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Cisplatin is a widely used cancer therapy drug that unfortunately has major side effects in normal tissues, notably nephrotoxicity in kidneys. Despite intensive research, the mechanism of cisplatin-induced nephrotoxicity remains [...]

In this article, the experimental tests were carried out to explore the performance, combustion and emissions by modifying the different nozzles hole size injectors such as (3 holes × Ø = 0.20 mm (modified)), (3 holes × Ø = 0.28 mm (Base)) and (3 holes × Ø = 0.20 mm (modified)). The experiments are performed on Kirloskar 4-stroke computerised solitary cylinder diesel engine fuelled with diesel at 1500 rpm, water-cooled direct injection diesel engine with eddy current dynamometer with the standard injection timing of 23° bTDC with an injection pressure of 210 bar was maintained constant throughout the experiment. From the results, it was pointed out that in all the three different nozzles (3 holes × Ø = 0.20 mm (modified)) improves the vaporisation, atomisation and air-fuel mixing are resulting in a shorter duration. The impressive results are seen in the performance, combustion and emissions. The only negative aspect is the NOx increasing with small orifice Nozzle Hole Diameter. [ABSTRACT FROM AUTHOR]

The edible and non-edible are the most important feedstocks is to produce biodiesel. Expressions regarding "first generation" and "second generation" of biodiesel are in popular usage. Among both the generations, the second generation is having a very good scope in the future. In this present article, the crude Mahua raw oil has 21% of free fatty acids (FFA). To minimize the FFA to less than 1%, Mahua methyl ester (MME) was produced with an open container as the reactor by two-step of esterification and transesterification methods. The first step was done by the acid catalyzed process by using 0.35 v/v i.e. 175ml of methanol and 1% v/v i.e. 5ml of concentrated H2SO4 mixed together and poured in 500ml of warmed preheated Mahua raw oil. The second step was done by alkaline catalyst process by using 0.25 v/v i.e. 125ml of methanol and 0.7% w/v i.e. 3.5gm KOH as catalyst are added in a product produced from the reaction of acid esterification. After two-step process, the crude biodiesel was washed with distilled water over again and later it was added with anhydrous CaCl2 (Calcium chloride) and heated gently at 50°C. The biodiesel with anhydrous CaCl2 was shaken vigorously and later separated from the biodiesel to obtain a clean MME biodiesel. These experimental method processes obtained a yield of 85% MME. The high FFA level for crude raw oil was improved to less than 1%. The obtained biodiesel of fuel chemical composition and properties were tested and compared the requirement of American standard for testing materials (ASTM D-6751). [ABSTRACT FROM AUTHOR]

Since MIT’s bold announcement of the OpenCourseWare initiative in 2001, the content of over 700 of its courses have been published on the Web and made available for free to the world. Important infrastructure initiatives have also been launched recently with a view to enabling the sustainable implementation of these educational programmes, through strengthening organizational capacity as well as through building open, standards‐based technology. Each of these initiatives point to a rich palette of transformational possibilities for education; together with the growing open source movement, they offer glimpses of a sustainable ecology of substantial and quality educational resources. This discussion piece will highlight some of the educational opportunity presented by MIT’s current information technology‐enabled educational agenda and related initiatives, along with their strategic underpinnings and implications. It will address various dimensions of their impact on the form and function of education. It will examine how these ambitious programmes achieve a vision characterized by an abundance of sustainable, transformative educational opportunities, not merely pervasive technology. [ABSTRACT FROM AUTHOR]

Abstract Background and Objective Systemic chronic inflammation is linked to metabolic syndrome, type-2 diabetes, and heart disease. Lipopolysaccharide (LPS), a Gram negative microbial product, triggers inflammation through toll-like-receptor-4 (TLR-4) signaling. It has been reported that dietary fatty acids also modulate inflammation through TLR-4. We investigated whether fish oil (FO) rich diet in comparison to saturated fat (SF) rich diet would confer protection from pathologies induced by LPS. Methods Twenty C57BL/6 mice were divided into two groups. One group received FO-diet and other received SF-diet ad libitum for 60 days. Diets were isocaloric containing 45% energy from fat. After 60-days of feeding, blood was collected after overnight fast. Mice were allowed to recover for 4-days, fasted for 5-hours, challenged with 100 ng/mL of LPS intraperitonially, and bled after 2-hours. After 7-days of recuperation, mice were challenged with 500 ng/mL of LPS intraperitonially and observed for physical health. Results Food intake was similar in FO- and SF-fed mice. FO-fed mice compared to SF-fed mice had significantly less body weight gain (P = 0.005), epididymal fat weight (P = 0.005), fasting blood glucose (70.8 vs 83.3 ng/dL; P < 0.05), HOMA-IR (5.0 vs 13.6; P < 0.019), and serum cholesterol (167 vs 94 mg/dL; P < 0.05). When challenged with LPS, FO-fed mice had significantly lower serum IL-1β compared to SF-fed mice (2.0 vs 30.0 pg/mL; P < 0.001). After LPS-challenge, SF-fed mice had higher mortality, lost more body weight, and had greater decrease in blood glucose compared to FO-fed mice. Conclusion Overall, FO-diet compared to SF-diet offered protection against deleterious effects of LPS in mice.

Abstract Background Toll-like receptor-4 (TLR4) triggers inflammatory signaling in response to microbial lipoploysaccharide. It has been reported that loss of TLR4 protected against saturated fat-induced inflammation and insulin resistance. It is not known whether loss of TLR4 function offers protection against trans fat (TF) induced obesity, inflammation, and insulin resistance. We investigated whether mice with loss of function mutation in TLR4 were resistant to TF-induced pathologies such as obesity, inflammation, hyperglycemia, and hyperinsulinemia. Methods C57BL/6j and C57BL/10 mice were cross bred to generate TLR4 mutant and wild type (WT). TLR4 mutant (n = 12) and WT (n = 12) mice were fed either low fat (LF) (13.5% fat energy) or high TF diets (60% fat energy) for 12 weeks. In vitro experiments were conducted on mouse macrophage cells (RAW 264.7 and J774A.1) to investigate whether elaidic (trans 18:1) or oleic acid (cis 18:1) would upregulate inflammatory markers. Results TLR4 mutant mice were ~26.4% heavier than WT mice. In both genotypes, mice that received TF diet were significantly heavier than those mice that received LF diet (P < 0.01). TLR4 mutant mice compared to WT mice had significantly higher fasting blood glucose, serum insulin, insulin resistance, serum leptin, and serum cholesterol when they received TF diet (P < 0.05). No upregulation of iNOS or COX2 in response to either elaidic or oleic acid in macrophage cells was observed. Conclusions Loss of function mutation in TLR4 not only did not protect mice from TF-induced obesity, hyperglycemia, hyperinsulinemia, and hypercholesterolemia but also exacerbated the above pathologies suggesting that functional TLR4 is necessary in attenuating TF-induced deleterious effects. It is likely that TF induces pathologies through pathways independent of TLR4.

Some novel substituted pyramidinopyrazoles and pyrimidinotriazoles have been synthesized by using 6-anisyl-5-cyano-2-hydrazino-3-N-methyl-3, 4-dihydropyrimidine-4-one as the starting material. Structures of these compounds have been established by IR, 1H NMR, Mass and elemental analysis data and have been evaluated for their antimicrobial activity. Significant antimicrobial activity was observed for some members of these series.

Aim: To assess the functional status of CYP3A4 substrate in experimental induced hepatotoxicity treated with N-acetyl L-cysteine and Green tea extract for a period of 14 days in rats. Materials and methods: Twenty four Wistar rats were divided into four groups of 6 rats each and induced hepatotoxicity with acetaminophen (500 mg/Kg po once daily for 3 days) in 3 groups. Group 1: Normal control, Group 2, 3 and 4 was administered distilled water (5 ml/kg po), N-acetyl L-cysteine (NAC; 300 mg/Kg po once daily) and Green tea extract (GTE; 100 mg/Kg po once daily), respectively subsequently for 11 days from the last dose of acetaminophen. Atorvastatin (10 mg/kg po) was administered on 15th day (24 h after conclusion of treatment schedule) in all the groups. The PK studies were conducted in order to evaluate the CYP3A4 activity using the specific substrate atorvastatin in all the groups. Results: Cmax, t1/2, AUC0-t and MRT of groups 2 and 4 were significantly (p<0.05) increased, while the total body clearance was significantly (p<0.05) decreased compared to normal control after single dose administration of atorvastatin. The kinetic profile of NAC-treated group 3 was comparable to group 1. Conclusion: All the pharmacokinetic parameters of atorvastatin revealed similar values when hepatotoxic control was compared to Green tea extract treated group, while N-acetyl L-cysteine treated group revealed significant alterations in the kinetic profile that support the functional status of CYP3A4 and hence suggesting hepatoprotective potential of NAC. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) affects more women than men. Although women live longer than men, it is not longevity alone, but other factors, including metabolic changes, that contribute to the higher risk of AD in women. Metabolic pathways have been implicated in AD progression, but studies to date examined targeted pathways, leaving many metabolites unmeasured. Sex is often a neglected biological variable, and most metabolomic studies were not designed to investigate sex differences in metabolomic profiles. Here, we performed untargeted metabolomic profiling of sera from male and female patients with mild cognitive impairment (MCI), a common precursor to AD, and matched controls. We discovered significant metabolic changes in individuals with MCI, and found several pathways that were strongly associated with sex. Peptide energy metabolism demonstrated sexual dimorphism. Lipid pathways exhibited the strongest differences between female and male MCI patients, including specific phosphatidylcholine lipids, lysophospholipids, long-chain fatty acids, and monoacylglycerols. 1-palmitoleoyl glycerol and 1-arachidonoyl glycerol were higher in female MCI subjects than in male MCI subjects with no differences between control males and females. Conversely, specific dicarboxylic fatty acids were lower in female MCI subjects than male MCI subjects. In cultured astrocytes, 1-arachidonoyl glycerol promoted phosphorylation of the transcriptional regulator sphingosine kinase 2, which was inhibited by the transient receptor potential vanilloid 1 receptor antagonists, as well as chromatin remodelling. Overall, we identified novel sex-specific metabolites in MCI patients that could serve as biomarkers of MCI in both sexes, help further define AD etiology, and reveal new potential prevention strategies for AD., Competing Interests: Declaration of competing interest Paul E. Schulz is a consultant and speaker for Eli Lilly, Eisai, and Acadia Pharmaceuticals., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Although the liver is the largest metabolic organ in the body, it is not alone in functionality and is assisted by "an organ inside an organ," the gut microbiota. This review attempts to shed light on the partnership between the liver and the gut microbiota in the metabolism of macronutrients (i.e., proteins, carbohydrates, and lipids). All nutrients absorbed by the small intestines are delivered to the liver for further metabolism. Undigested food that enters the colon is metabolized further by the gut microbiota that produces secondary metabolites, which are absorbed into portal circulation and reach the liver. These microbiota-derived metabolites and co-metabolites include ammonia, hydrogen sulfide, short-chain fatty acids, secondary bile acids, and trimethylamine N-oxide. Further, the liver produces several compounds, such as bile acids that can alter the gut microbial composition, which can in turn influence liver health. This review focuses on the metabolism of these microbiota metabolites and their influence on host physiology. Furthermore, the review briefly delineates the effect of the portosystemic shunt on the gut microbiota-liver axis, and current understanding of the treatments to target the gut microbiota-liver axis., (© 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Global prevalence of hypertension is on the rise, burdening healthcare, especially in developing countries where infectious diseases, such as malaria, are also rampant. Whether hypertension could predispose or increase susceptibility to malaria, however, has not been extensively explored. Previously, we reported that hypertension is associated with abnormal red blood cell (RBC) physiology and anemia. Since RBC are target host cells for malarial parasite, Plasmodium , we hypothesized that hypertensive patients with abnormal RBC physiology are at greater risk or susceptibility to Plasmodium infection. To test this hypothesis, normotensive (BPN/3J) and hypertensive (BPH/2J) mice were characterized for their RBC physiology and subsequently infected with Plasmodium yoelii ( P. yoelii ), a murine-specific non-lethal strain. When compared to BPN mice, BPH mice displayed microcytic anemia with RBC highly resistant to osmotic hemolysis. Further, BPH RBC exhibited greater membrane rigidity and an altered lipid composition, as evidenced by higher levels of phospholipids and saturated fatty acid, such as stearate (C18:0), along with lower levels of polyunsaturated fatty acid like arachidonate (C20:4). Moreover, BPH mice had significantly greater circulating Ter119 + CD71 + reticulocytes, or immature RBC, prone to P. yoelii infection. Upon infection with P. yoelii , BPH mice experienced significant body weight loss accompanied by sustained parasitemia, indices of anemia, and substantial increase in systemic pro-inflammatory mediators, compared to BPN mice, indicating that BPH mice were incompetent to clear P. yoelii infection. Collectively, these data demonstrate that aberrant RBC physiology observed in hypertensive BPH mice contributes to an increased susceptibility to P. yoelii infection and malaria-associated pathology., Competing Interests: The authors declare that they have no conflict of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Physiological Society.)

Background & Aims: Hepatocellular carcinoma (HCC) is a male-dominant disease, but targeted sex hormone therapies have not been successful. Bile acids are a potential liver carcinogen and are biomolecules with hormone-like effects. A few studies highlight their potential sex dimorphism in physiology and disease. We hypothesized that bile acids could be a potential molecular signature that explains sex disparity in HCC., Methods & Results: We used the farnesoid X receptor knockout (FxrKO) mouse model to study bile acid-dependent HCC. Temporal tracking of circulating bile acids determined more than 80% of FxrKO females developed spontaneous cholemia (ie, serum total bile acids ≥40 μmol/L) as early as 8 weeks old. Opposingly, FxrKO males were highly resistant to cholemia, with ∼23% incidence even when 26 weeks old. However, FxrKO males demonstrated higher levels of deoxycholate than females. Compared with males, FxrKO females had more severe cholestatic liver injury and further aberrancies in bile acid metabolism. Yet, FxrKO females expressed more detoxification transcripts and had greater renal excretion of bile acids. Intervention with CYP7A1 (rate limiting enzyme for bile acid biosynthesis) deficiency or taurine supplementation either completely or partially normalized bile acid levels and liver injury in FxrKO females. Despite higher cholemia prevalence in FxrKO females, their tumor burden was less compared with FxrKO males. An exception to this sex-dimorphic pattern was found in a subset of male and female FxrKO mice born with congenital cholemia due to portosystemic shunt, where both sexes had comparable robust HCC., Conclusions: Our study highlights bile acids as sex-dimorphic metabolites in HCC except in the case of portosystemic shunt., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Studies in rodents suggest that inulin supplements may be carcinogenic. We present a case implicating that this risk extends to humans. A healthy male from a family lacking history of cancer had his first cancer-screening colonoscopy at age 56. No intestinal polyps/abnormalities were detected. A second colonoscopy, performed 7 years later, revealed a tumor in the cecum, with evidence of metastasis to lymph nodes. The only known change in patient's lifestyle during that seven-year period was the addition of 4g of inulin powder as a daily supplement during the last 2 years. Such inulin consumption is a plausible contributor to his disease., (© 2024 The Authors.)

Sporadic occurrence of congenital portosystemic shunt (PSS) at a rate of ∼1 out of 10 among C57BL/6 J mice, which are widely used in biomedical research, results in aberrancies in serologic, metabolic, and physiologic parameters. Therefore, mice with PSS should be identified as outliers in research. Accordingly, we sought methods to, reliably and efficiently, identify PSS mice. Serum total bile acids ≥ 40 µm is a bona fide biomarker of PSS in mice but utility of this biomarker is limited by its cost and invasiveness, particularly if large numbers of mice are to be screened. This led us to investigate if assay of urine might serve as a simple, inexpensive, noninvasive means of PSS diagnosis. Metabolome profiling uncovered that Krebs cycle intermediates, that is, citrate, α-ketoglutarate, and fumarate, were strikingly and distinctly elevated in the urine of PSS mice. We leveraged the iron-chelating and pH-lowering properties of such metabolites as the basis for 3 urine-based PSS screening tests: urinary iron-chelation assay, pH strip test, and phenol red assay. Our findings demonstrate the feasibility of using these colorimetric assays, whereby their readout can be assessed by direct observation, to diagnose PSS in an inexpensive, rapid, and noninvasive manner. Application of our urinary PSS screening protocols can aid biomedical research by enabling stratification of PSS mice, which, at present, likely confound numerous ongoing studies., Competing Interests: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Physiological Society.)

Aging is a prominent risk factor for many neurodegenerative disorders, such as Alzheimer's disease (AD). Alzheimer's disease is characterized by progressive cognitive decline, memory loss, and neuropsychiatric and behavioral symptoms, accounting for most of the reported dementia cases. This disease is now becoming a major challenge and burden on modern society, especially with the aging population. Over the last few decades, a significant understanding of the pathophysiology of AD has been gained by studying amyloid deposition, hyperphosphorylated tau, synaptic dysfunction, oxidative stress, calcium dysregulation, and neuroinflammation. This review focuses on the role of non-canonical secondary structures of DNA/RNA G-quadruplexes (G4s, G4-DNA, and G4-RNA), G4-binding proteins (G4BPs), and helicases, and their roles in aging and AD. Being critically important for cellular function, G4s are involved in the regulation of DNA and RNA processes, such as replication, transcription, translation, RNA localization, and degradation. Recent studies have also highlighted G4-DNA's roles in inducing DNA double-strand breaks that cause genomic instability and G4-RNA's participation in regulating stress granule formation. This review emphasizes the significance of G4s in aging processes and how their homeostatic imbalance may contribute to the pathophysiology of AD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Vijay Kumar, Morales and Tsvetkov.)

Background: HCC is the most common primary liver cancer and a leading cause of cancer-related mortality. Gut microbiota is a large collection of microbes, predominately bacteria, that harbor the gastrointestinal tract. Changes in gut microbiota that deviate from the native composition, that is, "dysbiosis," is proposed as a probable diagnostic biomarker and a risk factor for HCC. However, whether gut microbiota dysbiosis is a cause or a consequence of HCC is unknown., Methods: To better understand the role of gut microbiota in HCC, mice deficient of toll-like receptor 5 (TLR5, a receptor for bacterial flagellin) as a model of spontaneous gut microbiota dysbiosis were crossed with farnesoid X receptor knockout mice (FxrKO), a genetic model for spontaneous HCC. Male FxrKO/Tlr5KO double knockout (DKO), FxrKO, Tlr5KO, and wild-type (WT) mice were aged to the 16-month HCC time point., Results: Compared with FxrKO mice, DKO mice had more severe hepatooncogenesis at the gross, histological, and transcript levels and this was associated with pronounced cholestatic liver injury. The bile acid dysmetabolism in FxrKO mice became more aberrant in the absence of TLR5 due in part to suppression of bile acid secretion and enhanced cholestasis. Out of the 14 enriched taxon signatures seen in the DKO gut microbiota, 50% were dominated by the Proteobacteria phylum with expansion of the gut pathobiont γ-Proteobacteria that is implicated in HCC., Conclusions: Collectively, introducing gut microbiota dysbiosis by TLR5 deletion exacerbated hepatocarcinogenesis in the FxrKO mouse model., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

The single largest contributor to human mortality is cardiovascular disease, the top risk factor for which is hypertension (HTN). The last two decades have placed much emphasis on the identification of genetic factors contributing to HTN. As a result, over 1,500 genetic alleles have been associated with human HTN. Mapping studies using genetic models of HTN have yielded hundreds of blood pressure (BP) loci but their individual effects on BP are minor, which limits opportunities to target them in the clinic. The value of collecting genome-wide association data is evident in ongoing research, which is beginning to utilize these data at individual-level genetic disparities combined with artificial intelligence (AI) strategies to develop a polygenic risk score (PRS) for the prediction of HTN. However, PRS alone may or may not be sufficient to account for the incidence and progression of HTN because genetics is responsible for <30% of the risk factors influencing the etiology of HTN pathogenesis. Therefore, integrating data from other nongenetic factors influencing BP regulation will be important to enhance the power of PRS. One such factor is the composition of gut microbiota, which constitute a more recently discovered important contributor to HTN. Studies to-date have clearly demonstrated that the transition from normal BP homeostasis to a state of elevated BP is linked to compositional changes in gut microbiota and its interaction with the host. Here, we first document evidence from studies on gut dysbiosis in animal models and patients with HTN followed by a discussion on the prospects of using microbiota data to develop a metagenomic risk score (MRS) for HTN to be combined with PRS and a clinical risk score (CRS). Finally, we propose that integrating AI to learn from the combined PRS, MRS and CRS may further enhance predictive power for the susceptibility and progression of HTN., Competing Interests: The authors declare none., (© The Author(s) 2023.)