Co-exposure to PVC microplastics and cadmium induces oxidative stress and fibrosis in duck pancreas.

PVC microplastics (PVC-MPs) are environmental pollutants that interact with cadmium (Cd) to exert various biological effects. Ducks belong to the waterfowl family of birds and therefore are at a higher risk of exposure to PVC-MPs and Cd than other animals. However, the effects of co-exposure of ducks to Cd and PVC-MPs are poorly understood. Here, we used Muscovy ducks to establish an in vivo model to explore the effects of co-exposure to 1 mg/L PVC-MPs and 50 mg/kg Cd on duck pancreas. After 2 months of treatment with 50 mg/kg Cd, pancreas weight decreased by 21 %, and the content of amylase and lipase increased by 25 % and 233 %. However, exposure to PVC-MPs did not significantly affect the pancreas. Moreover, co-exposure to PVC-MPs and Cd worsened the reduction of pancreas weight and disruption of pancreas function compared to exposure to either substance alone. Furthermore, our research has revealed that exposure to PVC-MPs or Cd disrupted mitochondrial structure, reduced ATP levels by 10 % and 18 %, inhibited antioxidant enzyme activity, and increased malondialdehyde levels by 153.8 % and 232.5 %. It was found that exposure to either PVC-MPs or Cd can induce inflammation and fibrosis in the duck pancreas. Notably, co-exposure to PVC-MPs and Cd exacerbated inflammation and fibrosis, with the content of IL-1, IL-6, and TNF-α increasing by 169 %, 199 %, and 98 %, compared to Cd exposure alone. The study emphasizes the significance of comprehending the potential hazards linked to exposure to these substances. In conclusion, it presents promising preliminary evidence that PVC-MPs accumulate in duck pancreas, and increase the accumulation of Cd. Co-exposure to PVC-MPs and Cd disrupts the structure and function of mitochondria and promotes the development of pancreas inflammation and fibrosis.

A critical review on male-female reproductive and developmental toxicity induced by micro-plastics and nano-plastics through different signaling pathways.

It is widely accepted that humans are constantly exposed to micro-plastics and nano-plastics through various routes, including inhalation of airborne particles, exposure to dust, and consumption of food and water. It is estimated that humans may consume thousand to millions of micro-plastic particles, equating to several milligrams per day. Prolonged exposure to micro-plastics and nano-plastics has been linked to negative effects on different living organisms, including neurotoxicity, gastrointestinal toxicity, nephrotoxicity, and hepatotoxicity, and developmental toxicities. The main purpose of this review is to explore the effect of micro-plastics and nano-plastics on the male and female reproductive system, as well as their offspring, and the associated mechanism implicated in the reproductive and developmental toxicities. Micro-plastics and nano-plastics have been shown to exert negative effects on the reproductive system of both male and female mammals and aquatic animals, including developmental impacts on gonads, gametes, embryo, and their subsequent generation. In addition, micro-plastics and nano-plastics impact the hypothalamic-pituitary axes, leading to oxidative stress, reproductive toxicity, neurotoxicity, cytotoxicity, developmental abnormalities, poor sperm quality, diminishes ovarian ovulation and immune toxicity. This study discusses the so many different signaling pathways associated in the male and female reproductive and developmental toxicity induced by micro-plastics and nano-plastics.

Computational exploration of the genomic assignments, molecular structure, and dynamics of the ccdABXn2 toxin-antitoxin homolog with its bacterial target, the DNA gyrase, in the entomopathogen Xenorhabdus nematophila.

Toxin-antitoxin (TA) modules, initially discovered on bacterial plasmids and subsequently identified within chromosomal contexts, hold a pivotal role in the realm of bacterial physiology. Among these, the pioneering TA system, ccd (Control of Cell Death), primarily localized on the F-plasmid, is known for its orchestration of plasmid replication with cellular division. Nonetheless, the precise functions of such systems within bacterial chromosomal settings remain a compelling subject that demands deeper investigation. To bridge this knowledge gap, our study focuses on exploring ccdABXn2, a chromosomally encoded TA module originating from the entomopathogenic bacterium Xenorhabdus nematophila. We meticulously delved into the system's genomic assignments, structural attributes, and functional interplay. Our findings uncovered intriguing patterns-CcdB toxin homologs exhibited higher conservation levels compared to their CcdA antitoxin counterparts. Moreover, we constructed secondary as well as tertiary models for both the CcdB toxin and CcdA antitoxin using threading techniques and subsequently validated their structural integrity. Our exploration extended to the identification of key interactions, including the peptide interaction with gyrase for the CcdB homolog and CcdB toxin interactions for the CcdA homolog, highlighting the intricate TA interaction network. Through docking and simulation analyses, we unequivocally demonstrated the inhibition of replication via binding the CcdB toxin to its target, DNA gyrase. These insights provide valuable knowledge about the metabolic and physiological roles of the chromosomally encoded ccdABXn2 TA module within the context of X. nematophila, significantly enhancing our comprehension of its functional significance within the intricate ecosystem of the bacterial host.Communicated by Ramaswamy H. Sarma.

Baicalin and N-acetylcysteine regulate choline metabolism via TFAM to attenuate cadmium-induced liver fibrosis.

(Background): Cadmium is an environmental pollutant associated with several liver diseases. Baicalin and N-Acetylcysteine have antioxidant and hepatoprotective effects. (Purpose): However, it is unclear whether baicalin and N-Acetylcysteine can alleviate Cadmium -induced liver fibrosis by regulating metabolism, or whether they exert a synergistic effect. (Study design): We treated Cadmium-poisoned mice with baicalin, N-Acetylcysteine, or baicalin+ N-Acetylcysteine. We studied the effects of baicalin and N-Acetylcysteine on Cadmium-induced liver fibers and their specific mechanisms. (Methods): We used C57BL/6 J mice, and AML12, and HSC-6T cells to establish in vitro assays and in vivo models. (Results): Metabolomics was used to detect the effect of baicalin and N-Acetylcysteine on liver metabolism, which showed that compared with the control group, the Cadmium group had increased fatty acid and amino acid levels, with significantly reduced choline and acetylcholine contents. Baicalin and N-Acetylcysteine alleviated these Cadmium-induced metabolic changes. We further showed that choline alleviated Cadmium -induced liver inflammation and fibrosis. In addition, cadmium significantly promoted extracellular leakage of lactic acid, while choline alleviated the cadmium -induced destruction of the cell membrane structure and lactic acid leakage. Western blotting showed that cadmium significantly reduced mitochondrial transcription factor A (TFAM) and Choline Kinase α(CHKα2) levels, and baicalin and N-Acetylcysteine reversed this effect. Overexpression of Tfam in mouse liver and AML12 cells increased the expression of CHKα2 and the choline content, alleviating and cadmium-induced lactic acid leakage, liver inflammation, and fibrosis. (Conclusion): Overall, baicalin and N-Acetylcysteine alleviated cadmium-induced liver damage, inflammation, and fibrosis to a greater extent than either drug alone. TFAM represents a target for baicalin and N-Acetylcysteine, and alleviated cadmium-induced liver inflammation and fibrosis by regulating hepatic choline metabolism.

Role of Mitochondrial Reactive Oxygen Species-Mediated Chaperone-Mediated Autophagy and Lipophagy in Baicalin and N-Acetylcysteine Mitigation of Cadmium-Induced Lipid Accumulation in Liver.

Cadmium (Cd) is a major health concern globally and can accumulate and cause damage in the liver for which there is no approved treatment. Baicalin and N-acetylcysteine (NAC) have been found to have protective effects against a variety of liver injuries, but it is not clear whether their combined use is effective in preventing and treating Cd-induced lipid accumulation. The study found that Cd increased the production of mitochondrial reactive oxygen species (mROS) and elevated the level of chaperone-mediated autophagy (CMA). Interestingly, mROS-mediated CMA exacerbates the Cd-induced inhibition of lipophagy. Baicalin and NAC counteracted inhibition of lipophagy by attenuating Cd-induced CMA, suggesting an interplay between CMA elevation, mitochondrial destruction, and mROS formation. Maintaining the stability of mitochondrial structure and function is essential for alleviating Cd-induced lipid accumulation in the liver. Choline is an essential component of the mitochondrial membrane and is responsible for maintaining its structure and function. Mitochondrial transcriptional factor A (TFAM) is involved in mitochondrial DNA transcriptional activation and replication. Our study revealed that the combination of baicalin and NAC can regulate choline metabolism through TFAM and thereby maintain mitochondrial structure and functionality. In summary, the combination of baicalin and NAC plays a more beneficial role in alleviating Cd-induced lipid accumulation than the drug alone, and the combination of baicalin and NAC can stabilize mitochondrial structure and function and inhibit mROS-mediated CMA through TFAM-choline, thereby promoting lipophagy to alleviate Cd-induced lipid accumulation.

TFAM-mediated intercellular lipid droplet transfer promotes cadmium-induced mice nonalcoholic fatty liver disease.

Cadmium (Cd) is an important environmental pollutant. Herein, we discovered a new way of lipid accumulation, where lipid droplets can be transferred across cells. In this study, mice and AML12 cells were used to establish models of Cd poisoning. After Cd treatment, the level of TFAM was reduced, thereby regulating the reconstitution of the cytosolic actin filament network. MYH9 is a myosin involved in cell polarization, migration, and movement of helper organelles. Rab18 is a member of the Rab GTPase family, which localizes to lipid droplets and regulates lipid drop dynamics. In this study, we found that Cd increases the interaction between MYH9 and Rab18. However, TFAM overexpression alleviated the increase in Cd-induced interaction between MYH9 and Rab18, thereby reducing the transfer of intercellular lipid droplets and the accumulation of intracellular lipids. Through a co-culture system, we found that the transferred lipid droplets can act as a signal to form an inflammatory storm-like effect, and ACSL4 can act as an effector to transfer lipid droplets and promote lipid accumulation in surrounding cells. These results suggest that TFAM can be used as a new therapeutic target for Cd-induced lipid accumulation in the liver.

Targeting of essential mycobacterial replication enzyme DnaG primase revealed Mitoxantrone and Vapreotide as novel mycobacterial growth inhibitors.

Tuberculosis (TB) is the second leading cause of mortality after COVID-19, with a global death toll of 1.6 million in 2021. The escalating situation of drug-resistant forms of TB has threatened the current TB management strategies. New therapeutics with novel mechanisms of action are urgently required to address the current global TB crisis. The essential mycobacterial primase DnaG with no structural homology to homo sapiens presents itself as a good candidate for drug targeting. In the present study, Mitoxantrone and Vapreotide, two FDA-approved drugs, were identified as potential anti-mycobacterial agents. Both Mitoxantrone and Vapreotide exhibit a strong Minimum Inhibitory Concentration (MIC) of ≤25µg/ml against both the virulent (M.tb-H37Rv) and avirulent (M.tb-H37Ra) strains of M.tb. Extending the validations further revealed the inhibitory potential drugs in ex vivo conditions. Leveraging the computational high-throughput multi-level docking procedures from the pool of ~2700 FDA-approved compounds, Mitoxantrone and Vapreotide were screened out as potential inhibitors of DnaG. Extensive 200 ns long all-atoms molecular dynamic simulation of DnaGDrugs complexes revealed that both drugs bind strongly and stabilize the DnaG during simulations. Reduced solvent exposure and confined motions of the active centre of DnaG upon complexation with drugs indicated that both drugs led to the closure of the active site of DnaG. From this study's findings, we propose Mitoxantrone and Vapreotide as potential anti-mycobacterial agents, with their novel mechanism of action against mycobacterial DnaG.

Unravelling the potential of Triflusal as an anti-TB repurposed drug by targeting replication protein DciA.

The increasing prevalence of drug-resistant Tuberculosis (TB) is imposing extreme difficulties in controlling the TB infection rate globally, making treatment critically challenging. To combat the prevailing situation, it is crucial to explore new anti-TB drugs with a novel mechanism of action and high efficacy. The Mycobacterium tuberculosis (M.tb)DciA is an essential protein involved in bacterial replication and regulates its growth. DciA interacts with DNA and provides critical help in binding other replication machinery proteins to the DNA. Moreover, the lack of any structural homology of M.tb DciA with human proteins makes it an appropriate target for drug development. In this study, FDA-approved drugs were virtually screened against M.tb DciA to identify potential inhibitors. Four drugs namely Lanreotide, Risedronate, Triflusal, and Zoledronic acid showed higher molecular docking scores. Further, molecular dynamics simulations analysis of DciA-drugs complexes reported stable interaction, more compactness, and reduced atomic motion. The anti-TB activity of drugs was further evaluated under in vitro and ex vivo conditions where Triflusal was observed to have the best possible activity with the MIC of 25 µg/ml. Our findings present novel DciA inhibitors and anti-TB activity of Triflusal. Further investigations on the use of Triflusal may lead to the discovery of a new anti-TB drug.

Osmoregulatory and immunological role of new canceled cells: Mitochondrial rich cells and its future perspective: A concise review.

Mitochondrial-rich cells (MRCs) are one of the most significant canceled type of epithelial cells. Morphologically these cells are totally different from other epithelial cells. These cells primarily implicated in sea-water and fresh-water adaptation, and acid-base regulation. However, in this review paper, we explored some of the most intriguing biological and immune-related functional developmental networks of MRCs. The main pinpoint, MRCs perform a dynamic osmoregulatory and immunological functional role in the gut and male reproductive system. The Na+/K+_ATPase (NKA) and Na+/K+/2Cl cotransporter (NKCC) are key acidifying proteins of MRCs for the ion-transporting function for intestinal homeostasis and maintenance of acidifying the luminal microenvironment in the male reproductive system. Further more importantly, MRCs play a novel immunological role through the exocrine secretion of nano-scale exosomes and multivesicular bodies (MVBs) pathway, which is very essential for sperm maturation, motility, acrosome reaction, and male sex hormones, and these an essential events to produce male gametes with optimal fertilizing ability. This effort is expected to promote the novel immunological role of MRCs, which might be essential for nano-scale exosome secretion.

Cadmium promotes nonalcoholic fatty liver disease by inhibiting intercellular mitochondrial transfer.

Mitochondrial transfer regulates intercellular communication, and mitochondria regulate cell metabolism and cell survival. However, the role and mechanism of mitochondrial transfer in Cd-induced nonalcoholic fatty liver disease (NAFLD) are unclear. The present study shows that mitochondria can be transferred between hepatocytes via microtubule-dependent tunneling nanotubes. After Cd treatment, mitochondria exhibit perinuclear aggregation in hepatocytes and blocked intercellular mitochondrial transfer. The different movement directions of mitochondria depend on their interaction with different motor proteins. The results show that Cd destroys the mitochondria-kinesin interaction, thus inhibiting mitochondrial transfer. Moreover, Cd increases the interaction of P62 with Dynactin1, promotes negative mitochondrial transport, and increases intracellular lipid accumulation. Mitochondria and hepatocyte co-culture significantly reduced Cd damage to hepatocytes and lipid accumulation. Thus, Cd blocks intercellular mitochondrial transfer by disrupting the microtubule system, inhibiting mitochondrial positive transport, and promoting their negative transport, thereby promoting the development of NAFLD.

Interactive mechanism between connexin43 and Cd-induced autophagic flux blockage and gap junctional intercellular communication dysfunction in rat hepatocytes.

Cadmium (Cd) is a significant environmental contaminant known for its potential hepatotoxic effects. However, the precise mechanisms underlying Cd-induced hepatotoxicity have yet to be fully understood. Therefore, the purpose of this study was to investigate the dynamic role of connexin 43 (Cx43) in response to Cd exposure, particularly its impact on gap junctional intercellular communication (GJIC) and autophagy in hepatocytes. To establish an in vitro model of Cd-induced hepatocyte injury, the Buffalo rat liver 3A cell line (BRL3A) was utilized.In order to elucidate the mechanism by which Cx43 influences Cd-induced hepatocyte toxic injury, inhibitors of Cx43 (Dynasore) and P-Cx43 (Ro318220) were employed in the model. The findings revealed that inhibiting Cx43 and its phosphorylation further compromised GJIC function, exacerbating the impairment, while also intensifying the blockage of autophagic flux. To gain further insight into the role of Cx43, siRNA was utilized to knock down Cx43 expression, yielding similar results. The down-regulation of Cx43 expression was found to worsen the morphological damage induced by cadmium exposure, diminish the cell proliferation capacity of BRL3A cells, and exacerbate the disruption of GJIC and autophagic flow caused by Cd.These findings suggest that Cx43 may serve as a potential therapeutic target for the treatment of liver damage resulting from Cd exposure. By targeting Cx43, it may be possible to mitigate the adverse effects of Cd on hepatocytes.

Co-exposure to cadmium and microplastics promotes liver fibrosis through the hemichannels -ATP-P2X7 pathway.

Microplastics (MPs) and cadmium (Cd) are important environmental pollutants, that damage the liver. However, the effect and mechanism of combined Cd and MPs exposure on liver fibrosis are still largely unknown. In this study investigated, Cd + MPs exposure increased superoxide anion production and promoted extracellular ATP release compared with exposure to Cd or MPs individually. Cd + MPs increased inflammatory cell infiltration, activated the P2X7-NLRP3 signaling pathway, and promoted inflammatory factor release. Cd + MPs aggravated Cd- or MPs-induced liver fibrosis and induced liver inflammation. In AML12/HSC-T6 cell in vitro poisoning model, exposure of AML12 cells to Cd + MPs increased the opening of connexin hemichannels and promoted extracellular ATP release. Treatment of HSC-T6 cells with the supernatant of AML12 cells exposed to Cd + MPs significantly promoted HSC-T6 cell activation. Treatment of HSC-T6 cells with different concentrations of ATP produced similar results. TAT-Gap19TFA, an inhibitor of connexin hemichannels, significantly inhibited the ATP release and activation of Cd + MPs-treated HSC-T6 cells. Finally, the expression of the ATP receptor P2X7 was silenced in HSC-T6 cells, which significantly inhibited their activation. In conclusion, exposure to Cd + MPs promoted liver fibrosis through the ATP-P2X7 pathway and synergistically affected liver inflammation and fibrosis.

Cross-Talk Between Selenium Nanoparticles and Cancer Treatment Through Autophagy.

Autophagy is commonly referred as self-eating and a complex cellular process that is involved in the digestion of protein and damaged organelles through a lysosome-dependent mechanism, and this mechanism is essential for maintaining proper cellular homeostasis. Selenium is a vital trace element that plays essential functions in antioxidant defense, redox state control, and range of particular metabolic processes. Selenium nanoparticles have become known as a promising agent for biomedical use, because of their high bioavailability, low toxicity, and degradability. However, and in recent years, they have attracted the interest of researchers in developing anticancer nano-drugs. Selenium nanoparticles can be used as a potential therapeutic agent or in combination with other agents to act as carriers for the development of new treatments. More intriguingly, selenium nanoparticles have been extensively shown to impact autophagy signaling, allowing selenium nanoparticles to be used as possible cancer treatment agents. This review explored the connections between selenium and autophagy, followed by developments and current advances of selenium nanoparticles for autophagy control in various clinical circumstances. Furthermore, this study examined the functions and possible processes of selenium nanoparticles in autophagy regulation, which may help us understand how selenium nanoparticles regulate autophagy for the potential cancer treatment.

A new insight of cadmium-induced cellular evidence of autophagic-associated spermiophagy during spermatogenesis.

Autophagy plays a dynamic role in spermatozoa development during spermatogenesis. However, the disruption of autophagic flux induces cell death under metal toxicity and severe oxidative stress. Therefore, we hypothesized that cadmium-induced autophagy might be involved in this mechanism. To verify this hypothesis, we studied cadmium-induced cellular evidence of autophagic-associated spermiophagy within the testis. In the present study, treatment with cadmium caused nuclear depressive disorders and vacuolated mitochondrial damage of Sertoli cells. In addition, spermiophagy through the cellular evidence of spermatozoa phagocytosis, the high lysosomal activity (lysosome engulfment and phagolysosome), and autophagy activity (autolysosome and autophagosome) were observed in the Sertoli cells. The immunohistochemistry of lysosomal membrane protein (LAMP2) to target the phagocytosis of spermatozoa revealed that the immunoreactivity of LAMP2 was overstimulated in the luminal compartment of testis's seminiferous tubules. In addition, the immunohistochemistry and immunofluorescence of autophagy-related protein and microtubule-associated light chain (LC3) results showed the strong immunoreactivity and immunosignaling of LC3 in the Sertoli cells of the testis. Moreover, cadmium caused the overactivation of the expression level of autophagy-related proteins, autophagy-related gene (ATG7), (ATG5), beclin1, LC3, sequestosome 1 (P62), and LAMP2 which were confirmed by western blotting. In summary, this study demonstrated that hazards related to cadmium-induced autophagic-associated spermiophagy with the disruption of autophagic flux, providing new insights into the toxicity of cadmium in mammals and representing a high risk to male fertility.

Melatonin alleviates cadmium-induced nonalcoholic fatty liver disease in ducks by alleviating autophagic flow arrest via PPAR-α and reducing oxidative stress.

Cadmium (Cd) is an important environmental pollutant that causes liver damage and induces nonalcoholic fatty liver disease (NAFLD). NAFLD is a fat accumulation disease and has significant effects on the body. Melatonin (Mel) is an endogenous protective molecule with antioxidant, anti-inflammatory, antiobesity, and antiaging effects. However, whether Mel can alleviate Cd-induced NAFLD and its mechanism remains unclear. First, in vivo, we found that Mel maintained mitochondrial structure and function, inhibited oxidative stress, and reduced Cd-induced liver injury. In addition, Mel alleviated lipid accumulation in the liver induced by Cd. In this process, Mel inhibits fatty acid production and promotes fatty acid oxidation. Interestingly, Mel regulated PPAR-α expression and alleviated Cd-induced autophagy blockade. In vitro model, the oil Red O staining, and WB results showed that Mel alleviated Cd-induced lipid accumulation. In addition, RAPA was used to activate autophagy to alleviate Cd-induced lipid accumulation, and TG was used to block autophagy flux to aggravate Cd-induced autophagy accumulation. After knocking down PPAR-α, the autophagosome fusion with lysosomes, and autophagic flux was inhibited and increased Cd-induced lipid accumulation. Mel alleviates mitochondrial damage and oxidative stress, and attenuates Cd-induced NAFLD by restoring the expression of PPAR-α and restoring autophagy flux.

Cadmium-induced impairment of spermatozoa development by reducing exosomal-MVBs secretion: a novel pathway.

Cadmium is a heavy environmental pollutant that presents a high risk to male-fertility and targets the different cellular and steroidogenic supporting germ cells networks during spermatogenesis. However, the mechanism accounting for its toxicity in multivesicular bodies (MVBs) biogenesis, and exosomal secretion associated with spermatozoa remains obscure. In the current study, the light and electron microscopy revealed that, the Sertoli cells perform a dynamic role with secretion of well-developed early endosomes (Ee) and MVBs pathway associated with spermatozoa during spermatogenesis. In addition, some apical blebs containing nano-scale exosomes located on the cell surface and after fragmentation nano-scale exosomes were directly linked with spermatozoa in the luminal compartment of seminiferous tubules, indicating normal spermatogenesis. Controversially, the cadmium treated group showed limited and deformed spermatozoa with damaging acromion process and mid-peace, and the cytoplasmic vacuolization of spermatids. After cadmium treatment, there is very limited biogenesis of MVBs inside the cytoplasm of Sertoli cells, and no obvious secretions of nano-scale exosomes interacted with spermatozoa. Interestingly, the cadmium treated group demonstrated relatively higher formation of autophagosomes and autolysosome, and the autophagosomes were enveloped by MVBs that later formed the amphisome which degraded by lysosomes, indicating the hypo-spermatogenesis. Moreover, cadmium declined the exosomal protein cluster of differentiation (CD63) and increased the autophagy-related proteins microtubule-associated light chain (LC3), sequestosome 1 (P62) and lysosomal-associated membrane protein 2 (LAMP2) expression level were confirmed by Western blotting. These results provide rich information regarding how cadmium is capable of triggering impaired spermatozoa development during spermatogenesis by reduction of MVBs pathway through high activation of autophagic pathway. This study explores the toxicant effect of cadmium on nano-scale exosomes secretion interacting with spermatozoa.

Spectacular role of epididymis and bio-active cargo of nano-scale exosome in sperm maturation: A review.

The epididymis is responsible for post-testicular sperm maturation as it provides a favorable environment for spermatozoa to gain the ability for movement and fertilization. The recent evidence has shown that, the spermatozoa are vulnerable to dynamic variations driven by various cellular exposure mechanisms mediated by epididymosomes. Exosomes provide new insight into a mechanism of intercellular communication because they provide direct evidence for the transfer of several important bio-active cargo elements (proteins, lipid, DNA, mRNA, microRNA, circular RNA, long noncoding RNA) between epididymis and spermatozoa. In broad sense, proteomic analysis of exosomes from epididymis indicates number of proteins that are involved in sperm motility, acrosomal reaction, prevent pre-mature sperm capacitation and male infertility. Pinpointing, how reproductive disorders are associated with bio-active cargo elements of nano-scale exosome in the male reproductive tract. Therefore, the current review presents evidence regarding the distinctive characteristics and functions of nano-scale exosome in the male reproductive tract in both pathological and physiological developments, and argue that these vesicles serve as an important regulator of male reproduction, fertility, and disease susceptibility.

Reactive Oxygen Species Control Osteoblast Apoptosis through SIRT1/PGC-1α/P53Lys382 Signaling, Mediating the Onset of Cd-Induced Osteoporosis.

The imbalance between osteogenesis and osteoclastogenesis is a feature of bone metabolic disease. Cadmium (Cd) exposure causes human bone loss and osteoporosis (OP) through bioaccumulation of the food chain. However, the impact of Cd on bone tissues and the underlying molecular mechanisms are not well-characterized. In the current study, we found that the Cd concentration in bone tissues of OP patients was higher than normal subjects; meanwhile, the nuclear silent information regulator of transcription 1 (SIRT1) protein expression level was significantly decreased, which is a new star molecule to treat OP. It is further revealed that SIRT1 activation markedly reprograms bone metabolic and stress-response pathways that incline with osteoblast (OB) apoptosis. Suppressing reactive oxygen species (ROS) release with N-acetyl-l-cysteine (NAC) abolished Cd-induced reduction of SIRT1 protein, deacetylation of P53, OB apoptosis, and attenuated OP. Conversely, overexpression of SIRT1 suppressed Cd-induced ROS release. SIRT1 overexpression in vivo and in vitro dampened PGC-1α protein, acetylation of P53 at lysine 382, and caspase-dependent apoptosis. These results reveal that ROS/SIRT1 controls P53 acetylation and coordinates OB apoptosis involved in the onset of OP.

Taurine Alleviates Cadmium-Induced Hepatotoxicity by Regulating Autophagy Flux.

Our previous studies have confirmed that cadmium (Cd) exposure causes hepatotoxicity; it also induces autophagy and blocks the autophagy flux. Therefore, we hypothesized that Cd hepatotoxicity could be alleviated through nutritional intervention. Taurine (Tau) has various biological functions such as acting as an antioxidant, acting as an anti-inflammatory, and stabilizing cell membranes. In order to explore the protective effect and internal mechanism of Tau on Cd-induced hepatotoxicity, normal rat liver cell line BRL3A cells were treated with Cd alone or in combination with Tau to detect cell injury and autophagy-related indexes in this study. We found that Tau can alleviate Cd-induced cell-proliferation decline and morphological changes in the cell. In addition, Tau activates autophagy and alleviates the blockage of Cd-induced autophagy flux. In this process, lysosome acidification and degradation were enhanced, and autophagosomes were further fused with lysosomes. Then, we found that Tau alleviated autophagic flux block by promoting the transfer of membrane fusion proteins STX17 and SNAP29 to autophagosomes and the translocation of VAMP8 to lysosomes, which in turn attenuated the hepatocyte injury induced by Cd exposure. This will further reveal the hepatotoxicity mechanism of Cd and provide the theoretical basis for the prevention and treatment of Cd poisoning.

The Mechanism of Osteoprotegerin-Induced Osteoclast Pyroptosis In Vitro.

Osteoprotegerin (OPG) is a new member of the tumor necrosis factor (TNF) receptor superfamily, which can inhibit the differentiation and activity of osteoclasts by binding to nuclear factor kappa B receptor activator (RANK) competitively with nuclear factor kappa B receptor activator ligand (RANKL). The previous experiments found that OPG can induce apoptosis of mature osteoclasts in vitro, which can inhibit the activity of mature osteoclasts, thereby exerting its role in protecting bone tissue. In addition, pyroptosis is a new type of cell death that is different from apoptosis. It is unclear whether OPG can induce mature osteoclast pyroptosis and thereby play its role in protecting bone tissue. In this study, the results showed that compared with the control group, the survival rate of osteoclasts in the OPG group was significantly reduced, and the contents of IL-1ß, IL-18, and LDH in the supernatant both increased. Many osteoclast plasma membranes were observed to rupture in bright fields, and OPG induced loss of their morphology. Flow cytometry was used to analyze the pyroptosis rate; OPG significantly increased the osteoclast pyroptosis rate. To further reveal the mechanism of OPG-induced osteoclast pyroptosis, we examined the expression level of pyroptosis-related genes and proteins, and the results found that OPG increased the expression of NLRP3, ASC, caspase-1, and GSDMD-N compared with the control group. In summary, OPG can induce osteoclast pyroptosis, and its mechanism is related to the expression levels of ASC, NLRP3, caspase 1 and GSDMD, which were included in the classical pathway of pyroptosis.