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Objective: Adrenocortical responsiveness is critical for maintaining glucocorticoids production and homeostasis during stress. We sought to investigate adrenocortical responsiveness during hypoxia in mice and the mechanisms responsible for the regulation of adrenal responsiveness. Methods: (1) Adult male WT mice were randomly divided into four groups: normoxia, hypoxia (24h), hypoxia (72h), hypoxia (72h) + GYY4137(hydrogen sulfide (H2S) donor, 133mmol/kg/day); (2) WT mice were randomly divided into four groups: sham, adrenalectomy (ADX), sham+hypoxia, ADX+hypoxia; (3) Cse-/- mice were randomly divided into two groups: Cse-/-, Cse-/- +GYY4137. Results: The circulatory level of corticosteroid induced by ACTH stimulation was significantly reduced in the mice with hypoxia compared with control mice. The mortality rate induced by lipopolysaccharide (LPS) increased during hypoxia. Cystathionine-γ-lyase (CSE) expression was significantly reduced in adrenal glands during hypoxia. GYY4137 treatment significantly increased adrenal responsiveness and attenuated NLRP3 inflammasome activation in mice treated by hypoxia and Cse-/- mice. Furthermore, The sulfhydrated level of PSMA7 in adrenal gland was decreased in the mice with hypoxia and Cse-/- mice. PSMA7 was S-sulfhydrated at cysteine 70. Blockage of S-sulfhydration of PSMA7 increased NLRP3 expression in adrenocortical cells. Conclusion: Reduced H2S production mediated hypo-adrenocortical responsiveness and NLRP3 inflammasome activation via PAMA7 S-sulfhydration during hypoxia. [ABSTRACT FROM AUTHOR]

Sepsis-associated acute kidney injury (SA-AKI) results in significant morbidity and mortality, and ferroptosis may play a role in its pathogenesis. Our aim was to examine the effect of exogenous H2S (GYY4137) on ferroptosis and AKI in in vivo and in vitro models of sepsis and explore the possible mechanism involved. Sepsis was induced by cecal ligation and puncture (CLP) in male C57BL/6 mice, which were randomly divided into the sham, CLP, and CLP + GYY4137 group. The indicators of SA-AKI were most prominent at 24 h after CLP, and analysis of the protein expression of ferroptosis indicators showed that ferroptosis was also exacerbated at 24 h after CLP. Moreover, the level of the endogenous H2S synthase CSE (Cystathionine-γ-lyase) and endogenous H2S significantly decreased after CLP. Treatment with GYY4137 reversed or attenuated all these changes. In the in vitro experiments, LPS was used to simulate SA-AKI in mouse renal glomerular endothelial cells (MRGECs). Measurement of ferroptosis-related markers and products of mitochondrial oxidative stress showed that GYY4137 could attenuate ferroptosis and regulate mitochondrial oxidative stress. These findings imply that GYY4137 alleviates SA-AKI by inhibiting ferroptosis triggered by excessive mitochondrial oxidative stress. Thus, GYY4137 may be an effective drug for the clinical treatment of SA-AKI. [ABSTRACT FROM AUTHOR]

How an organism dies is a fundamental yet poorly understood question in biology. An organism can die of many causes, including stress‐induced phenoptosis, also defined as organismic death that is regulated by its genome‐encoded programs. The mechanism of stress‐induced phenoptosis is still largely unknown. Here, we show that transient but severe freezing‐thaw stress (FTS) in Caenorhabditis elegans induces rapid and robust phenoptosis that is regulated by G‐protein coupled receptor (GPCR) signaling. RNAi screens identify the GPCR‐encoding fshr‐1 in mediating transcriptional responses to FTS. FSHR‐1 increases ligand interaction upon FTS and activates a cyclic AMP‐PKA cascade leading to a genetic program to promote organismic death under severe stress. FSHR‐1/GPCR signaling up‐regulates the bZIP‐type transcription factor ZIP‐10, linking FTS to expression of genes involved in lipid remodeling, proteostasis, and aging. A mathematical model suggests how genes may promote organismic death under severe stress conditions, potentially benefiting growth of the clonal population with individuals less stressed and more reproductively privileged. Our studies reveal the roles of FSHR‐1/GPCR‐mediated signaling in stress‐induced gene expression and phenoptosis in C. elegans, providing empirical new insights into mechanisms of stress‐induced phenoptosis with evolutionary implications. [ABSTRACT FROM AUTHOR]

The Wenjiaping granite, as one of the few Late Jurassic granites in the Songpan–Garzê fold belt (SGFB), can provide an important clue for comprehensively recognizing the tectonic evolution and mineralization of this belt. In this contribution, we present new age and geochemical data for this pluton to better constrain its petrogenesis and discuss the tectonic and metallogenic implications. LA‐ICP‐MS zircon U–Pb dating shows that the Wenjiaping pluton was emplaced at ~159 Ma. The granite contains minor amphibole, and exhibits slightly peraluminous characteristics (A/CNK = 1.03–1.10) and lower initial Sr–Pb isotope ratios than those of the Liwu Group, which excludes the possibility that the Wenjiaping granite was derived from partial melting of the metasedimentary rock‐dominated Liwu Group as previously suggested. Significantly, high Sr/Y (40.93–54.30), LaN/YbN (39.64–56.64), and K2O/NaO (0.77–1.11) ratios, low MgO (0.47%–0.86%) and Cr (25.1–41.3 ppm) contents, and relatively enriched Sr–Nd–Pb–Hf isotope compositions of the Wenjiaping granite are comparable to those of the Late Triassic adakitic rocks in the SGFB, indicating that they probably share a similar source. Combined with previous researches, we propose that large‐scale detachment of the Jianglang dome caused by post‐collisional lithospheric extension in the SGFB‐induced decompressional partial melting of the Precambrian basement rocks can account for the generation of the Late Jurassic Wenjiaping pluton. In addition, our results also suggest that the Wenjiaping pluton probably cannot supply abundant metal elements for the Liwu‐type Cu‐polymetallic deposits in the Jianglang dome, SGFB. [ABSTRACT FROM AUTHOR]

In a previous study, we showed that endogenous hydrogen sulfide (H 2 S) plays a key role in the maintenance of intact adrenal cortex function via the protection of mitochondrial function during endoxemia. We further investigated whether mitochondria-mediated apoptosis is involved in H 2 S protection of adrenal function. LPS treatment resulted in mitochondria-mediated apoptosis in the adrenal glands of male mice, and these effects were prevented by the H 2 S donor GYY4137. In the model of Y1 cells, the LPS-induced mitochondria-mediated apoptosis and blunt response to ACTH were rescued by GYY4137. The H 2 S-generating enzyme cystathionine-β-synthase (CBS) knockout heterozygous (CBS +/- ) mice showed mitochondria-mediated apoptosis in the adrenal gland and adrenal insufficiency. GYY4137 treatment restored adrenal function and eliminated mitochondria-mediated apoptosis. Maleimide assay combined with mass spectrometry analysis showed that a number of proteins in mitochondria were S-sulfhydrated in the adrenal gland. ATP5A1 was further confirmed as S-sulfhydrated using a modified biotin switch assay. The level of S-sulfhydrated ATP5A1 was decreased in the adrenal gland of endotoxemic and CBS +/- mice, which was restored by GYY4137. ATP5A1 was identified as sulfhydrated at cysteine 244 by H 2 S. Overexpression of the cysteine 244 mutant ATP5A1 in Y1 cells resulted in a loss of LPS-induced mitochondria-mediated apoptosis and GYY4137 restoration of LPS-induced hyporesponsiveness to ACTH. Collectively, the present study revealed that decreased H 2 S generation leads to mitochondrial-mediated apoptosis in the adrenal cortex and a blunt response to ACTH. S-sulfhydration of ATP5A1 at cysteine 244 is an important molecular mechanism by which H 2 S maintains mitochondrial function and steroidogenesis in the adrenal glands. [ABSTRACT FROM AUTHOR]

The Pennsylvanian to lower Permian succession at Madiyi, South China, represents a nearshore mixed siliciclastic‐carbonate system characterized by cyclic sedimentation patterns along a depth gradient from continental siliciclastics to marine open platform carbonates. Various palaeokarst features related to subaerial exposure are widely distributed. Additionally, pedogenesis was pervasive. The identification of twenty‐eight sedimentary cycles grouped into five sequences allows the reconstruction of a relative sea‐level curve. The cycles represent higher frequency changes superimposed on the long‐term evolution. After the initial transgression, the sea level remained relatively low in the late Bashkirian to early Moscovian. Then, it rose stepwise until a major drop occurred in the late Moscovian. Afterwards, the sea level rose again, but marine sedimentation ceased during at least the early Kasimovian. The area was flooded in the late Kasimovian, and the sea level rose until a late Gzhelian sea‐level drop. The subsequent marine sequence contains uppermost Gzhelian to upper Asselian deposits, which are capped by lower Permian continental facies associated with a major regional regression. Shallow to deeper marine sedimentary settings recorded high‐frequency sea‐level changes throughout South China during the late Bashkirian to Asselian. The main transgression–regression cycles are clearly associated with different depositional settings during several time intervals. Furthermore, the good correlations among South China, Ukraine, and the U.S. Mid‐continent are rooted in the impact of Gondwanan glaciations on the global sedimentation patterns. However, not all changes at Madiyi are the result of glacio‐eustatic sea‐level fluctuations; some are related to the local subsidence history and the rise of the Xuefeng Uplift. [ABSTRACT FROM AUTHOR]

Sepsis is considered as a life-threatening organ dysfunction caused by a dysregulated response of the host to an infection. Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a life-threatening condition, and is the type of organ injury that is most commonly induced by sepsis. Resveratrol (RSV) has been shown to exert a wide range of therapeutic effects due to its anti-inflammatory and anti-oxidant properties. The present study aimed to investigate whether RSV could mitigate sepsis-induced ALI/ARDS, and also to unravel the underlying mechanism. The model of sepsis was established by applying the cecal ligation and puncture (CLP) method, and mitochondria from the lung tissue were isolated to assess mitochondrial function, as determined from measuring mitochondrial superoxide production using MitoSOX red mitochondrial superoxide indicator and the membrane potential. It was found that RSV could exert a protective role in CLP-induced ALI/ARDS, as evidenced by moderate levels of inflammatory cell infiltration and interstitial edema, as well as decreased levels of C-reactive protein (P<0.01), interleukin (IL)-6 (P<0.01), IL-1β (P<0.01) and tumor necrosis factor-α (P<0.01). Moreover, phospholipid scramblase 3 (PLSCR-3)-mediated mitochondrial dysfunction and mitophagy were shown to contribute towards the CLP-caused lung damage, which was reversed upon RSV administration, as demonstrated by improved mitochondrial function and markedly reduced increases in the protein levels of autophagy related (ATG)5 (P<0.01), ATG7 (P<0.05) and microtubule-associated protein 1A/1B-light chain 3 (LC3-Ⅰ/Ⅱ) (P<0.01), and a significantly increased expression of P62 (P<0.05). In addition, with regard to the CLP-induced lung injury in the mouse model, overexpression of PLSCR-3 was found to remove the beneficial effects observed upon RSV treatment. Taken together, the results of the present study have uncovered a novel molecular mechanism through which RSV may alleviate ALI/ARDS via regulating PLSCR-3-mediated mitochondrial dysfunction and mitophagy in CLP-induced mouse model. [ABSTRACT FROM AUTHOR]

This paper describes a sensor employing a gel formed from an interpenetrating polymer network of poly(vinyl alcohol) and a copolymer of N-isopropylacrylamide and acrylic acid. This gel exhibits a continuous volume-phase transition that is strongly dependent on the presence of polyvalent metal ions in the gel solvent. A sensor apparatus has been constructed that estimates, in real time, the transition temperature of a gel. When this sensor is loaded with a gel sensitive to metal ions, it could be used to detect the presence and identity of metal ions in a solution. [ABSTRACT FROM PUBLISHER]

Objectives: The objective of this study was to investigate whether skeletal muscle cystathionine γ-lyase (CTH) contributes to high-fat diet (HFD)-induced metabolic disorders using skeletal muscle Cth knockout ( Cth Δskm ) mice., Methods: The Cth Δskm mice and littermate Cth-floxed ( Cth f/f ) mice were fed with either HFD or chow diet for 13 weeks. Metabolomics and transcriptome analysis were used to assess the impact of CTH deficiency in skeletal muscle., Results: Metabolomics coupled with transcriptome showed that Cth Δskm mice displayed impaired energy metabolism and some signaling pathways linked to insulin resistance (IR) in skeletal muscle although the mice had normal insulin sensitivity. HFD led to reduced CTH expression and impaired energy metabolism in skeletal muscle in Cth f/f mice. CTH deficiency and HFD had some common pathways enriched in the aspects of amino acid metabolism, carbon metabolism, and fatty acid metabolism. Cth Δskm +HFD mice exhibited increased body weight gain, fasting blood glucose, plasma insulin, and IR, and reduced glucose transporter 4 and CD36 expression in skeletal muscle compared to Cth f/f +HFD mice. Impaired mitochondria and irregular arrangement in myofilament occurred in Cth Δskm +HFD mice. Omics analysis showed differential pathways enriched between Cth Δskm mice and Cth f/f mice upon HFD. More severity in impaired energy metabolism, reduced AMPK signaling, and increased oxidative stress and ferroptosis occurred in Cth Δskm +HFD mice compared to Cth f/f +HFD mice., Discussion: Our results indicate that skeletal muscle CTH expression dysregulation contributes to metabolism disorders upon HFD.

Understanding the in vivo transport process provides guidelines for designing ideal nanoparticles (NPs) with higher efficacy and fewer off-target effects. Many factors, such as particle size, morphology, surface potential, structural stability, and etc., may influence the delivering process of NPs due to the existence of various physiological barriers within the body. Herein, we summarise the distinct influences of NP physicochemical properties on the four consecutive in vivo transport steps: (1) navigating with bloodstream within blood vessels, (2) transport across vasculature walls into tumour tissues, (3) intratumoural transport through the interstitial space, and (4) cellular uptake & intracellular delivery by cancerous cells. We found that the philosophy behind the current consensus for NP design has certain similarities to the "Yin-Yang" theory in traditional Chinese culture. Almost all physicochemical properties, regardless of big or small sizes, long or short length, positive or negative zeta potentials, are double-edged swords. The balance of potential benefits and side effects, drug selectivity and accessibility should be fully considered when optimising particle design, similar to the "Yin-Yang harmony". This paper presents a comprehensive review of the advancements in NPs research, focusing on their distinct features in tumour targeting, drug delivery, and cell uptake. Additionally, it deliberates on future developmental trends and potential obstacles, thereby aiming to uncover the ways these characteristics influence the NPs' biological activity and provide theoretical guidance for the targeted delivery of NPs., Competing Interests: Conflicts of interest statement: None.

Objective: Hydrogen sulfide (H2S), generated in the myocardium predominantly via cystathionine-γ-lyase (CSE), is cardioprotective. The objectives of the present study were to investigate the effects of estrogens on CSE expression and H2S generation in the myocardium and to examine whether serum 17β-estradiol (E2) level is associated with CSE activity and H2S generation and whether H2S or E2 level is associated with proinflammatory cytokines and oxidative stress status., Methods: Ovariectomized Sprague-Dawley rats received subcutaneous E2 (30 μg/kg/d) or vehicle for 12 weeks. At the end of the 12-week treatment, CSE expression, H2S generation, reduced glutathione/oxidized glutathione (GSH/GSSG) ratio, total antioxidant capacity (T-AOC), superoxide dismutase (SOD) activity, catalase (CAT) activity, interleukin (IL)-6 concentration, and tumor necrosis factor-α (TNF-α) concentration in the left ventricle were determined., Results: E2 increased CSE expression and H2S generation in the myocardium of ovariectomized rats. H2S production rate and serum E2 were positively correlated. E2 increased GSH/GSSG ratio, T-AOC, CAT, and SOD activity but decreased IL-6 and TNF-α levels. Serum E2 level was positively correlated with GSH/GSSG ratio, T-AOC, CAT, and SOD activity, and inversely correlated with IL-6 and TNF-α levels. H2S generation rate was positively correlated with T-AOC and GSH/GSSG ratio, and inversely correlated with IL-6 and TNF-α levels., Conclusions: E2 increases CSE expression and endogenous H2S generation in the myocardium. The effects of E2 are associated with decreased oxidative stress and inflammatory status. Our data suggest that estrogens might exert cardioprotective effects through up-regulation of CSE expression and H2S generation.

Objectives: Reversible adrenal insufficiency frequently has been diagnosed in critically ill patients with sepsis who have either low basal cortisol levels or low cortisol responses to adrenocorticotropic hormone (ACTH) stimulation. It is generally accepted that a phenomenon called "endotoxin tolerance" contributes to immunosuppression during sepsis. The present study was to investigate whether endotoxin tolerance occurs in the adrenal gland, leading to hyporesponsiveness of adrenal gland during sepsis., Design: Controlled laboratory experiment., Setting: University research laboratory., Subjects: Sprague-Dawley male rats 200-250 g and primary isolated adrenal fasciculata-reticularis cells., Interventions: Rats received intra-arterial injection of purified lipopolysaccharide (0.5 mg/kg) through indwelling femoral arterial catheters, and 24 hrs later the adrenocortical sensitivity to exogenous ACTH (10 ng/kg) was detected. Primary fasciculata-reticularis cells were pretreated with lipopolysaccharide at 0.1-100 ng/mL or with ACTH at 0.01-10 ng/mL and then challenged, in fresh media, with 1 μg/mL lipopolysaccharide or 10 ng/mL ACTH., Measurements and Main Results: Toll-like receptor 4 was expressed in adrenal gland and primary fasciculata-reticularis cells. Plasma corticosterone response to ACTH was decreased in rats receiving preinjection of lipopolysaccharide. Lipopolysaccharide pretreatment caused a significant decrease in corticosterone production in response to subsequent ACTH and lipopolysaccharide stimulation in primary fasciculata-reticularis cells. Lipopolysaccharide pretreatment inhibited ACTH- and lipopolysaccharide-induced expression of steroid metabolizing enzymes. Lipopolysaccharide significantly decreased Toll-like receptor 4 and ACTH receptor expression., Conclusions: Pre-exposure to lipopolysaccharide resulted in hyporesponsiveness to ACTH stimulation in rats. In vitro, lipopolysaccharide pretreatment impaired corticosterone production of fasciculata-reticularis cells in response to ACTH and lipopolysaccharide, which was associated with decreased expression of synthetic enzymes required for corticosterone production. Our results indicate that endotoxin tolerance of adrenal gland is one of the mechanisms for adrenocortical insufficiency during sepsis.