Male Liver Research Articles

LY354740, an agonist of glutamatergic metabotropic receptor mGlu2/3 increases the cytochrome P450 2D (CYP2D) activity in the frontal cortical area of rat brain.

Our previous studies indicated that changes in the functioning of the brain glutamatergic system involving the NMDA receptor may affect cytochrome P450 2D (CYP2D) in the brain. Since CYP2D may contribute to the metabolism of neurotransmitters and neurosteroids engaged in the pathology and pharmacology of neuropsychiatric diseases, in the present work we have investigated the effect of compound LY354740, an agonist of glutamatergic metabotropic receptor mGlu2/3, on brain and liver CYP2D. The activity (high performance liquid chromatography with fluorescence detection) and protein levels (Western blotting) of CYP2D were measured in the microsomes from the liver and different brain areas of male Wistar rats after 5day-treatment with LY354740 (10mg/kg ip). The results were analyzed statistically using Student's t-test. Among the investigated brain areas, the highest CYP2D activity was found in the cerebellum and brainstem, which exceeded that in the thalamus, cortex, hippocampus and frontal cortex. The mGlu2/3 receptor agonist LY354740 administered for five consecutive days significantly increased the protein level and activity of CYP2D in the frontal cortex. Such a tendency was also observed in the other brain areas. LY354740 did not affect the CYP2D activity in the liver. Repeated administration of the mGlu2/3 receptor agonist, the compound LY354740 specifically increases the protein level and activity of CYP2D in the frontal cortex, which may accelerate dopamine synthesis via an alternative CYP2D-mediated route in the mesocortical dopaminergic pathway, and thus may contribute to the beneficial pharmacological effect on negative symptoms of schizophrenia.

Distribution of progesterone receptors and the membrane component of progesterone receptor in various organs and tissues of male and female rats

Progesterone regulates reproductive processes and affects many functions of various non-reproductive organs. Its effects in mammals and humans are mediated by nuclear (nPRs) and membrane progesterone receptors (mPRs). The action of progesterone through different types of receptors may differ significantly and has tissue specific features. The expression of known types and subtypes of progesterone receptors in the tissues of male and female rats has been studied fragmentarily. The purpose of our work was to study the expression of five mPRs genes, as well as the nPRs gene and the membrane component of the progesterone receptor PGRMC I in the reproductive organs and in 17 non-reproductive tissues of male and female rats using reverse transcription followed by real-time PCR. In this study, it was shown that a high level of nPRs gene expression in rats is found not only in reproductive organs of females (uterus, ovary, mammary glands), but also in seminal vesicles of males, in the brain and trachea of both sexes, in blood vessels, and in the pancreas of females. The highest level of expression of mPRs genes of all subtypes was found in the testes, while expression of the gene encoding nPRs was practically undetectable in them. Expression of genes encoding mPRs was also detected in the liver and spleen of male and female rats, while expression of the gene encoding nPRs was at background levels. Virtually no expression of nPRs, mPRs, and membrane component of progesterone receptor (PGRMC I) genes was detected in muscle, and its level was very low in the heart in animals of both sexes. We found sex-specific differentiation of nuclear and membrane receptor mRNA levels in rats in non-reproductive tissues, characterized by a predominance of nPRs transcripts and three subtypes of mPRs (α, β, δ) in females and two subtypes of mPRs (γ, ε) in males. Data on the presence of progesterone receptors in tissues not involved in reproduction confirm the effect of progesterone on these organs. High levels of mRNA for various progesterone receptors in the tissues of male rats, such as the pancreas, lungs, kidney, and trachea, indicate an important physiological role of progestins not only in females, but also in males, which is still poorly understood. The work also discusses the known functions of progesterone receptors in the tissues studied.

Estrogen receptors regulate sex disparity in the immune responses during zebrafish liver regeneration following partial hepatectomy

Immune responses play crucial roles in liver regeneration following partial hepatectomy (PH). Previous studies using the rodent PH models have shown that liver regeneration following PH has sex disparity. However, the sex disparity in the immune responses to PH and its relationship with sex-biased liver regeneration has not been investigated yet. In the current study, we applied the zebrafish PH model to study these issues and found that male zebrafish have earlier immune responses than female zebrafish following PH. By depleting macrophages before PH, we confirmed that liver regeneration following PH in zebrafish requires the participation of macrophages. In addition, activation of estrogen receptors inhibited the upregulation of inflammatory factors in male livers and reduced hepatocyte proliferation at the early stage of PH-induced liver regeneration. Therefore, the male-biased liver regeneration and immune responses in zebrafish following PH could be regulated by estrogen receptor activities.

Exploring In Vitro Antibiofilm Potential and In Vivo Toxicity Assessment of Gold Nanoparticles.

In this study, biogenically synthesized AuNPs were first characterized via UV visible spectroscopy, SEM, XRD, and FTIR followed by toxicity evaluation using mice model. UV-visible spectroscopy of biogenic AuNPs showed peaks at 540-549 nm, while FTIR spectrum showed various functional groups involving O-H, Amide I, Amide II, O-H, C-H groups, and so on. SEM showed the size variation from 30 to 60 nm. Antibacterial potential against pathogenic isolates showed bigger ZOI (31.0 mm) against Pseudomonas aeruginosa AuNPs. Antibiofilm activity showing up to 100% inhibition at 90 µg mL-1 concentration of AuNPs. Toxicity evaluation showed LD50 as 70 mg kg-1. Exposure to AuNPs caused significant changes in the levels of serum AST (p < 0.05) at 100-150 mg kg-1 of AuNPs exposure. Histopathology of male albino mice kidney and liver revealed that mice exposed to maximum concentration of AuNPs showed necrosis, cell distortion, and hepatocytes detachment. Present study showed that biologically synthesized AuNPs possess effective antimicrobial and biofilm inhibitory potential. AuNPs strong bactericidal effect even at lower concentration suggest that NPs could have excellent potential for combating pathogens. In conclusion, nanotechnology may revolutionize human life and medical industry by developing innovative drugs with the potential to treat diseases in shorter and noninvasive time period. Hence, in vitro biosafety and experimental observations followed by in vivo outcomes are crucial in shifting the novel therapeutics into medical practice thus leading further into their future development.

The Effect of Copper Nanoparticles on Liver Metabolism Depends on the Type of Dietary Fiber.

A diet enriched with copper nanoparticles (CuNPs) exhibits a wide range of effects on liver metabolism, both positive and negative. Dietary fibers are the key components that may affect the absorption of minerals, including copper, and change their impact on organisms. Therefore, this study investigated whether and how supplementation with different sources of dietary fiber (cellulose, pectin, inulin, and psyllium) affects the function of CuNPs in the liver of male Wistar rats. The results showed that CuNPs at different doses had varying effects on lipid metabolism and inflammation in the liver. Specifically, higher doses of CuNPs were associated with increased lipid accumulation and the activation of pro-inflammatory mechanisms. However, combining CuNPs with dietary fibers, such as psyllium and inulin, was beneficial in mitigating the effects of the examined nanoparticles, leading to reduced fat, cholesterol, and triglycerides in the liver. Combining psyllium with CuNPs showed the most substantial effect on liver metabolism and inflammation parameters. Furthermore, hepatic histology analyses showed that adding psyllium to the diet with CuNPs reduces changes associated with fat accumulation and mononuclear cell infiltration. The observed beneficial changes in the liver may have been related to a reduction in the gene expression level of sterol regulatory element-binding protein 1 and peroxisome proliferator-activated receptor gamma and cyclooxygenase-2. In conclusion, enriching the diet with dietary fibers such as psyllium can regulate the action of CuNPs, thereby improving lipid metabolism and reducing inflammation in the liver.

Beta vulgaris L. beetroot protects against iron-induced liver injury by restoring antioxidant pathways and regulating cellular functions

Beta vulgaris L. is a root vegetable that is consumed mainly as a food additive. This study aimed to describe the protective effect of B. vulgaris on Fe2+-mediated oxidative liver damage through in vitro, ex vivo, and in silico studies to establish a strong rationale for its protective effect. To induce oxidative damage, we incubated the livers of healthy male rats with 0.1 mM FeSO4 to induce oxidative injury and coincubated them with an aqueous extract of B. vulgaris root (BVFE) (15–240 µg/mL). Induction of liver damage significantly (p < .05) decreased the levels of GSH, SOD, CAT, and ENTPDase activities, with a corresponding increase in MDA and NO levels and Na+/K+ ATPase, G6 Pase, and F-1,6-BPase enzyme activities. BVFE treatment (p < .05) reduced these levels and activities to almost normal levels, with the most prominent effects observed at 240 µg/mL BVFE. An HPLC investigation revealed sixteen compounds in BVFE, with quercetin being the most abundant. Chlorogenic acid and iso-orientation showed the highest binding affinities for G6 Pase and Na+/K + ATPase, respectively. These findings suggest that B. vulgaris can protect against Fe2+-mediated liver damage by suppressing oxidative stress and cholinergic and purinergic activities while regulating gluconeogenesis. Overall, the hepatoprotective activity of this extract might be driven by the synergistic effect of the identified compounds and their probable interactions with target proteins.

Lower-dose vs high-dose oral bisphenol S action of lipid metabolism in liver of male SD rat via mediating different SREBP isoforms

Bisphenol S (BPS) is commonly used for the industrial production of thermal paper, polycarbonate plastics, epoxy resins and other materials. Studies have reported that BPS can lead to triglyceride (TAG) or/and cholesterol (CHO) accumulation in the liver in zebrafish and mice, but the reasons for the different types of lipids that accumulate in the liver following BPS exposure are unclear. Here, the influences of lower-dose (10 mg/kg body weight/day) and high-dose (50 mg/kg body weight/day) BPS exposure to male SD rats on the accumulation of different lipids in the liver were explored. The results indicated that BPS treatment increased the levels of acetyl-CoA and glycogen in the liver. A lower dose of BPS upregulated the mRNA and protein expression levels of sterol regulatory element-binding protein 1 (srebp1), which is involved in the de novo synthesis of TAG in the liver, thus promoting the synthesis of glycerides (diacetylglyceride and TAG). However, a higher dose of BPS induced CHO accumulation, but inhibited the mRNA expression of genes (i.e., srebp2, hmgcr and hmgcs) involved in the de novo synthesis of CHO in the liver. Excessive accumulation of glycerides and CHO led to destruction of the physiological structure of rat liver, causing disorders in liver function. Our data provide new insight into the different mechanisms by which glyceride and CHO accumulate in the liver after BPS exposure.

Age- and sex-related variations of normal spleen T1rho and the more stable liver T1rho to spleen T1rho ratio.

We aim to evaluate the potential age- and sex-related variations of normative values of spleen T1rho.Two T1rho sequences were used, with one based on fast spin echo sequence (FSE) and the other based on gradient echo sequence (GRE). Spleen and liver FSE T1rho values were measured in 52 healthy volunteers (36 females, 16 males), and spleen and liver GRE T1rho values were measured in 14 healthy volunteers (6 females, 8 males).For FSE data, an age-related decreasing trend of spleen T1rho was noted for both females and males. This trend was consistent with female liver T1rho values, while such a trend was not noted for male liver T1rho. Females had a higher T1rho than males, both for the spleen (92.8 vs 77.3 ms, p<0.0001) and for the liver (44.2 vs. 38.9 ms, p<0.0001, FSE data). The spleen T1rho value was approximately double the liver T1rho value. The spleen T1rho and liver T1rho were positively correlated, both for FSE data (r=0.611) and GRE data (r=0.541). When the spleen T1rho was used to normalize the liver T1rho, the ratio of T1rholiver/T1rhospleen largely removed the sex and age effect. The spleen T1rho in menstrual phase women was 10.7% lower (p=0.012) than that of non-menstrual phase women, while the liver T1rho in menstrual phase women was 3.8% lower than that of non-menstrual phase women.Since women in the menstrual phase tend to have lower body iron, the fact that both liver T1rho and spleen T1rho are shorter among women in the menstrual phase than women in the non-menstrual phase indicates that liver and spleen T1rho physiological variations may not be dominantly affected by the iron content of the tissue. If a pathology has only affected the liver while the spleen is normal, there is a possibility the ratio T1rholiver/T1rhospleen may offer better characterization of liver pathologies. · There is an age-related decreasing trend of spleen T1rho.. · Females have a higher spleen T1rho than males.. · The spleen T1rho value is approximately double the liver T1rho value.. · Spleen T1rho and liver T1rho are positively correlated.. · Wáng YXJ, Yu W-L, Deng M. Age- and sex-related variations of normal spleen T1rho and the more stable liver T1rho to spleen T1rho ratio. Fortschr Röntgenstr 2024; DOI 10.1055/a-2428-7409.

Metabolic dysfunction-associated steatotic liver disease exhibits sex-specific microbial heterogeneity within intestinal compartments.

Evidence suggests that the gastrointestinal microbiome plays a significant role in the biology of metabolic dysfunction-associated steatotic liver disease (MASLD). However, it remains unclear whether disparities in the gut microbiome across intestinal tissular compartments between the sexes lead to MASLD pathogenesis. Sex-specific analyses of microbiome composition in two anatomically distinct regions of the gut, the small intestine and colon, were performed using an experimental model of MASLD. The study involved male and female spontaneously hypertensive rats and the Wistar-Kyoto control rat strain, which were fed either a standard chow diet or a high-fat diet for 12 weeks to induce MASLD (12 rats per group). High-throughput 16S sequencing was used for microbiome analysis. There were significant differences in the overall microbiome composition of male and female rats with MASLD, including variations in topographical gut regions. The beta diversity of the jejunal and colon microbiomes was higher in female rats than in male rats (PERMANOVA p-value=0.001). Sex-specific analysis and discriminant features using LEfSe showed considerable variation in bacterial abundance, along with distinct functional properties, in the jejunum and colon of animals with MASLD. Significantly elevated levels of lipopolysaccharide and protein expression of Toll-like receptor 4 were observed in the livers of male rats with MASLD compared with their female counterparts. This study uncovered sexual dimorphism in the gut microbiome of MASLD and identified microbial heterogeneity within intestinal compartments. Insights into sex-specific variations in gut microbiome composition could facilitate customised treatment strategies.

In Vivo Study of Physiological, and Histological Effects of Mercury Oxide on Liver and Kidney in Male Wistar Rats

In Vivo Study of Physiological, and Histological Effects of Mercury Oxide on Liver and Kidney in Male Wistar Rats

Sex hormone receptors, calcium-binding protein and Yap1 signaling regulate sex-dependent liver cell proliferation following partial hepatectomy.

Partial hepatectomy (PH) is commonly used to treat patients with hepatocellular carcinoma. The recovery of patients from PH depends on the initiation of liver regeneration, a process that mainly relies on liver cell proliferation. As sex affects the human liver regeneration progress, we investigated sex disparity in PH-induced liver regeneration in adult zebrafish. We found that, after PH, males began liver regeneration earlier than females in terms of liver cell proliferation and liver mass recovery, and this was associated with earlier activation of Yap1 signaling in male than female livers. We also found that androgen receptors regulated the sex-biased liver regeneration in a Yap1-dependent manner and that activated estrogen receptors are responsible for the later onset of female hepatocyte proliferation. Furthermore, we identified that S100A1, a calcium-binding protein, regulates the sex disparity in liver regeneration, as heterozygous S100A1 knockout inhibited Yap1 activity in male livers and delayed hepatocyte proliferation in males following PH. Thus, multiple pathways and/or their interplays contribute to the sex disparity in liver regeneration, suggesting that sex-biased therapeutic strategies are required for patients who have received PH-based therapies.

Estimation of Radiation Equivalent Dose and Lifetime Attributable Risk from Pediatric CAP CT Examination

Aim: This study aims to estimate equivalent doses (EqDs) and life attributable risks (LARs) for pediatric patients who underwent chest–abdominal–pelvic (CAP) CT examinations in Madinah, Saudi Arabia. Methodology: This retrospective study collected data from 120 pediatric patients who underwent CAP CT examinations. The data were categorized by the age and gender of the pediatric patients. Then, the EqDs were computed using the NCICT (National Cancer Institute dosimetry system for computed tomography) program, and LARs were estimated from the equivalent dose (EqD) results using age- and gender-specific cancer risk models found in the Committee on the Biological Effects of Ionizing Radiation (BEIR) VII Phase 2 (2006). Results: The EqD range was 0.9 to 7.55 mSv for the prostate and colon (males and females), respectively. LARs for female breast and lung cancers were considered to have the highest values among the age groups. Nevertheless, LARs of the colon, liver, and leukemia cancers were higher for males than females. The LAR range of cancer incidence was 0.6 to 63.1 per 100,000 cases for prostate (aged 10–≤15 years) and breast (females aged 1≤–&lt;5 years), respectively. The LAR range of cancer mortality was 0.1 to 41.9 per 100,000 cases for prostate (aged 10–≤15 years) and lung (females aged 1≤–&lt;5 years). Conclusions: LARs of all cancer incidence and mortality from CAP CT examination were higher for pediatric females than males (with an average of 54%). This highlights the importance of considering pediatric patient gender and implementing optimization and protective measures in CAP CT examinations. LARs of breast and lung (for females) and colon (for males) cancers were found to have the highest values among the age groups. However, LARs of cancer incidence and mortality for colon, liver, and leukemia for males were higher than those for females.

Endocrine-Disruptive Effects of Adenylate Cyclase Activator Forskolin: In Vitro and In Vivo Evidence.

Forskolin (FSK) is a potent adenylate cyclase activator and may display endocrine-disruptive effects via the disruption of steroidogenesis. Here, we tested this hypothesis by use of the in vitro H295R steroidogenesis assay and the in vivo long-term medaka (Oryzias latipes) exposure assay. The results from the H295R assay demonstrated that the transcriptional levels of a series of genes involved in steroidogenesis, including HSD3B2, CYP11A, CYP11B2, CYP17, CYP19, and CYP21, were remarkably up-regulated. Meanwhile, the productions of estrogens (17β-estradiol (17β-E2) and estrone (E1)) and progestins (progesterone (PGT) and 17-hydroxyprogesterone (17-HPT)) were significantly increased, and those of androgens (androstenedione (ADD) and testosterone (TTR)) were significantly inhibited. After waterborne exposure of medaka to FSK for 100 days, the gene expressions of HMGR, HSD17B1, CYP17B, CYP19A, and CYP21A were significantly enhanced in the gonads of male medaka. 17β-E2 was remarkably induced, although without statistical significance. In addition, the biomarker genes for estrogenicity, including VTG-I, VTG-II, CHG-H, and CHG-L, were significantly induced in male medaka livers. Pathological damage to their gonads was further identified. Therefore, the results demonstrated that FSK modulates the transcriptions of steroidogenesis genes and alters hormone levels in vitro and in vivo, which is a mark of endocrine disruption in organisms.

Zinc Sulfate and α-tocopherol Supplementation Enhance Reproductive Performance in Male Albino Rats (Rattus norvegicus) With Lead Acetate Toxicity

Metal toxicity from lead affects reproductive organ function by activating reactive oxygen species processes. This study aims to see how α-tocopherol and zinc sulfate (ZnSO4) affect gonads, liver, follicle-stimulating hormone, luteinizing hormone, spermatogenesis (the amount of spermatogonia, spermatocytes, and spermatids), and Leydig cells in male albino rats (Rattus norvegicus) exposed to lead acetate Pb(CH3COO)2. The samples used were 25 male Wistar rats aged 4 months, separated into five groups. For 30 days, all treatment groups were exposed to Pb(CH3COO)2 at a level of 50-mg/kg body weight (BW). The T1 group was given a dosage of 100-mg/kg BW of α-tocopherol. The ZnSO4 was given to the T2 group at a dose of 0.54-mg/kg BW. Meanwhile, the T3 group was given a mixture of ZnSO4 at 0.54-mg/kg BW and α-tocopherol at 100-mg/kg BW orally. ELISA test was carried out to determine the level of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in a blood plasma sample of 100 μl / 1 mg. Histopathological observations made on the liver included counting damaged cells and seminiferous tubules that included counting the amount of spermatogonia, spermatocytes, spermatids, Sertoli cells, and Leydig cells. Using SPSS 20 software, the collected data were analyzed using analysis of variance, followed by Duncan’s test with a 95% simultaneous confidence level. The highest average levels of FSH and LH in the T3 group were 3.6162 mIU/mL and 14.9658 mIU/mL. The finding showed that Pb(CH3COO)2 caused disruptions in the spermatogenesis and Leydig cell processes. Exogenous antioxidants in combination with ZnSO4 and α-tocopherol had significant effect on enhancing reproductive performance in animals exposed to Pb(CH3COO)2.

Sirt2 Regulates Liver Metabolism in a Sex-Specific Manner.

Sirtuin-2 (Sirt2), an NAD+-dependent lysine deacylase enzyme, has previously been implicated as a regulator of glucose metabolism, but the specific mechanisms remain poorly defined. Here, we observed that Sirt2-/- males, but not females, have decreased body fat, moderate hypoglycemia upon fasting, and perturbed glucose handling during exercise compared to wild type controls. Conversion of injected lactate, pyruvate, and glycerol boluses into glucose via gluconeogenesis was impaired, but only in males. Primary Sirt2-/- male hepatocytes exhibited reduced glycolysis and reduced mitochondrial respiration. RNAseq and proteomics were used to interrogate the mechanisms behind this liver phenotype. Loss of Sirt2 did not lead to transcriptional dysregulation, as very few genes were altered in the transcriptome. In keeping with this, there were also negligible changes to protein abundance. Site-specific quantification of the hepatic acetylome, however, showed that 13% of all detected acetylated peptides were significantly increased in Sirt2-/- male liver versus wild type, representing putative Sirt2 target sites. Strikingly, none of these putative target sites were hyperacetylated in Sirt2-/- female liver. The target sites in the male liver were distributed across mitochondria (44%), cytoplasm (32%), nucleus (8%), and other compartments (16%). Despite the high number of putative mitochondrial Sirt2 targets, Sirt2 antigen was not detected in purified wild type liver mitochondria, suggesting that Sirt2's regulation of mitochondrial function occurs from outside the organelle. We conclude that Sirt2 regulates hepatic protein acetylation and metabolism in a sex-specific manner.

Azoospermia and multi-organ damage in juvenile rats exposed to α-Terpineol from weaning to sexual maturity

This study aimed to evaluate the repeated oral administration of α-terpineol in juvenile Wistar rats over a 70-day period. The objective was to assess the potential systemic and reproductive toxicity of α-terpineol when administered by gavage at doses of 75, 150, and 300 mg/kg/day to juvenile Wistar rats for 70 days from postnatal day 24. The control group received corn oil for 70 days. During the study, various parameters were evaluated, including clinical signs, body weight, food intake, neurobehavioral observations, haematology, serum biochemistry, organ weights, steroidogenic gene expression, and histopathological examination. No toxicity-related changes were observed in body weight, food intake, neurobehavioral observations, or steroidogenic gene expression. However, sperm evaluation revealed a complete absence of sperm and delayed sexual maturation. Total cholesterol was significantly elevated in both sexes, and serum testosterone was reduced at the 150 and 300 mg/kg doses. Microscopic examination showed severe pathological changes in the testes, epididymis, liver, and kidneys of both males and females. After the 14-day recovery period, total cholesterol levels returned to the normal range, but no recovery was observed in the other organs. The no-observed-adverse-effect level was 75 mg/kg/day for male rats based on the histopathological findings in the testes, liver, and kidneys, and for female rats based on the kidney and liver histopathology.

Mitigating the effects of time in the heart and liver: The variable effects of short- and long-term caloric restriction

Caloric restriction (CR) is known for its anti-aging benefits, partly due to reduced oxidative stress and enhanced antioxidant defense. However, CR outcomes vary based on its intensity, timing, and duration. This study explored CR's effects on antioxidant activity in the heart and liver of male Wistar rats during aging. We investigated two CR paradigms: long-term CR (LTCR), started early in life, and short-term CR (STCR), initiated in middle or old age for 3 months. Contrary to previous findings of short-term CR deleterious effects of on the nervous system, our results revealed increased levels of key antioxidants after STCR. More specifically, we found an increase in GSH-Px and GSH under STCR that was particularly pronounced in the liver, while an increase in CAT and GR activities was observed in the heart of the STCR groups. Catalase was characterized as an enzyme particularly responsive to CR, as its activity was also increased in both the liver and heart after long-term caloric restriction. Our results highlight a significant tissue-specific response to CR and contribute to our understanding of the dynamic effects of CR, which in turn has implications for refining its therapeutic potential in combating age-related decline.

The subchronic toxicity of higher olefins in Han Wistar rats

Higher olefins (HO) are a category of unsaturated hydrocarbons widely used in industry applications to make products essential for daily human life. Establishing safe exposure limits requires a solid data matrix that facilitates understanding of their toxicological profile. This in turn allows for data to be read across to other members of the category, which are structurally similar and have predictable physico-chemical properties. Five independent subchronic oral toxicity studies were conducted in Wistar rats with Oct-1-ene, Nonene, branched, Octadec-1-ene, Octadecene and hydrocarbon C12-30, olefin-rich, ethylene polymn. by product, at doses ranging from 20 to 1000 mg/kg bw. These HO were selected considering gut absorption, carbon chain length, double-bond position and carbon backbone structural variations. Generally, limited and non-adverse toxicity effects were observed at the end of the treatment for short carbon chain HO. For instance, alpha 2u-globulin nephropathy in the male rats and liver hypertrophy. No clear trend in systemic toxicity was linked to the double-bond position. Key factors for hazard assessment include absorption, carbon chain length, and branching, with Nonene, branched, identified as the worst-case substance. Taken together, the no observed adverse effect level (NOAEL) of each HO in these subchronic studies was set at the highest dose tested.

Sex differences in Murine MASH evoked by a Fructose-Palmitate-Cholesterol-Enriched Diet

Background/AimsMetabolic syndrome-associated steatotic liver disease (MASLD) and metabolic syndrome-associated steatohepatitis (MASH) have global prevalence rates exceeding 25% and 3-6%, respectively. The introduction of high fructose corn syrup to the diet in the 1970s has been linked to metabolic and hepatic disturbances. Despite these associations, the potential for sex-dependent responses resulting from fructose-containing diets on MASLD/MASH has not been addressed. MethodsFemale and male C57BL/6J mice were fed fructose-palmitate-cholesterol (“FPC-(non-alcoholic steatohepatitis) (NASH)”) diet versus standard chow (SC) for 16 weeks (N=40 mice). At sacrifice, plasma and liver were retrieved, the latter for single nucleus RNA sequencing. Publicly-available data sets of human male and female MASH liver were probed. ResultsThe FPC-NASH diet induced metabolic dysfunction in both female and male mice, with females exhibiting more severe hepatic steatosis (p=0.0262), inflammation (p=0.0206), and fibrosis (p<0.0001). Single-nucleus RNA sequencing revealed distinct sex-specific transcriptional profiles in hepatocytes and stellate cells responding to the FPC-NASH diet compared to the SC diet. In female mice, compared to males, pathways associated with lipid and metabolic processes in hepatocytes and cell-cell communication and adhesion in stellate cells were enriched. Metabolic flux analyses demonstrated reduced bile acid metabolism in female mice and human hepatocytes in FPC-NASH and MASH conditions, respectively, compared to their male counterparts. ConclusionsMolecular profiling of hepatocytes and stellate cells in FPC-NASH diet-fed mice revealed significant sex differences mirrored in human MASH. The identification of intrinsic, within-sex, diet-dependent disparities underscores the critical need to include both male and female subjects in MAFLD/MASH studies and clinical trials. Impact and ImplicationsDespite the importance of metabolic syndrome-associated steatohepatitis (MASH) in impairment of human health, the potential for and mechanisms of sex-dependent responses have yet to be well-studied, particularly with respect to the possible influence of high fructose corn syrup additives to the diet, which has been linked to metabolic and hepatic disturbances. In a mouse model of fructose supplementation to a NASH diet, female mice displayed significantly higher MASH scores (steatosis, inflammation and fibrosis) compared to male mice. Single nucleus RNA sequencing of liver revealed intrinsic, diet-dependent molecular disparities within sex, which were exaggerated when comparing female versus male mice fed the fructose-containing NASH diet; many of these findings were recapitulated in human female versus male MASH patients. Our findings of dysregulated bile acid metabolism and androgen receptor-related within-sex increases in testosterone in female versus male mice fed fructose-NASH diet versus standard chow diet highlight potential mechanistic explanations and therapeutic targets for addressing sex differences and underscore the need to study both sexes in animal models and human MASH.

The COVID-19 pandemic and associated declines in cancer incidence by race/ethnicity and census-tract level SES, rurality, and persistent poverty status.

The COVID-19 pandemic had a significant impact on cancer screening and treatment, particularly in 2020. However, no single study has comprehensively analyzed its effects on cancer incidence and disparities among groups such as race/ethnicity, socioeconomic status (SES), persistent poverty (PP), and rurality. Utilizing the recent data from the United States National Cancer Institute's Surveillance, Epidemiology, and End Results Program, we calculated delay- and age-adjusted incidence rates for 13 cancer sites in 2020 and 2015-2019. Percent changes (PCs) of rates in 2020 compared to 2015-2019 were measured and compared across race/ethnic, census tract-level SES, PP, and rurality groups. Overall, incidence rates decreased from 2015-2019 to 2020, with varying PCs by cancer sites and population groups. Notably, NH Blacks showed significantly larger PCs than NH Whites in female lung, prostate, and colon cancers (e.g., prostate cancer: NH Blacks -7.3, 95% CI: [-9.0, -5.5]; NH Whites: -3.1, 95% CI: [-3.9, -2.2]). Significantly larger PCs were observed for the lowest versus highest SES groups (prostate cancer), PP versus non-PP groups (prostate and female breast cancer), and all urban versus rural areas (prostate, female breast, female and male lung, colon, cervix, melanoma, liver, bladder, and kidney cancer). The COVID-19 pandemic coincided with reduction in incidence rates in the U.S. in 2020 and was associated with worsening disparities among groups, including race/ethnicity, SES, rurality, and PP groups, across most cancer sites. Further investigation is needed to understand the specific effects of COVID-19 on different population groups of interest.