular studies. BWT data showed ALC significantly improves balance and gait in the demyelinating mouse model. Histological staining represented ALC effectively increased remyelination in the CC. Biochemical evaluations demonstrated ALC decreased the malondialdehyde level with a parallel increase in the reduced glutathione and catalase activity levels in the CC. Molecular analysis revealed that ALC significantly increased the expression of oligodendrocyte transcription-2 (Olig-2) and Poly lipoproteins (Plp) genes in the CC. ALC improved balance and motor coordination in the demyelinated mouse model. It may be by reducing the levels of free radicals and increasing the expression of Olig-2 and Plp as myelin-related genes. [ABSTRACT FROM AUTHOR]

Introduction: α-amylase inhibitors are an important class of second-line antihyperglycemic drugs. They slow down the breakdown and absorption of carbohydrates, reducing peak glucose concentration with meals. Recent reports have also shown other beneficial effects of α-amylase inhibitors on type 2 diabetes mellitus (T2DM). Material and Methods: T2DM was modeled by keeping C57BL/6 mice on a high-fat diet for 21 weeks. Starting at week 18, the animals were orally administered acarbose at a dose of 24 mg/kg or the comparative drug metformin at a dose of 200 mg/kg for 4 weeks. Body weight gain, visceral fat mass, and adipocyte diameter were monitored during the period of test substances administration. At weeks 17, 19 and 21 of the study, glucose tolerance starch test and insulin resistance test were performed, and fasting blood glucose was measured. Results: Administration of acarbose for 2 and 4 weeks resulted in a significant reduction of postprandial glucose concentration in the starch test; glucose AUC was significantly lower after administration of acarbose at a dose of 24 mg/kg on the background of T2DM modeling. Acarbose at a dose of 24 mg/kg effectively reduced fasting glucose concentration after 2 and 4 weeks of daily treatment on par with metformin. Administration of acarbose at a dose of 24 mg/kg for 2 and 4 weeks resulted in a significant decrease in the glucose AUC in the insulin resistance test. Acarbose promoted a significant decrease in adipocyte diameter and body weight gain against the background of T2DM modeling. Conclusion: Long-term acarbose administration at a daily dose of 24 mg/kg is effective in reducing postprandial glucose concentration in mice with T2DM due to its α-amylase inhibitory activity. Additionally, it can alleviate insulin resistance, lower fasting glucose concentration, and prevent obesity development by stimulating GLP-1 secretion. [ABSTRACT FROM AUTHOR]

The exact mechanisms of MS (multiple sclerosis) evolution are still unknown. However, the development of EAE (experimental autoimmune encephalomyelitis simulating human MS) in C57BL/6 mice occurs due to the violation of bone marrow hematopoietic stem cell differentiation profiles, leading to the production of toxic for human autoantibody splitting MBP (myelin basic protein), MOG (mouse oligodendrocyte glycoprotein), five histones, DNA, and RNA. Here, we first analyzed the changes in the relative phosphatase activity of IgGs from C57BL/6 mice blood over time, corresponding to three stages of EAE: onset, acute, and remission. Antibodies have been shown to catalyze the hydrolysis of p-nitrophenyl phosphate at several optimal pH values, mainly in the range of 6.5–7.0 and 8.5–9.5. During the spontaneous development of EAE, the most optimal value is pH 6.5. At 50 days after the birth of mice, the phosphatase activity of IgGs at pH 8.8 is 1.6-fold higher than at pH 6.5. During spontaneous development of EAE from 50 to 100 days, an increase in phosphatase activity is observed at pH 6.5 but a decrease at pH 8.8. After mice were immunized with DNA–histone complex by 20 and 60 days, phosphatase activity increased respectively by 65.3 and 109.5 fold (pH 6.5) and 128.4 and 233.6 fold (pH 8.8). Treatment of mice with MOG at the acute phase of EAE development (20 days) leads to a maximal increase in the phosphatase activity of 117.6 fold (pH 6.5) and 494.7 fold (pH 8.8). The acceleration of EAE development after mice treatment with MOG and DNA–histone complex results in increased production of lymphocytes synthesizing antibodies with phosphatase activity. All data show that IgG phosphatase activity could be essential in EAE pathogenesis. [ABSTRACT FROM AUTHOR]

Introduction: Numerous studies have demonstrated that C57BL/6 mice exhibit superior growth rates and overall growth performance compared to DBA mice. To investigate whether this discrepancy in growth performance is linked to the composition of gut microorganisms, we conducted fecal microbiome transplantation (FMT) experiments. Methods: Specifically, we transplanted fecal fluids from adult C57BL/6 mice, high-fat C57BL/6 mice, and Wistar rats into weaned DBA mice (0.2mL/d), and subsequently analyzed their gut contents and gene expression through 16S rRNA sequencing and transcriptome sequencing. During the test period, C57BL/6 mice and Wistar rats were provided with a normal diet, and high-fat C57BL/6 mice were provided with a high-fat diet. Results: The results of our study revealed that mice receiving FMT from all three donor groups exhibited significantly higher daily weight gain and serum triglyceride (TG) levels compared to mice of CK group. 16S rRNA sequensing unveiled substantial differences in the abundance and function of the gut microbiota between the FMT groups and the CK group. Transcriptome analysis revealed a total of 988 differential genes, consisting of 759 up-regulated genes and 187 down-regulated genes, between the three experimental groups and the CK group. Functional Gene Ontology (GO) annotation suggested that these genes were primarily linked to lipid metabolism, coagulation, and immunity. Pearson correlation analysis was performed on the differential genes and clusters, and it revealed significant correlations, mainly related to processes such as fatty acid metabolism, fat digestion and absorption, and cholesterol metabolism. Discussion: In summary, FMT from dominant strains improved the growth performance of DBA mice, including body weight gain, institutional growth, and immune performance. This change may be due to the increase of probiotic content in the intestinal tract by FMT and subsequent alteration of intestinal gene expression. However, the effects of cross-species fecal transplantation on the intestinal flora and gene expression of recipient mice were not significant. [ABSTRACT FROM AUTHOR]

Tobacco-specific nitrosamines (TSNAs) are emitted during smoking and form indoors by nitrosation of nicotine. Two of them, N'-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), are human carcinogens with No Significant Risk Levels (NSRLs) of 500 and 14 ng day-1, respectively. Another TSNA, 4-(methylnitrosamino)-4-(3-pyridyl) butanal (NNA), shows genotoxic and mutagenic activity in vitro. Here, we present additional evidence of genotoxicity of NNA, an assessment of TSNA dermal uptake, and predicted exposure risks through different pathways. Dermal uptake was investigated by evaluating the penetration of NNK and nicotine through mice skin. Comparable mouse urine metabolite profiles suggested that both compounds were absorbed and metabolized via similar mechanisms. We then investigated the effects of skin constituents on the reaction of adsorbed nicotine with nitrous acid (epidermal chemistry). Higher TSNA concentrations were formed on cellulose and cotton substrates that were precoated with human skin oils and sweat compared to clean substrates. These results were combined with reported air, dust, and surface concentrations to assess NNK intake. Five different exposure pathways exceeded the NSRL under realistic scenarios, including inhalation, dust ingestion, direct dermal contact, gas-to-skin deposition, and epidermal nitrosation of nicotine. These results illustrate potential long-term health risks for nonsmokers in homes contaminated with thirdhand tobacco smoke.

The regulation of the mammalian circadian clock is largely dependent on heredity. In model animals for circadian rhythm studies, C57BL/6 and BALB/c mice exhibit considerable differences in their adaptation to circadian disruption, yet deeper comparisons remain unexplored. Here, we have established embryonic fibroblast cells derived from C57BL/6 mice (MEF) and BALB/c (BALB/3T3) mice, which have been transfected with the Bmal1 promoter-driven luciferase (Bmal1-Luc) reporter gene. Next, dexamethasone was applied for various cyclic stimulations, which revealed that Bmal1 bioluminescence of MEF cells was entrained to 24 to 26 h cycles, whereas BALB/3T3 cells have a wider range (22 to 28 h) with lower amplitudes. Behaviorally, BALB/c mice swiftly adapted to a 6-h advance light/dark cycle, unlike C57BL/6 mice. Furthermore, we found the expression of the circadian rhythm gene Npas2 in BALB/c mice is significantly lower than that in C57BL/6 mice. This observation is consistent with the differentially expressed genes (DEGs) in the intestine and lung tissues of C57BL/6 and BALB/c mice, based on the RNA-seq datasets downloaded from the Gene Expression Omnibus (GEO). In summary, our study uncovers that BALB/c mice possess greater resilience in circadian rhythm than C57BL/6 mice, both cellular and behaviorally, identifying potential genes underlying this difference.

Type 2 diabetes mellitus develops due to a combination of genetic and environmental factors. C57BL/6 mice prone to obesity and leptin resistance were kept on a high-fat diet for 21 weeks. The animals showed a significant increase in fasting and postprandial glucose levels and body weight, the development of insulin resistance, and by week 18, an increase in the serum TNFα level. Metformin therapy at a dose of 250 mg/kg was effective against the background of disturbances in carbohydrate metabolism: animals showed a significant decrease in insulin resistance and TNFα level. [ABSTRACT FROM AUTHOR]

This study aimed to enhance the effectiveness and water solubility of Minoxidil (MXD) by producing its nanocrystal structure, which improves its vasodilator properties and promotes hair growth. In the current study, the hair growth-stimulating activity of the MXD nanoparticles (MXD-NPs) was compared with the hydroethanolic rosemary (RSY) extract on the C57BL/6 mice. The MXD-NPs were produced through a bead mill and ultrasonic process and characterized using various techniques. The cytotoxicity of MXD-NPs was studied on human dermal fibroblasts, and their hair growth-stimulating activity was analyzed in C57BL/6 mice. The results showed that MXD-NPs significantly increased the hair growth rate in mice compared to commercial MXD and hydroethanolic rosemary extract as they were delivered safely and specifically to the target pilosebaceous follicles. The follicular uptake of MXD-NPs was also increased compared to commercial MXD, leading to improved pilosebaceous follicle re-growth and hair growth in treated mice. Therefore, MXD-NPs have the potential to be a safe and efficient iso-formulation structure for hair growth promotion. [ABSTRACT FROM AUTHOR]

The effect of stevia leaf extract, saccharinate, and cyclamate in various dosages on the glycogen content of blood leukocytes in C57BL/6 mice as a necessary substrate for the realization of phagocytosis was studied. An increase in glycogen content was found in all experimental groups treated with sweeteners at a dosage of 10 mg/g of body weight. The effect of sweeteners on the differential leukocyte counts was found only in mice receiving the stevia leaf extract at a dosage of 10 mg/g of body weight manifested as an increase neutrophil-to-lymphocyte ratio (NLR). The data obtained expand our understanding of the metabolism of sugar substitutes in an organism and their influence on physiological systems, in particular, the hematopoietic and immune systems. [ABSTRACT FROM AUTHOR]

The intricate relationship between sleep and leukocyte trafficking has garnered intense attention, particularly their homing dynamics to secondary lymphoid organs under normal and restricted sleep (SR). Considering the scarcity of information regarding circadian rhythms in major histocompatibility class I (MHC-I) expression in SR, we designed a study that assessed the temporal expression of MHC-I in murine lymph nodes and spleen and the subsequent effects of sleep recovery. Male C57BL/6, housed in 12:12 light/dark cycle, were grouped into control (C) and SR. SR was carried for one week before lymphoid tissues were sampled at selected time points and assessed for leukocyte number and MHC-I expression.SR resulted in 21% decrease in granulocyte and 24% increase in agranulocyte numbers.In C, MHC-I expression pattern in lymph nodes was bimodal and relatively higher than splenocytes during the animal’s active phase (110.2 ± 1.8 vs 81.9 ± 3.8, respectively; p = 0.002). Splenocytes; however, showed a bimodal pattern upon SR, with higher protein levels during the rest than the activity period (154.6 + 36.2 vs 99.5 + 15.9, respectively; p = 0.002), suggesting preparedness for a potential infection. Furthermore, SR caused a significant drop in MHC-I expression at the onset of rest with 57% and 30% reduction in lymph nodes and splenocytes, respectively. However, the overall protein expression collectively taken from both lymphoid tissues remained stable, emphasizing its indispensable role in immunological homeostasis. This stability coincided with the restoration of protein levels to baseline after a short sleep recovery period, resembling a reset for MHC-I antigen presentation following a week of SR.Understanding the interplay between MHC-I expression and contextual factors could enhance treatment protocols, refining the efficacy and time precision of glucocorticoid-based therapies in immune modulation.

AIM:To investigate the neuroprotective effect of 17β-estradiol(E2)on retina light damage in BALB/c and C57BL/6 mice and provide experimental data for the successful construction of a research model for E2 against retinal light damage.METHODS:Totally 40～45 adult female BALB/c or C57BL/6 mice were divided into six groups, 6 for each group: normal control, ovariectomized control, ovariectomized light(mice were stimulated with continuous white light at 10000 lx for 4, 8, 12, 16, and 24h after 14d of ovariectomy), intravitreal administration sham operation, saline and E2 pre-treatment groups(2μL saline or 10-5mol/L E2 were intravitreal injected respectively after 14d of ovariectomy operation and 24h of dark adaptation). The morphological and functional changes of the retina were detected by paraffin section HE staining, TUNEL staining and electroretinogram.RESULTS:In the ovariectomized light group, the thickness of the inner/outer nuclear layer decreased significantly from the 4h stimulation of 10000 lx white light group. Intravitreal administration of E2 significantly inhibited the apoptosis of retinal cells in the two strains of mice(P

Neoangiogenesis, a hallmark feature of all malignancies, is robust in glioblastoma (GBM). Vascular endothelial growth factor (VEGF) has long been regarded as the primary pro-angiogenic molecule in GBM. However, anti-VEGF therapies have had little clinical efficacy, highlighting the need to explore VEGF-independent mechanisms of neoangiogenesis. Olfactomedin-like 3 (OLFML3), a secreted glycoprotein, is an established proangiogenic factor in many cancers, but its role in GBM neoangiogenesis is unknown. To gain insight into the role of OLFML3 in microglia-mediated angiogenesis, we assessed endothelial cell (EC) viability, migration and differentiation following (1) siRNA knockdown targeting endogenous EC Olfml3 and (2) EC exposure to human recombinant OLFML3 (rhOLFML3; 10 ng/mL, 48 h), and conditioned medium (CM) from isogenic control and Olfml3−/− microglia (48 h). Despite a 70% reduction in Olfml3 mRNA levels, EC angiogenic parameters were not affected. However, exposure to both rhOLFML3 and isogenic control microglial CM increased EC viability (p < 0.01), migration (p < 0.05) and differentiation (p < 0.05). Strikingly, these increases were abolished, or markedly attenuated, following exposure to Olfml3−/− microglial CM despite corresponding increased microglial secretion of VEGF-A (p < 0.0001). Consistent with reports in non-CNS malignancies, we have demonstrated that OLFML3, specifically microglia-derived OLFML3, promotes VEGF-independent angiogenesis in primary brain microvascular ECs and may provide a complementary target to mitigate neovascularization in GBM.

The present study explores the molecular mechanism of anti-obesity effect of total lutein oxidized products (LOPs) in high-fat diet-induced obese C57BL/6 mice. Total LOPs (50, 100, 200 mg/kg b.wt.) were intubated for 22 weeks. Lipid profile, peroxides, AST, ALT, GST activities, lipid metabolizing enzymes/molecules, 3T3-L1 cell differentiation, TGF-β1 and p38 MAPK expressions were studied. Total LOPs at 100 mg/kg b.wt. reduced plasma and hepatic cholesterol, triglycerides, phospholipids, ALT and AST activities. FAS and CPT activities were inhibited in the liver homogenate, and epididymal WAT (eWAT). Total LOPs at 200 mg/kg b.wt. reduced HMGCoA:Mevalonate in eWAT, lipid peroxides in eWAT and liver. GST activity was high in the liver and eWAT. Total LOPs (100μg/ml) suppressed adipogenesis and decreased the accumulation of lipid droplets from two to eight days. Adiponectin was upregulated, PPAR γ, lipoprotein lipase, TGF-β1, and p38 MAPK were down-regulated. The results have shown that total LOPs are potent anti-obese molecules.ABBREVIATIONS: AIN 93G: American institute of nutrition 93 for growth; ALT: alanine transaminase; AST: aspartate transaminase; CEBPα: ccaat/enhancer binding protein α; C-DNA: complementary deoxyribonucleic acid; CPT: carnitine palmitoyl transferase; GST: glutathione-S-transferase; ELISA: enzyme-linked immune sorbent assay; FAS: fatty acid synthase; HDL: high-density lipoprotein; HFD: high-fat diet; HMG CoA: β-Hydroxy β-methylglutaryl-Coenzyme A; LDL: low-density lipoprotein; LOPs: total lutein oxidized products; LPL: lipoprotein lipase; MDA-Malonaldehyde; MTT: 3-(4,5-dimethylthiazol-2-yl)−2,5-diphenyl tetrazolium bromide; MVA: mevalonate; p38MAPK: p38 mitogen-activated protein kinases; RNA: ribonucleic acid; RTq-PCR: quantitative reverse transcription polymerase chain reaction; PPAR-γ: peroxisome proliferator-activated receptor-gamma; TGF-β1: transforming growth factor beta 1; WAT: white adipose tissue.

Depressive disorders are common psychopathologies highly comorbid with other mental diseases, especially post-traumatic stress disorder, with overt gender differences in susceptibility. The Disc1-Q31L mutant mice are characterized by depression-like behavior and disrupted molecular pathways involved in fear memory. Here, we assess the sex- and strain differences in learning and extinction of a conditioned passive avoidance response (CPAR) in male and female Disc1-Q31L mice vs. control C57BL/6 mice. Overall, male and female mice of both strains learned equally well but differed in fear memory extinction, i.e. the ability to form a new safety memory trace in the dark compartment of the test apparatus, previously associated with aversion. C57BL/6 female mice revealed poorer CPAR extinction than males, while both sexes showed strain differences in the extinction dynamics. While Disc1-Q31L male mice reached total extinction later than C57BL/6 males, Disc1-Q31L females exhibited no extinction throughout all 24 testing days. Collectively, this not only supports the role of Disc1 in fear memory extinction but also shows sex-dependent impact of its Q31L mutation in this process. [ABSTRACT FROM AUTHOR]

It was previously established that the original dipeptide mimetic of the 4th loop of NT-3, hexamethylenediamide bis-(N-monosuccinyl-L-asparaginyl-L-asparagine) (GTS-301), has a pronounced neuroprotective effect in vitro at concentrations of 10–5–10–12 М. In the present study, experiments on the streptozotocin-induced diabetes model in C57Bl/6 mice showed that GTS-301, when administered intraperitoneally for 32 days at doses of 0.1 and 0.5 mg/kg, has antidiabetic activity manifested in a reduction of hyperglycemia and polydipsia and in an increase in animal survival. The results obtained confirm the concept of the similarity of neurochemical mechanisms underlying the regulation of functions of neurons and β-cells. [ABSTRACT FROM AUTHOR]

The activity in the open field, short- and long-term memory in the novel object recognition test, and gait features were evaluated in 6- and 12-month-old male C57BL/6 mice. The levels of norepinephrine, dopamine, serotonin, and their metabolites were determined in the cerebellum and frontal cortex. In the observed age range, a decrease in locomotion speed, impairment of gait initiation and stability, and long-term memory deficit were revealed. In the cerebral cortex, reduced levels of dopamine and its metabolites and accelerated metabolism of all neurotransmitters under study were found. In the cerebellum, the content of all studied monoamines was elevated, while dopamine metabolism was decelerated. Analysis of correlations between the neurochemical and behavioral parameters showed that the mechanisms of compensation of brain functions during the early aging may be associated with an increase in activity of the monoaminergic systems in the cerebellum. [ABSTRACT FROM AUTHOR]

Mulberry leaves contain α-glucosidase inhibitors, which have hypoglycemic effects and are considered functional foods. However, few reports have covered the effects of mulberry leaf components on normal gut microbiota and gut metabolites. Herein, gut microbiota analysis and NMR-based metabolomics were performed on the feces of mulberry leaf powder (MLP)-treated mice to determine the effects of long-term MLP consumption. Gut microbiota in the mouse were analyzed using 16S-rRNA gene sequencing, and no significant differences were revealed in the diversity and community structure of the gut microbiota in the C57BL/6 mice with or without MLP supplementation. Thirty-nine metabolites were identified via 1H-NMR analysis, and carbohydrates and amino acids were significantly (p < 0.01–0.05) altered upon MLP treatment. In the MLP-treated group, there was a marked increase and decrease in maltose and glucose concentrations, respectively, possibly due to the degradation inhibitory activity of oligosaccharides. After 5 weeks, all amino acid concentrations decreased. Furthermore, despite clear fluctuations in fecal saccharide concentrations, short-chain fatty acid production via intestinal bacterial metabolism was not strongly affected. This study provides the knowledge that MLP administration can alter the gut metabolites without affecting the normal gut microbiota, which is useful for considering MLP as a healthy food source. [ABSTRACT FROM AUTHOR]

The proposed deep space exploration to the moon and later to Mars will result in astronauts receiving significant chronic exposures to space radiation (SR). SR exposure results in multiple neurocognitive impairments. Recently, our cross-species (mouse/rat) studies reported impaired associative memory formation in both species following a chronic 6-month low dose exposure to a mixed field of neutrons (1 mGy/day for a total dose pf 18 cGy). In the present study, we report neutron exposure induced synaptic plasticity in the medial prefrontal cortex, accompanied by microglial activation and significant synaptic loss in the hippocampus. In a parallel study, neutron exposure was also found to alter fluorescence assisted single synaptosome LTP (FASS-LTP) in the hippocampus of rats, that may be related to a reduced ability to insert AMPAR into the post-synaptic membrane, which may arise from increased phosphorylation of the serine 845 residue of the GluA1 subunit. Thus, we demonstrate for the first time, that low dose chronic neutron irradiation impacts homeostatic synaptic plasticity in the hippocampal-cortical circuit in two rodent species, and that the ability to successfully encode associative recognition memory is a dynamic, multicircuit process, possibly involving compensatory changes in AMPAR density on the synaptic surface.

Abstract Obesity and diabetes mellitus are common metabolic diseases prevalent worldwide. Mice are commonly used to study the pathogenesis of these two conditions. Obesity and diabetes mellitus are induced by administering a high‐fat diet in many studies although other diet‐induced models are also used. Several factors may influence the outcome of the studies done to study diet‐induced obesity in mice. The immune system plays a crucial role in the susceptibility of mice to develop obesity and metabolic disease. In this article, the reasons for differences in susceptibility to develop obesity and diabetes mellitus in mice in response to high‐fat‐diet feeding and the influence of immunological bias of the mice strain used in studies are evaluated. Mice strains that induce proinflammatory and Th1‐type immune responses are found to be susceptible to high‐fat‐diet‐induced obesity. A few studies which directly compared the effect of a high‐fat diet on obesity and diabetic phenotype in Th1‐ and Th2‐biased mice strains were briefly analyzed. Based on the observations, it is proposed that the liver and adipose tissue may respond differently to high‐fat‐diet feeding regimens in Th1‐ and Th2‐biased mice strains. For instance, in Th1‐biased mice, adipose tissue fat content was high both in the baseline as well as in response to a high‐fat diet whereas in the liver, it was found to be less. It can be inferred that the immune responses to diet‐induced models may provide insights into the pathogenesis of obesity and diabetes mellitus.

The exact mechanisms of MS (multiple sclerosis) evolution are still unknown. However, the development of EAE (experimental autoimmune encephalomyelitis simulating human MS) in C57BL/6 mice occurs due to the violation of bone marrow hematopoietic stem cell differentiation profiles, leading to the production of toxic for human autoantibody splitting MBP (myelin basic protein), MOG (mouse oligodendrocyte glycoprotein), five histones, DNA, and RNA. Here, we first analyzed the changes in the relative phosphatase activity of IgGs from C57BL/6 mice blood over time, corresponding to three stages of EAE: onset, acute, and remission. Antibodies have been shown to catalyze the hydrolysis of p-nitrophenyl phosphate at several optimal pH values, mainly in the range of 6.5–7.0 and 8.5–9.5. During the spontaneous development of EAE, the most optimal value is pH 6.5. At 50 days after the birth of mice, the phosphatase activity of IgGs at pH 8.8 is 1.6-fold higher than at pH 6.5. During spontaneous development of EAE from 50 to 100 days, an increase in phosphatase activity is observed at pH 6.5 but a decrease at pH 8.8. After mice were immunized with DNA–histone complex by 20 and 60 days, phosphatase activity increased respectively by 65.3 and 109.5 fold (pH 6.5) and 128.4 and 233.6 fold (pH 8.8). Treatment of mice with MOG at the acute phase of EAE development (20 days) leads to a maximal increase in the phosphatase activity of 117.6 fold (pH 6.5) and 494.7 fold (pH 8.8). The acceleration of EAE development after mice treatment with MOG and DNA–histone complex results in increased production of lymphocytes synthesizing antibodies with phosphatase activity. All data show that IgG phosphatase activity could be essential in EAE pathogenesis.

Introduction: For in vivo inhalation studies, aerosol dosimetry links aerosol exposure and deposited dose within the respiratory tract. Aerosol dosimetry programs like the Multiple Path Particle Deposition model utilize respiratory tract geometry, respiratory physiology, and aerosol properties to predict particle deposition within the respiratory tract. A challenge to wider use of these dosimetry programs for in vivo inhalation studies is the lack of species-specific or strain specific respiratory tract anatomy, and in some cases, strain specific respiratory physiology data. The objective of this work was to develop aerosol dosimetry predictions for the in vivo human disease models of chronic obstructive pulmonary disease (COPD; C57BL/6 mice) cardiovascular disease (CVD; ApoE-/- mice), and lung cancer (AJ mice) using the Multiple Path Particle Deposition dosimetry model. Methods: Microcomputed tomography derived tracheobronchial geometry data were combined with available pulmonary geometry data for C57BL/6, ApoE-/-, and AJ mice and incorporated into the Multiple Path Particle Deposition dosimetry model. Mouse strain specific respiratory physiology literature values were used as input into the Multiple Path Particle Deposition dosimetry model. Results: The resulting particle deposition predictions compared well with the very limited strain specific experimental particle deposition data. Since multiple tracheobronchial geometries and thus pulmonary anatomies were used for C57BL/6 and ApoE-/- mice, an estimate of intrastrain variability in predicted particle deposition was obtained. Discussion and Conclusions: The intrastrain variability in predicted particle deposition for C57BL/6 and ApoE-/- mice was always smaller in the tracheobronchial compared to pulmonary airways. The differences in reported respiratory physiology values for C57BL/6 mice resulted in greater intrastrain variability in predicted particle deposition than observed with the different tracheobronchial geometries and pulmonary anatomies. These mouse strain specific aerosol dosimetry predictions can provide insight into the delivered dose to specific respiratory tract regions that can be correlated with in vivo endpoints. [ABSTRACT FROM AUTHOR]

The antiobesity effects of kimchi with catechin and lactic acid bacteria as starters were studied in C57BL/6 mice with high-fat diet (HFD)-induced obesity. We prepared four types of kimchi: commercial kimchi, standard kimchi, green tea functional kimchi, and catechin functional kimchi (CFK). Body weight and weight of adipose tissue were significantly lower in the kimchi-treated groups than in the HFD and Salt (HFD +1.5% NaCl) groups. In addition, in the CFK group, the serum levels of triglycerides, total cholesterol, and low-density lipoprotein cholesterol were significantly lower and those of high-density lipoprotein cholesterol were markedly higher than the corresponding levels in the HFD and Salt groups. Moreover, CFK reduced fat cells and crown-like structures in the liver and epididymal fat tissues. The protein expression of adipo/lipogenesis-related genes in the liver and epididymal fat tissues was significantly lower (1.90–7.48-fold) in the CFK group than in the HFD and Salt groups, concurrent with upregulation of lipolysis-related genes (1.71–3.38-fold) and downregulation of inflammation-related genes (3.17–5.06-fold) in epididymal fat tissues. In addition, CFK modulated the gut microbiomes of obese mice by increasing the abundance of Bacteroidetes (7.61%), while in contrast, Firmicutes (82.21%) decreased. In addition, the presence of the Erysipelotrichaceae (8.37%) family in the CFK group decreased, while the number of beneficial bacteria of the families, Akkermansiaceae (6.74%), Lachnospiraceae (14.95%), and Lactobacillaceae (38.41%), increased. Thus, CFK exhibited an antiobesity effect through its modulation of lipid metabolism and the microbiome. [ABSTRACT FROM AUTHOR]

Abstract—Based on the special role of the β-arrestin signal protein in the processes of neuronal plasticity and receptor activation, the effects of the nootropic drugs Piracetam (2-oxo-1-pyrrodinyl-acetamide, UCB 6215, 200 mg/kg, IP), and Noopept (ethyl ether N-phenyl-acetyl-L-prolyl-glycine, GVS-111, 0.5 mg/kg, IP) were studied in mice with congenital deficiency of β-arrestin-2 (BARR2-KO mice) and in C57Bl/6 mice (wild type for the BARR2-KO, WT strain). Serotonin (5-HT)2A) and NMDA-receptors of the brain, which play an important role in cognitive processes but differ in structure and activation mechanism, were chosen as the objects of the study. Using radioligand analysis, it was found that the BARR2-KO mice differ from the C57Bl/6 in significantly higher density (Bmax) of both NMDA-receptors in the hippocampus (by 85%) and 5-HT2A-receptors in the cerebral cortex (by 54%). Interestingly, both drugs after chronic administration increased the number of NMDA-receptors in the hippocampus in both BARR2-KO (Piracetam by 76% and Noopept by 78%) and C57Bl/6 strains (Piracetam by 112% and Noopept by 49%). At the same time, the effects of both drugs on the density of serotonin 5-HT2A-receptors in BARR2-KO and C57Bl/6 mice were not the same. In particular, Piracetam caused an increase in the density of 5-HT2A-receptors in the cerebral cortex of BARR2-KO mice by 31%, whereas, in the C57Bl/6, neither Piracetam nor Noopept had any effect. Thus, the absence of the β-arrestin signaling protein in BARR2-KO mice is accompanied by an increase in the density of NMDA- and 5-HT2A-receptors in the brain. At the same time, the different effects of Piracetam and Noopept on NMDA-receptors both in the mice with congenital β-arrestin deficiency and in the strain with normal expression may indicate that this type of receptors is a common primary target for the action of nootropics of various structures. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the regulating effect of black jerusalem artichoke oligosaccharide on the blood lipid level in hyperlipidemic mice and give a preliminary investigation to the mechanism of lowering blood lipid. Methods: According to the evaluation method of auxiliary hypolipidemic function in the national standard, C57BL/6 mice were fed with high-fat diet to establish a mixed hyperlipidemia animal model. The model animals were randomly divided into MC group (MC), active control group (AC), black jerusalem artichoke oligosaccharide low, medium and high dose groups (OSL, OSM, OSH). At the same time, a blank control group (CK) was set up. There were eight mice in each group, and the dose of gavage was 0.2 mL/d for each mouse. Gavage had lasted for 46 days. CK group and MC group were given normal saline, AC group was given 1.0 mg/(kg·bw) atorvastatin, and black jerusalem artichoke oligosaccharide groups were given 0.25, 1.25, 2.50 g/(kg.bw) black jerusalem artichoke oligosaccharide solution respectively. The blood lipid level and the contents of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) in serum were detected. The morphological changes of mouse liver were observed. The expression of sterol regulatory element binding protein-1c (SREBP-1c) and peroxisome proliferator activated receptor-γ (PPAR-γ) in mouse liver were detected. Results: The triglyceride (TG), total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) in the MC group were significantly higher than those in the CK (P

Abstract Background Flight and freezing are two vital defensive behaviors that mice display to avoid natural enemies. When they are exposed to innate threats, visual cues are processed and transmitted by the visual system into the emotional nuclei and finally transmitted to the periaqueductal gray (PAG) to induce defensive behaviors. However, how the dorsal PAG (dPAG) encodes the two defensive behaviors is unclear. Methods Multi‐array electrodes were implanted in the dPAG nuclei of C57BL/6 mice. Two kinds of visual stimuli (looming and sweeping) were used to induce defensive behaviors in mice. Neural signals under different defense behaviors were recorded, and the encoding characteristics of the two behaviors were extracted and analyzed from spike firing and frequency oscillations. Finally, synchronization of neural activity during the defense process was analyzed. Results The neural activity between flight and freezing behaviors showed different firing patterns, and the differences in the inter‐spike interval distribution were mainly reflected in the 2–10 ms period. The frequency band activities under both defensive behaviors were concentrated in the theta band; the active frequency of flight was ~8 to 10 Hz, whereas that of freezing behavior was ~6 to 8 Hz. The network connection density under both defense behaviors was significantly higher than the period before and after defensive behavior occurred, indicating that there was a high synchronization of neural activity during the defense process. Conclusions The dPAG nuclei of mice have different coding features between flight and freezing behaviors; during strong looming stimulation, fast neuro‐instinctive decision making is required while encountering weak sweeping stimulation, and computable planning late behavior is predicted in the early stage. The frequency band activities under both defensive behaviors were concentrated in the theta band. There was a high synchronization of neural activity during the defense process, which may be a key factor triggering different defensive behaviors.

Histones play vital roles in chromatin function and gene transcription; however, they are very harmful in the intercellular space because they stimulate systemic inflammatory and toxic responses. Myelin basic protein (MBP) is the major protein of the axon myelin–proteolipid sheath. Antibodies–abzymes with various catalytic activities are specific features of some autoimmune diseases. IgGs against individual histones (H2A, H1, H2B, H3, and H4) and MBP were isolated from the blood of experimental-autoimmune-encephalomyelitis-prone C57BL/6 mice by several affinity chromatographies. These Abs–abzymes corresponded to various stages of EAE development: spontaneous EAE, MOG, and DNA–histones accelerated the onset, acute, and remission stages. IgGs-abzymes against MBP and five individual histones showed unusual polyreactivity in the complex formation and enzymatic cross-reactivity in the specific hydrolysis of the H2A histone. All the IgGs of 3-month-old mice (zero time) against MBP and individual histones demonstrated from 4 to 35 different H2A hydrolysis sites. The spontaneous development of EAE over 60 days led to a significant change in the type and number of H2A histone hydrolysis sites by IgGs against five histones and MBP. Mice treatment with MOG and the DNA–histone complex changed the type and number of H2A hydrolysis sites compared to zero time. The minimum number (4) of different H2A hydrolysis sites was found for IgGs against H2A (zero time), while the maximum (35) for anti-H2B IgGs (60 days after mice treatment with DNA–histone complex). Overall, it was first demonstrated that at different stages of EAE evolution, IgGs–abzymes against individual histones and MBP could significantly differ in the number and type of specific sites of H2A hydrolysis. The possible reasons for the catalytic cross-reactivity and great differences in the number and type of histone H2A cleavage sites were analyzed. [ABSTRACT FROM AUTHOR]

We studied the effects of oral administration of Afobazole in a dose of 10 mg/kg for 5 days on depressive-like behavior of male C57BL/6 mice in the tail suspension test in comparison with amitriptyline (10 mg/kg) or fluoxetine (20 mg/kg) treatment. Afobazole produced an antidepressant effect similar to amitriptyline, but inferior to fluoxetine. The σ1 receptor antagonist BD-1047 in a dose of 5 mg/kg blocked the antidepressant effect of Afobazole, which indicates the involvement of σ1 receptors in the antidepressant effect of the drug. [ABSTRACT FROM AUTHOR]

Inhibition of arginase from natural compounds has been proposed as a therapeutic approach for the treatment of cardiovascular diseases. Therefore, this study aims to evaluate the arginase inhibitory activity of isolated compounds. Based on bioactivity-guided fractionation, the ethyl acetate fraction was further subjected to column chromatography to obtain seven compounds (1-7). The chemical structures of the isolated compounds were determined by analyzing NMR spectral data and referring to data from the literature. The arginase II inhibitory activity of compounds 1-7 were investigated in vitro using an enzyme solution prepared from the kidney of anesthetized C57BL/6 mice. Compounds 1, 2, and 7 potentially inhibit arginase II activity, with IC50 values ranging from 8.1 to 14.2 µM, whereas the remaining compounds were inactive. This study is the first to assess compounds isolated from C. sappan heartwood with regard to their arginase inhibitory activity. [ABSTRACT FROM AUTHOR]

It was shown that the spontaneous development of experimental encephalomyelitis (EAE) in C57BL/6 mice occurs due to changes in the profile of bone marrow stem cells differentiation. This leads to the appearance of lymphocytes producing antibodies-abzymes that hydrolyze DNA, myelin basic protein (MBP), and histones. The activity of abzymes in the hydrolysis of these auto-antigens slowly but constantly increases during the spontaneous development of EAE. Treatment of mice with myelin oligodendrocyte glycoprotein (MOG) leads to a sharp increase in the activity of these abzymes with their maximum at 20 days (acute phase) after immunization. In this work, we analyzed changes in the activity of IgG-abzymes hydrolyzing (pA)23, (pC)23, (pU)23, and six miRNAs (miR-9-5p, miR-219a-5p, miR-326, miR-155-5p, miR-21-3p, and miR-146a-3p) before and after mice immunization with MOG. Unlike abzymes hydrolyzing DNA, MBP, and histones, the spontaneous development of EAE leads not to an increase but to a permanent decrease of IgGs activity of hydrolysis of RNA-substrates. Treatment of mice with MOG resulted in a sharp but transient increase in the activity of antibodies by day 7 (onset of the disease), followed by a sharp decrease in activity 20–40 days after immunization. A significant difference in the production of abzymes against DNA, MBP, and histones before and after mice immunization with MOG with those against RNAs may be since the expression of many miRNAs decreased with age. This can lead to a decrease in the production of antibodies and abzymes that hydrolyze miRNAs with age mice. [ABSTRACT FROM AUTHOR]

ObjectiveTo investigate the dynamic changes of autophagy in infarcted cortex at different stages after ischemic stroke, and the relationship between phospholipase D1 (PLD1) activity, autophagy, and the neurological function in mice.MethodsFirstly, twenty-one male C57BL/6 mice at age of 8 weeks were used to establish ischemic stroke models, and they were randomly divided into sham surgery and ischemic stroke groups. The groups were furtherly divided into 4-, 6-, 8-, 12-, 24-, and 72-hour groups according to the onset of ischemic strok with three mice in each group. Dynamic expression and change of autophagy-related protein LC3 in the infarcted cortex were observed using Western blotting method and immunofluorescence staining. Secondly, thirty-six male C57BL/6 mice at age of 8 weeks were randomly divided into the sham surgery group, the PBS treatment group, and different concentrations of phospholipase D activity inhibitor 5-fluoro-2-indolyl des-chlorohalopemide (FIPI) treatment groups containing 0.3, 0.9, 1.8, and 3.6 mg/kg, respectively. Each group comprised six mice. The optimal FIPI concentration and its effects on neurological function and infarcted volume were assessed by adhesive removal and whisker tests and TTC staining. Furthermore, nine male C57BL/6 mice at age of 8 weeks were divided into sham surgery group, intraperitoneal administration of PBS group, and 0.9 mg/kg FIPI group. Each group comprised three mice. The effects of FIPI on changes in autophagy-related protein LC3 were examined by Western blotting. Finally, thirty-six adult male C57BL/6 mice at age of 8 weeks were divided into sham surgery group, intraperitoneal administration of PBS group, and 0.9 mg/kg FIPI treatment groups at four time points (0, 4, 8, and 12 hours) after ischemic stroke. Furthermore, the neurological functions and infarcted volume were assessed by the adhesive removal and whisker tests as well as TTC staining with six mice in each group.ResultsThe ratio of LC3-Ⅱ/β-actin in the infarcted cortex increased, peaked at 24 hours (P＜0.05), and then gradually declined after ischemic stroke. Compared with the PBS group, the administration of 0.9 mg/kg FIPI significantly decreased the ratio of LC3-Ⅱ/β-actin (P＜0.05), reduced the infarcted area (P＜0.05), and ameliorated neurological functions (P＜0.05) more than those observed in the other concentration groups. Compared with the PBS group, in addition to 0.9 mg/kg FIPI without delay, the administration of 0.9 mg/kg FIPI at 4-, 8-, and 12-hour after ischemic stroke could also decrease the infracted volume (P＜0.05) and improve the neurological function (P＜0.05).ConclusionThe change of autophagy was the most obvious at 24-hour after ischemic stroke and inhibition of PLD1 could improve the recovery of neurological function after ischemic stroke. Meanwhile, in addition to administration of 0.9 mg/kg FIPI without delay, 4-, 8-, and 12-hour after ischemic stroke could also shrink the infracted volume and improve the neurological function. The inhibition of the PLD1 could extend the therapeutic window and provide a novel therapeutic strategy for the clinical treatment of cerebral stroke.

The exact mechanisms of the evolution of multiple sclerosis are still unknown. At the same time, the development in C57BL/6 mice of experimental autoimmune encephalomyelitis (EAE, simulating human multiple sclerosis) happens as a result of the violation of bone marrow hematopoietic stem cell differentiation profiles integrated with the production of toxic auto-antibodies splitting the basic myelin protein, myelin oligodendrocyte glycoprotein (MOG), histones, and DNA. It has been shown that IgGs from the plasma of healthy humans and autoimmune patients oxidize many different compounds due to their peroxidase (H2O2-dependent) and oxidoreductase (H2O2-independent) activities. Here, we first analyzed the changes in the relative catalase activity of IgGs from C57BL/6 mice blood plasma over time at different stages of the EAE development (onset, acute, and remission phases). It was shown that the catalase activity of IgGs of 3-month-old mice is, on average, relatively low (kcat = 40.7 min−1), but it increases during 60 days of spontaneous development of EAE 57.4-fold (kcat = 2.3 × 103 min−1). The catalase activity of antibodies increases by a factor of 57.4 by 20 days after the immunization of mice with MOG (kcat = 2.3 × 103 min−1), corresponding to the acute phase of EAE development, and 52.7–fold by 60 days after the treatment of mice with a DNA–histone complex (kcat = 2.1 × 103 min−1). It is the acceleration of the EAE development after the treatment of mice with MOG that leads to the increased production of lymphocytes synthesizing antibodies with catalase activity. All data show that the IgGs' catalase activity can play an essential role in reducing the H2O2 concentration and protecting mice from oxidative stress. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) infection persists as a leading cause of mortality and morbidity globally, especially in developing and underdeveloped countries. The prevalence of TB-DM (diabetes mellitus) is higher in low- and middle-income countries where TB and DM are most prevalent. Epidemiological data suggest that slight obesity reduces the risk of TB, whereas DM increases the risk of pulmonary TB. Diets can alter the levels of body fat mass and body mass index by regulating systemic adiposity. Earlier, using a transgenic Mtb-infected murine model, we demonstrated that loss of body fat increased the risk of pulmonary bacterial load and pathology. In the present study, we investigated whether increased adiposity alters pulmonary pathology and bacterial load using C57BL/6 mice infected with HN878 Mtb strain and fed a medium-fat diet (MFD). We analyzed the effects of MFD on the lung during acute and chronic infections by comparing the results to those obtained with infected mice fed a regular diet (RD). Histological and biochemical analyses demonstrated that MFD reduces bacterial burden by increasing the activation of immune cells in the lungs during acute infection and reduces necrosis in the lungs during chronic infection by decreasing lipid accumulation. Our data suggest that slight adiposity likely protects the host during active TB infection by regulating immune and metabolic conditions in the lungs. [ABSTRACT FROM AUTHOR]

The present study explores the molecular mechanism of anti-obesity effect of total lutein oxidized products (LOPs) in high-fat diet-induced obese C57BL/6 mice. Total LOPs (50, 100, 200 mg/kg b.wt.) were intubated for 22 weeks. Lipid profile, peroxides, AST, ALT, GST activities, lipid metabolizing enzymes/molecules, 3T3-L1 cell differentiation, TGF-β1 and p38 MAPK expressions were studied. Total LOPs at 100 mg/kg b.wt. reduced plasma and hepatic cholesterol, triglycerides, phospholipids, ALT and AST activities. FAS and CPT activities were inhibited in the liver homogenate, and epididymal WAT (eWAT). Total LOPs at 200 mg/kg b.wt. reduced HMGCoA:Mevalonate in eWAT, lipid peroxides in eWAT and liver. GST activity was high in the liver and eWAT. Total LOPs (100μg/ml) suppressed adipogenesis and decreased the accumulation of lipid droplets from two to eight days. Adiponectin was upregulated, PPAR γ, lipoprotein lipase, TGF-β1, and p38 MAPK were down-regulated. The results have shown that total LOPs are potent anti-obese molecules. ABBREVIATIONS: AIN 93G: American institute of nutrition 93 for growth; ALT: alanine transaminase; AST: aspartate transaminase; CEBPα: ccaat/enhancer binding protein α; C-DNA: complementary deoxyribonucleic acid; CPT: carnitine palmitoyl transferase; GST: glutathione-S-transferase; ELISA: enzyme-linked immune sorbent assay; FAS: fatty acid synthase; HDL: high-density lipoprotein; HFD: high-fat diet; HMG CoA: β-Hydroxy β-methylglutaryl-Coenzyme A; LDL: low-density lipoprotein; LOPs: total lutein oxidized products; LPL: lipoprotein lipase; MDA-Malonaldehyde; MTT: 3-(4,5-dimethylthiazol-2-yl)−2,5-diphenyl tetrazolium bromide; MVA: mevalonate; p38MAPK: p38 mitogen-activated protein kinases; RNA: ribonucleic acid; RTq-PCR: quantitative reverse transcription polymerase chain reaction; PPAR-γ: peroxisome proliferator-activated receptor-gamma; TGF-β1: transforming growth factor beta 1; WAT: white adipose tissue. [ABSTRACT FROM AUTHOR]

Using a model of Lewis lung carcinoma (LLC) in vitro and in vivo, we previously demonstrated increased antitumor activity in CD8+ T-cells reprogrammed with an MEK inhibitor and PD-1 blocker. In this follow-up study, we carried out the reprogramming of human CD8+ T-cells (hrT-cell) using the MEK inhibitor and PD-1 blocker and targeted LLC cells. The effects of hrT-cell therapy were studied in a mouse model of spontaneous metastasis of a solid LLC tumor. We found antimetastatic activity of hrT-cells, a decrease in the number of cancer cells and cancer stem cells in the lungs, and an increase in the number of T-cells in the blood (including effector T-cells). Thus, reprogramming of human CD8+ T-cells with an MEK inhibitor and PD-1 blocker with targeted training by tumor target cells is a potential platform for developing a new approach to targeted lung cancer therapy. [ABSTRACT FROM AUTHOR]

The aim of the study was to investigate the effect of AMP-activated protein kinase activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) on the consequences of metabolic syndrome and type 2 diabetes induced by the consumption of a high-fat diet (HFD) in male C57Bl/6 mice. Additionally, the animals from group 6 were administered Methotrexate (MTX) at a dose of 1 mg/kg in parallel with AICAR, which slows down the metabolism of AICAR. The animals were recorded with signs of metabolic syndrome and type 2 diabetes mellitus by recording their body weights, glucose and insulin levels, and the calculating HOMA-IRs. At the end of the study, at the end of the 13th week, during necropsy, the internal organs were assessed, the masses of the organs were recorded, and special attention was paid to visceral fat, assessing its amount and the mass of the fat surrounding epididymis. The biochemical parameters and histology of the internal organs and tissues were assessed. The animals showed signs of metabolic syndrome and type 2 diabetes, namely, weight gain, hyperglycemia, hyperinsulinemia, an increase in the amount and mass of abdominal fat, and metabolic disorders, all expressed in a pathological change in biochemical parameters and pathological changes in internal organs. The AICAR treatment led to a decrease in body weight, a decrease in the amount and mass of abdominal fat, and an improvement in the pathomorphological picture of internal organs. However, some hepatotoxic effects were observed when the animals, on a received standard diet (STD), were treated with AICAR starting from the first day of the study. The additional administration of MTX, an AICAR metabolic inhibitor, did not improve its efficacy. Thus, AICAR has therapeutic potential for the treatment of metabolic syndrome and type 2 diabetes. [ABSTRACT FROM AUTHOR]