In the murine testis, self-renewal of spermatogonial stem cells (SSCs) requires glial cell line-derived neurotrophic factor (GDNF) secreted from neighboring somatic cells. However, it not clear how ...GDNF promotes self-renewal
or what downstream signaling pathways are required for SSC maintenance. We found that GDNF is normally expressed cyclically during spermatogenesis. Stage-specific ectopic expression of GDNF caused the accumulation of a GFRA1
LIN28
A
population, which has enhanced SSC activity compared with wild type, suggesting that GDNF normally limits self-renewal to specific stages. Despite the increase in SSC cell number, EdU labeling during steady-stage spermatogenesis, and during recovery after busulfan-mediated spermatogonial depletion, indicated that GDNF promotes self-renewal by blocking differentiation and not by promoting proliferation. Increased GDNF signaling led to increased phosphorylation of AKT3 in undifferentiated spermatogonia, but not of AKT1 or AKT2, and was independent of RPS6 phosphorylation, suggesting that AKT3 functions in SSC self-renewal or progenitor cell expansion.
The growing number of deaths related to sepsis has become a major concern for past few years. Sepsis is a complex pathological reactions that is explained by series of host response to microbial ...insult. The resulted systemic reactions are manifested by early appearance of proinflammatory cytokines leading to hyperinflammatory phase which is followed by septic shock and death of the patient. The present study has revealed that antibiotics are not self-sufficient to control the complex mechanism of sepsis. Moreover prolonged and unnecessary administration of antibiotics may lead to antibiotic resistance to pathogens. In addition to this, immunosuppressive medications are selective and have targeted approach to certain study population. Drugs from herbal origin have shown to possess a mammoth of immunomodulatory potential by suppressing proinflammatory and anti-inflammatory cytokines exhibiting no or minimal unwanted secondary responses. Concomitantly, herbal plants tend to modulate oxidative stress level and haematological imbalance during inflammatory diseased conditions. Natural compounds have gained much attention for the treatment of several clinical complications. Considering the promising responses of medicinal plants with less/no side effects and easy procurement, comprehensive research on herbal plants to treat sepsis should be contemplated.
c-Jun NH(2)-terminal kinase (JNK) activation plays a major role in acetaminophen (APAP)-induced hepatotoxicity. However, the exact mechanism of APAP-induced JNK activation is incompletely understood. ...It has been established that apoptosis signal-regulating kinase 1 (ASK1) regulates the late phase of APAP-induced JNK activation, but the mitogen-activated protein kinase kinase kinase that mediates the initial phase of APAP-induced JNK activation has not been identified. Oxidative stress produced during APAP metabolism causes JNK activation, which promotes mitochondrial dysfunction and results in the amplification of oxidative stress. Therefore, inhibition of the initial phase of JNK activation may be key to protection against APAP-induced liver injury. The goal of this study was to determine whether mixed-lineage kinase 3 (MLK3) mediates the initial, ASK1-independent phase of APAP-induced JNK activation and thus promotes drug-induced hepatotoxicity. We found that MLK3 was activated by oxidative stress and was required for JNK activation in response to oxidative stress. Loss of MLK3 attenuated APAP-induced JNK activation and hepatocyte death in vitro, independent of receptor-interacting protein 1. Moreover, JNK and glycogen synthase kinase 3β activation was significantly attenuated, and Mcl-1 degradation was inhibited in APAP-treated MLK3-knockout mice. Furthermore, we showed that loss of MLK3 increased expression of glutamate cysteine ligase, accelerated hepatic GSH recovery, and decreased production of reactive oxygen species after APAP treatment. MLK3-deficient mice were significantly protected from APAP-induced liver injury, compared with wild-type mice. Together, these studies establish a novel role for MLK3 in APAP-induced JNK activation and hepatotoxicity, and they suggest MLK3 as a possible target in the treatment of APAP-induced liver injury.
Stem cells support tissue maintenance by balancing self-renewal and differentiation. In mice, it is believed that a homogeneous stem cell population of single spermatogonia supports spermatogenesis, ...and that differentiation, which is accompanied by the formation of connected cells (cysts) of increasing length, is linear and nonreversible. We evaluated this model with the use of lineage analysis and live imaging, and found that this putative stem cell population is not homogeneous. Instead, the stem cell pool that supports steady-state spermatogenesis is contained within a subpopulation of single spermatogonia. We also found that cysts are not committed to differentiation and appear to recover stem cell potential by fragmentation, and that the fate of individual spermatogonial populations was markedly altered during regeneration after damage. Thus, there are multiple and reversible paths from stem cells to differentiation, and these may also occur in other systems.
Previous studies with
Geobacter sulfurreducens have demonstrated that OmcS, an abundant
c-type cytochrome that is only loosely bound to the outer surface, plays an important role in electron transfer ...to Fe(III) oxides as well as other extracellular electron acceptors. In order to further investigate the function of OmcS, it was purified from a strain that overproduces the protein. Purified OmcS had a molecular mass of 47
015
Da, and six low-spin
bis-histidinyl hexacoordinated heme groups. Its midpoint redox potential was −212
mV. A thermal stability analysis showed that the cooperative melting of purified OmcS occurs in the range of 65–82
°C. Far UV circular dichroism spectroscopy indicated that the secondary structure of purified OmcS consists of about 10% α-helix and abundant disordered structures. Dithionite-reduced OmcS was able to transfer electrons to a variety of substrates of environmental importance including insoluble Fe(III) oxide, Mn(IV) oxide and humic substances. Stopped flow analysis revealed that the reaction rate of OmcS oxidation has a hyperbolic dependence on the concentration of the studied substrates. A ten-fold faster reaction rate with anthraquinone-2,6-disulfonate (AQDS) (25.2
s
−
1
) was observed as compared to that with Fe(III) citrate (2.9
s
−
1
). The results, coupled with previous localization and gene deletion studies, suggest that OmcS is well-suited to play an important role in extracellular electron transfer.
► OmcS has low spin,
bis-his hexacoordinated heme groups. ► Midpoint redox potential of −212
mV. ► It is able to reduce various soluble and insoluble metals such as iron, manganese, gold, uranium, and humic substances in vitro. ► Stopped flow analysis revealed that the reaction rate of OmcS oxidation has a hyperbolic dependence on the concentration of the studied substrates. ► A ten-fold faster reaction rate with anthraquinone-2,6-disulfonate (AQDS) (25.2
s
−
1
) was observed as compared to that with Fe(III) citrate (2.9
s
−
1
).
Background & Aims Saturated free fatty acid (SFA)-stimulated c-Jun NH2 -terminal kinase (JNK) activation is associated with the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, the ...mechanisms responsible for the effects of SFA are incompletely understood. The goal of this study was to determine the molecular mechanisms by which SFA induce JNK activation in hepatocytes. Methods We used siRNA-mediated knockdown in Hepa1c1c7 and AML12 cell lines, as well as primary mouse hepatocytes for these studies. Results The current model for JNK activation by SFA involves endoplasmic reticulum (ER) stress, which induces JNK activation through an inositol requiring enzyme 1 (IRE1α) Apoptosis Regulating Kinase 1 (ASK1)-dependent mechanism. Here, we find that SFA-induced JNK activation is not inhibited in the absence of IRE1α and ASK1. Instead we show that activation of the small GTP-binding proteins Cdc42 and Rac1 is required for SFA-stimulated MLK3-dependent activation of JNK in hepatocytes. In addition, we demonstrate that SFA-induced cell death in hepatocytes is independent of IRE1α, but dependent on Cdc42, Rac1, and MLK3. Conclusions Our results demonstrate that Cdc42 and Rac1, rather than ER stress, are important components of a SFA-stimulated signaling pathway that regulates MLK3-dependent activation of JNK in hepatocytes.
The objective of this study is to measure the relationship between sleep quality and health-related quality of life (HRQOL), in Indian population with type 2 diabetes mellitus (T2DM).
A ...cross-sectional study, included a total of 300 patients with T2DM. All participants were responding to the Pittsburgh Sleep Quality Index (PSQI) and European Quality of Life-5 Dimensions Questionnaire (EQ-5D). A PSQI global score ≥5 was defined as poor sleep quality. EQ-5D visual analogue scale (VAS), determining the overall health status. Logistic regression analysis was used to examine the association between PSQI and EQ-5D. All the study data were analysed using the SPSS software version 20.0. Values of p < 0.05 were considered statistically significant.
The mean age of included participants were 55.29. Majority of the participants (55.3%) were identified as “poor sleepers” and female (31.3%) contributing higher proportion. Poor sleepers had significantly lower the HRQoL (p < 0.001). After adjustment, poor sleep quality was significantly associated with a lower HRQoL; EQ-5D index (OR = 1.080, 95%, CI: 1.015–1.148, p < 0.05), and EQ-5D VAS (OR = 1.092, 95%, CI: 1.021–1.176, p < 0.01). Overall, the EQ-5D index and EQ-5D VAS were found to be an independent predictors of sleep quality.
Poor sleep quality is prevalent in Indian T2DM population, and it imparts negative impact on several dimensions of EQ-5D that characterising the daily activities performance. Therefore, further real-world studies are needed to determine the causal relationship between T2DM patients and measure of objective sleep and their impact on health.
•Poor sleep is most prevalent in people with type 2 diabetes mellitus (T2DM).•Poor sleepers had detrimental effect on health-related quality of life (HRQoL) among T2DM.•Sleep hygiene could be potential predictor of HRQoL among T2DM.•Sleep issue must address among patients with T2DM under routine diabetes care.•This study provides an evidence on humanistic burden of T2DM.
Standardized and reproducible preclinical models that recapitulate the dynamics of prostate cancer are urgently needed. We established a bank of transplantable patient-derived prostate cancer ...xenografts that capture the biologic and molecular heterogeneity currently confounding prognostication and therapy development. Xenografts preserved the histopathology, genome architecture, and global gene expression of donor tumors. Moreover, their aggressiveness matched patient observations, and their response to androgen withdrawal correlated with tumor subtype. The panel includes the first xenografts generated from needle biopsy tissue obtained at diagnosis. This advance was exploited to generate independent xenografts from different sites of a primary site, enabling functional dissection of tumor heterogeneity. Prolonged exposure of adenocarcinoma xenografts to androgen withdrawal led to castration-resistant prostate cancer, including the first-in-field model of complete transdifferentiation into lethal neuroendocrine prostate cancer. Further analysis of this model supports the hypothesis that neuroendocrine prostate cancer can evolve directly from adenocarcinoma via an adaptive response and yielded a set of genes potentially involved in neuroendocrine transdifferentiation. We predict that these next-generation models will be transformative for advancing mechanistic understanding of disease progression, response to therapy, and personalized oncology.
ABSTRACTThe extensive modification in different land operations fueled by rapid urbanization is a matter of great concern. It is not just a simple process of exchange within different classes as we ...think; moreover, it is one of the most responsible factors for the change in biological rotations of the natural system. India, one of the fastest-urbanizing nations, is expected to be the home of the most urban residents by 2050, likely resulting in various undesirable issues in emerging and existing cities. The review highlights the apprehensive sides of sprawl and land use/land cover (LULC) changes in the Indian context. It also aims to assist the researchers in exploring the scope and relevance of sprawl measurement techniques for emerging urban settlements through the collected literature. A multi-stage sampling method is used to scrutinize the secondary source-based information regarding the research work. In total, 58 studies of recognized journals have been appraised systematically from 1981 to 2022. The findings reveal that increasing accidental growth caused by rapid urbanization is the leading cause of the change in LULC and irreparable environmental loss. 77.58 percent of studies have reported that geospatial technology, models, and numerical methods are more relevant to urban planners and officials for sprawl measurement and LULC change detection. So, the administration should address the accidental urban growth in its initial phase with a priority for sustainable urbanization.
Mucosal-associated invariant T (MAIT) cells are protective against tuberculous and non-tuberculous mycobacterial infections with poorly understood mechanisms. Despite an innate-like nature, MAIT cell ...responses remain heterogeneous in bacterial infections. To comprehensively characterize MAIT activation programs responding to different bacteria, we stimulated MAIT cells with
to compare with Bacillus Calmette-Guérin (BCG), which remains the only licensed vaccine and a feasible tool for investigating anti-mycobacterial immunity in humans. Upon sequencing mRNA from the activated and inactivated CD8
MAIT cells, results demonstrated the altered MAIT cell gene profiles by each bacterium with upregulated expression of activation markers, transcription factors, cytokines, and cytolytic mediators crucial in anti-mycobacterial responses. Compared with
, BCG altered more MAIT cell genes to enhance cell survival and cytolysis. Flow cytometry analyses similarly displayed a more upregulated protein expression of B-cell lymphoma 2 and T-box transcription factor Eomesodermin in BCG compared to
stimulations. Thus, the transcriptomic program and protein expression of MAIT cells together displayed enhanced pro-survival and cytotoxic programs in response to BCG stimulation, supporting BCG induces cell-mediated effector responses of MAIT cells to fight mycobacterial infections.
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