Biology subjects

Selvarani, R.

Publications and source records attributed to Selvarani, R..

5 recordsLinked to original sources

bioRxiv2026

Maternal Obesity Decreases Offspring Lifespan

Data in mice, nonhuman primates, and in humans demonstrate that exposure to maternal obesity increases the risk of multiple diseases in offspring. However, little is known about the aging effects of maternal obesity on the offspring. This study shows that maternal obesity significantly reduced the lifespan of both male and female mice born to obese dams despite being weaned onto a healthy diet at three weeks of age. This reduction in longevity was linked to an increase in age-related fibrotic pathology across multiple organs, e.g., liver, heart, and kidney. Gompertz analysis of the lifespan data showed that maternal obesity offspring have reduced lifespan due to detrimental changes established early during development rather than factors that modify aging later-in-life. These findings are translationally significant as they demonstrate that the growing prevalence of MO may lead to a decrease in overall lifespan and increase in age-related diseases in the next generation.

physiology↗

bioRxiv2024

Non-Necroptotic Roles of MLKL in Diet-Induced Obesity, Liver Pathology, and Insulin Sensitivity: Insights from a High Fat, High Fructose, High Cholesterol Diet Mouse Model

Chronic inflammation is a key player in metabolic dysfunction-associated fatty liver disease (MAFLD) progression. Necroptosis, an inflammatory cell death pathway, is elevated in MAFLD patients and mouse models, yet its role is unclear due to diverse mouse models and inhibition strategies. In our study, we inhibited necroptosis by targeting mixed lineage kinase domain like pseudokinase (MLKL), the terminal effector of necroptosis, in a high-fat, high-fructose, high-cholesterol (HFHFrHC) mouse model of diet-induced MAFLD mouse model. Despite HFHFrHC diet upregulating MLKL (2.5-fold), WT mice livers showed no increase in necroptosis markers or associated proinflammatory cytokines. Surprisingly, Mlkl-/-mice experienced exacerbated liver inflammation without protection from diet-induced liver damage, steatosis, or fibrosis. In contrast, Mlkl+/- mice showed significant reduction in these parameters that was associated with elevated Ppar and Ppar{gamma} levels. Both Mlkl-/-and Mlkl+/- mice on HFHFrHC diet resisted diet-induced obesity, attributed to increased beiging, enhanced oxygen consumption and energy expenditure due to adipose tissue, and exhibited improved insulin sensitivity. These findings highlight the tissue specific effects of MLKL on the liver and adipose tissue, and suggest a dose-dependent effect of MLKL on liver pathology.

biochemistry↗

bioRxiv2022

Senolytic Treatment Reduces Cell Senescence and Necroptosis in Sod1 Knockout Mice that is Associated with Reduced Inflammation and Hepatocellular Carcinoma

The goal of this study was to test the role cellular senescence plays in the increase in inflammation, chronic liver disease, and hepatocellular carcinoma, which are seen in mice null for Cu/Zn-Superoxide dismutase (Sod1KO). To inhibit senescence, six-month-old wildtype (WT) and Sod1KO mice were given the senolytics, dasatinib and quercetin (D+Q) for seven months. D+Q treatment reduced the expression of p16 in the livers of Sod1KO mice to WT levels as well as the expression of several SASP (senescence associated secretory phenotype) factors (IL-6, IL-1{beta}, CXCL-1, and GDF-15). D+Q treatment also reduced markers of inflammation in livers of the Sod1KO mice, e.g., cytokines, chemokines, macropthage levels, and Kupffer cell clusters. D+Q treatment had no effect on various markers of liver fibrosis in the Sod1KO mice but reduced the expression of genes involved in liver cancer (Myc, Tgfbr2, Socs3, and Cdkn2a) as well as dramatically reducing the incidence of hepatocellular carcinoma. Surprisingly, D+Q also reduced markers of necroptosis (phosphorylated and oligomerized MLKL) in the Sod1KO mice to WT levels. We also found that inhibiting necroptosis in the Sod1KO mice with necrostatin-1s reduced the markers of cellular senescence (p16, p21, and p53). The data from our study suggest that an interaction occurs between cellular senescence and necroptosis in the liver of Sod1KO mice. We propose that these two cell fates interact through a positive feedback loop resulting in a cycle amplifying both cellular senescence and necroptosis leading to inflammaging and age-associated pathology in the Sod1KO mice.

biochemistry↗

bioRxiv2021

Necroptosis contributes to chronic inflammation and fibrosis in aging liver

Inflammaging, characterized by an increase in low-grade chronic inflammation with age, is a hallmark of aging and is strongly associated with various age-related diseases, including chronic liver disease (CLD) and hepatocellular carcinoma (HCC). Because necroptosis is a cell death pathway that induces inflammation through the release of DAMPs, we tested the hypothesis that age-associated increase in necroptosis contributes to chronic inflammation in aging liver. Phosphorylation of MLKL and MLKL-oligomers, markers of necroptosis, as well as phosphorylation of RIPK3 and RIPK1 were significantly upregulated in the livers of old mice relative to young mice and this increase occurred in the later half of life (i.e., after 18 months of age). Markers of M1 macrophages, expression of proinflammatory cytokines (TNF, IL6 and IL-1{beta}), and markers of fibrosis were significantly upregulated in the liver with age and the change in necroptosis paralleled the changes in inflammation and fibrosis. Hepatocytes and liver macrophages isolated from old mice showed elevated levels of necroptosis markers as well as increased expression of proinflammatory cytokines relative to young mice. Short term treatment with the necroptosis inhibitor, necrostatin-1s (Nec-1s), reduced necroptosis, markers of M1 macrophages, expression of proinflammatory cytokines, and markers of fibrosis in the livers of old mice. Thus, our data show for the first time that liver aging is associated with increased necroptosis and necroptosis contributes to chronic inflammation in the liver, which in turn appears to contribute to liver fibrosis and possibly CLD. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=158 SRC="FIGDIR/small/460953v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@15ab761org.highwire.dtl.DTLVardef@bd7336org.highwire.dtl.DTLVardef@1d6e3bcorg.highwire.dtl.DTLVardef@10159eb_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2020

Role of necroptosis in chronic hepatic inflammation and liver disease in Cu/Zn superoxide dismutase deficient mice

Mice deficient in the antioxidant enzyme Cu/Zn-superoxide dismutase (Sod1-/- or Sod1KO mice) develop spontaneous hepatocellular carcinoma (HCC) with age. Similar to humans, HCC development in Sod1KO mice progresses from fatty liver disease to non-alcoholic steatohepatitis (NASH) with fibrosis, which eventually progresses to HCC. Because liver inflammation is the main mechanism that drives the disease progression in chronic liver disease (CLD) and because necroptosis is a major source of inflammation, we tested the hypothesis that increased necroptosis in the liver plays a role in increased inflammation and progression to fibrosis and HCC in Sod1KO mice. Phosphorylation of MLKL (P-MLKL), a well-accepted marker of necroptosis, and expression of MLKL protein were significantly increased in the livers of Sod1KO mice compared to WT mice indicating increased necroptosis. Similarly, phosphorylation of RIPK3 and RIPK3 protein levels were also significantly increased. Markers of pro-inflammatory M1 macrophages, NLRP3 inflammasome, and transcript levels of pro-inflammatory cytokines and chemokines, e.g., TNF, IL-6, IL-1{beta}, and Ccl2 that are associated with human NASH and HCC, were significantly increased. Markers of fibrosis and oncogenic transcription factor STAT3 were also upregulated in the livers of Sod1KO mice. Short term treatment of Sod1KO mice with necrostatin-1s (Nec-1s), a necroptosis inhibitor, significantly reduced necroptosis, pro-inflammatory cytokines, fibrosis markers and STAT3 activation. Our data show for the first time that necroptosis-mediated inflammation contributes to fibrosis and HCC progression in Sod1KO mice, a mouse model of accelerated aging and progressive HCC development. These findings suggest that necroptosis might be a target for treating NASH and HCC.

biochemistry↗