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Background: Submucosal fibrosis (OSF) of the oral cavity is a chronic scarring disease. Arecoline (Are) is the driving factor for the occurrence and deterioration of OSF. Curcumin plays a vital anti‐inflammatory role in Are‐induced OSF development. However, its potential pharmacological mechanism needs to be elucidated. Methods: The relative molecular level was measured via qRT‐PCR or Western blot. MTT assay, transwell assay and flow cytometry detected cell proliferation, migration, and apoptosis. The correlation between hypoxia‐inducible factor‐1α (HIF‐1α) and LTBP2 promoter was confirmed through dual‐luciferase reporter assay. ELISA was performed to detect inflammatory cytokines levels. Results: Curcumin alleviated Are‐induced oral mucosal fibroblast cells fibrosis by reducing oral mucosa fibroblasts viability, promoting cell apoptosis, suppressing cell migration, and down‐regulating the levels of fibrosis markers and inflammatory factors. Curcumin relieved Are‐induced OSF via inhibiting HIF‐1α. Mechanically, HIF‐1α bound to the promoter of LTBP2 to transcriptionally activated LTBP2. LTBP2 knockdown relieved Are‐induced OSF, and curcumin down‐regulated LTBP2 via inhibiting HIF‐1α to relieve Are‐induced OSF. Moreover, curcumin decreased NF‐κB signal associated proteins via inhibiting LTBP2 to relieve Are‐induced OSF. Conclusion: Curcumin reduced the transcription level of LTBP2 by inhibiting HIF‐1α, thereby inactivating NF‐κB pathway to alleviate Are‐induced OSF. [ABSTRACT FROM AUTHOR]

BACKGROUND: Obesity induces insulin resistance and chronic inflammation, impacting human health. The relationship between obesity, gut microbiota, and regulatory mechanisms has been studied extensively. Dendrobium officinale polysaccharide (DOP), a traditional Chinese herbal medicine, potentially reduces insulin resistance. However, the mechanism through which DOP affects gut microbiota and alleviates obesity‐induced insulin resistance in rats requires further investigation. RESULTS: The current study aimed to assess the impact of DOP on gut microbiota and insulin resistance in rats on a high‐fat diet. The results revealed that DOP effectively reduced blood lipids, glucose disorders, oxidative stress, and inflammatory infiltration in the liver of obese Sprague Dawley rats. This was achieved by downregulating SOCS3 expression and upregulating insulin receptor substrate‐1 (IRS‐1) by regulating the JAK/STAT/SOCS3 signaling pathway. Notably, DOP intervention enhanced the abundance of beneficial gut microbiota and reduced harmful microbiota. Correlation analysis demonstrated significant associations among intestinal microbiota, SOCS3‐mediated IRS‐1 expression, and inflammatory factors. CONCLUSION: Dendrobium officinale polysaccharide regulated the gut microbiota, enhanced IRS‐1 expression, and mitigated liver injury and insulin resistance due to a high‐fat diet. These findings depict the potential anti‐insulin resistance properties of DOP and offer further evidence for addressing obesity and its complications. © 2023 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Sperm is the key media between the father's aberrant exposure and the offspring's phenotype. Whether paternal hypertension affects offspring through sperm epigenetics remains to be explored. To investigate the underlying mechanisms, we constructed a hypertensive mice model induced by drinking l -NAME and found that spermatocytes and spermatids in the testis were increased significantly after l -NAME treatment. The sequencing of sperm showed that tsRNA profiles changed with 315 tsRNAs (195 up-regulated and 120 down-regulated) altered. Meanwhile, KEGG pathway analysis showed that the target genes of these altered tsRNAs were involved in influencing some important signaling pathways, such as the cAMP signaling path, the mTOR signaling path, the Hippo signaling path, and the Ras signaling path. Bioinformatics of tsRNA-miRNA-mRNA pathway interactions revealed several ceRNA mechanisms, such as tsRNA-00051, the ceRNA of miR-128-1-5p, co-targeting Agap1. This study provides evidence for enriching and further understanding the pathophysiology and paternal epigenetic mechanisms of testicular reproduction, as well as contributing to a rethinking of the transgenerational reprogramming mechanisms of paternal exposure in hypertension. • l -NAME-induced paternal hypertension alters sperm tsRNA profiles. • KEGG analysis of the altered sperm tsRNA sequence shows that affected signaling pathways are involved in cell growth, development, metabolism, and aging. • The tsRNA-miRNA-mRNA expression network provides a possible mechanism for the effects of hypertension on sperm function and offspring development. [ABSTRACT FROM AUTHOR]

Endoplasmic reticulum (ER) stress is a common cellular stress response that is triggered by a variety of conditions that disturb cellular homeostasis, and induces cell apoptosis. Autophagy, an important and evolutionarily conserved mechanism for maintaining cellular homeostasis, is closely related to the apoptosis induced by ER stress. There are common upstream signaling pathways between autophagy and apoptosis induced by ER stress, including PERK/ATF4, IRE1α, ATF6, and Ca2+. Autophagy can not only block the induction of apoptosis by inhibiting the activation of apoptosis-associated caspase which could reduce cellular injury, but also help to induce apoptosis. In addition, the activation of apoptosis-related proteins can also inhibit autophagy by degrading autophagy-related proteins, such as Beclin-1, Atg4D, Atg3, and Atg5. Although the interactions of different autophagy- and apoptosis-related proteins, and also common upstream signaling pathways have been found, the potential regulatory mechanisms have not been clearly understood. In this review, we summarize the dual role of autophagy, and the interplay and potential regulatory mechanisms between autophagy and apoptosis under ER stress condition. [ABSTRACT FROM AUTHOR]

Hypoxia occurs in a series of supraphysiological circumstances, for instance, sleep disorders, myocardial infarction and cerebral stroke, that can induce a systematic inflammatory response. Such a response may then lead to a widespread dysfunction and cell injury. Autophagy, a cellular homeostatic process that governs the turnover of damaged organelles and proteins, can be triggered by multiple forms of extra- and intracellular stress, for example, hypoxia, nutrient deprivation and reactive oxygen specie. Central to this process is the formation of double-membrane vesicles, thereby autophagosomes sequester portions of cytosol and deliver them to the lysosomes for a breakdown. In recent years, several distinct oxygen-sensing pathways that regulate the cellular response to autophagy have been defined. For instance, hypoxia influences autophagy in part through the activation of the hypoxia-inducible factor (HIF)-dependent pathways. In chronic and moderate hypoxia, autophagy plays a protective role by mediating the removal of the damaged organelles and protein. Moreover, three additional oxygen-sensitive signaling pathways are also associated with the activation of autophagy. These include mammalian target of rapamycin (mTOR) kinase, unfolded protein response (UPR)- and PKCδ-JNK1-dependent pathways. Contrary to the protective effects of autophagy, during rapid and severe oxygen fluctuations, autophagy may be detrimental and induce cell death. In this review, we highlight a serious of recent advances on how autophagy is regulated at the molecular level and on final consequences of cell under different hypoxic environment. [ABSTRACT FROM AUTHOR]

Bladder cancer is a common tumour of the urinary system, and more than 90% is urothelial carcinoma. Therefore, it is important for discovering the key target genes and molecules of bladder tumour cell metastasis and invasion. Our research initially explored the regulation of deltaN p63 on the progression and metastasis of bladder cancer and found that deltaN p63 can influence the occurrence of EMT through PTEN and ultimately regulate the growth and metastasis of bladder cancer. In summary, this study identified a new EMT regulator, deltaN p63, further revealed the mechanism of the invasion and metastasis of bladder cancer cells, and provided a theoretical basis for finding new target molecules and drugs to treat bladder cancer. In conclusion, this study will further reveal the mechanism of tumour cell invasion and metastasis and provide a theoretical basis for cancer treatment to find new target molecules and drugs. [ABSTRACT FROM AUTHOR]

Simple Summary: The Chinese soft-shelled turtle (Trionyx sinensis) is an important cultured reptile in East Asia. Hemorrhagic sepsis caused by Aeromonas hydrophila infection is the dominant disease in the aquaculture of Chinese soft-shelled turtles, while the molecular pathology is far from clear due to the lag of research on turtle immunology. It has been reported in mammals and fish that the dysfunction of immune responses to pathogen infections causes host tissue hemorrhagic sepsis. In this study, two groups of turtles with different susceptibility to A. hydrophila infection are found. A comparative transcriptome strategy is adopted to examine the gene expression profiles in liver and spleen for these two phenotypes of turtles post A. hydrophila infection, for the first time revealing the full picture of immune mechanisms against A. hydrophila, which provides new insight into the molecular pathology during A. hydrophila infection in T. sinensis. The findings will promote further investigations on pathogenic mechanisms of hemorrhagic sepsis caused by A. hydrophila infection in T. sinensis, and also will benefit their culture industry. Although hemorrhagic sepsis caused by Aeromonas hydrophila infection is the dominant disease in the aquaculture of Chinese soft-shelled turtle, information on its molecular pathology is seriously limited. In this study, ninety turtles intraperitoneally injected with A. hydrophila exhibited two different phenotypes based on the pathological symptoms, referred to as active and inactive turtles. Comparative transcriptomes of liver and spleen from these two groups at 6, 24, and 72 h post-injection (hpi) were further analyzed. The results showed that cytokine–cytokine receptor interaction, PRRs mediated signaling pathway, apoptosis, and phagocytosis enriched in active and inactive turtles were significantly different. Pro-inflammatory cytokines, the TLR signaling pathway, NLR signaling pathway, and RLR signaling pathway mediating cytokine expression, and apoptosis-related genes, were significantly up-regulated in inactive turtles at the early stage (6 hpi). The significant up-regulation of phagocytosis-related genes occurred at 24 hpi in inactive turtles and relatively lagged behind those in active turtles. The anti-inflammatory cytokine, IL10, was significantly up-regulated during the tested periods (6, 24, and 72 hpi) in active turtles. These findings offer valuable information for the understanding of molecular immunopathogenesis after A. hydrophila infection, and facilitate further investigations on strategies against hemorrhagic sepsis in Chinese soft-shelled turtle T. sinensis. [ABSTRACT FROM AUTHOR]

[Display omitted] • 18 new water-soluble matrine-type alkaloids and 22 known ones were isolated from Sophora alopecuroides. • Bis-amide matrine-type alkaloids provides new sight to develop novel modificatory strategies based on A or B ring. • The preliminary anti-neuroinflammatory structure–activity relationships of matrine-type alkaloids were established. • Anti-neuroinflammatory mechanism may related to the NF- κ B signaling pathway by suppressing the phosphorylation of I κ B α and p65 subunit. A phytochemical investigation on the alkaloids from water-soluble part of Sophora alopecuroides led to obtain forty matrine-type alkaloids (1 – 40) including eighteen new ones (1 – 18), which covers almost all positions of the oxygen substitution in matrine-type structure. Notably, eight compounds (1 – 8) belong to rare bis-amide matrine-type alkaloid. The new structures were determined based on extensive spectroscopic data, electronic circular dichroism (ECD) calculations, and six instances, verified by X-ray crystallography. Most of isolates showed anti-neuroinflammatory activities based on the expression of tumor necrosis factor (TNF)- α and interleukin (IL)-6 in BV2 microglia cells. Especially, compound 39 can suppress those two mediator secretions in a dose-dependent manner with IC 50 values of 21.6 ± 0.5 and 16.7 ± 0.8 μM, respectively. Further mechanistic study revealed that 39 suppressed the phosphorylation of I κ B α and p65 subunit to regulate the NF- κ B signaling pathway. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is a major cause of chronic disability and death in young adults worldwide. Multiple cellular, molecular and biochemical changes impact the development and outcome of TBI. Neuronal cell apoptosis, which is an important pathological change in secondary brain damage, is crucial to determine the functional recovery after TBI. miR-21, a widely-reported oncogene, which can reduce cell apoptosis in cancer, has been confirmed to be a pronounced up-regulated miRNA after TBI in animal model. Our study is designed to investigate whether miR-21 has the function of antiapoptosis in experimental TBI model in vitro and to explore the possible regulatory mechanism of miR-21 on neuronal apoptosis. The scratch cell injury was performed to mimic TBI-induced apoptosis in neurons, and miR-21 agomir/antagomir was transfected to up-/down-regulate the miR-21 level. Our data suggests that miR-21 can reduce the number of TUNEL-positive neurons. Meanwhile, miR-21 decreased the expression level of PTEN, and increased the phosphorylation of Akt significantly. In neurons transfected with miR-21 agomir, the expression of Bcl-2 was promoted while the caspase-3, caspase-9 and Bax level were down-regulated, which are crucially the downstream apoptosis-related proteins of PTEN-Akt signaling pathway. In conclusion, miR-21 can exert the function of reducing neuronal apoptosis through activating the PTEN-Akt signaling pathway. Our research provides new insights into the molecular mechanisms of neuronal apoptosis following TBI, which reminds that miR-21may be a potential therapeutic target for TBI treatment. [ABSTRACT FROM AUTHOR]

• Silencing VCAM-1 and BMSCs synergistically improve cardiac function of MI rats. • Injection with BMSCs and sh-VCAM-1 increases CPR and survival rate of MI rats. • Injection with BMSCs and sh-VCAM-1 reduce the IS and myocardial apoptosis. • sh-VCAM-1 could inhibit the NF-κB signaling pathway. • sh-VCAM-1 enhances the therapeutic effects of BMSCs by NF-κB pathway. Bone mesenchymal stem cells (BMSCs) has been well known to exert therapeutic potential for patients with myocardial infarction (MI). VCAM-1 can promote the migration of lymphocytes to the inflammatory zone. In the present study, we tried to explore whether VCAM-1 silenced-BMSCs have better therapeutic effects on MI. BMSCs were isolated and cultured followed by treatment of a lentivirus silencing VCAM-1 and NF-κB activator (PMA). Besides, MI rat models were also established and injected with treated BMSCs to detect the effect of VCAM-1 silenced-BMSCs in MI, as evidenced by detection of cardiac function, survival of rats within 72 h, infarct size and myocardial cell apoptosis. Moreover, the expression of NF-κB-regulated gene products was also determined. The implantation of sh-VCAM-1 BMSCs into MI rats resulted in more reductions in myocardial infarct size as well as myocardial cell apoptosis, improved cardiac function, the number of survived rats within 72 h, and survival time within 72 h compared with the individual treatments of either BMSCs or control. In addition, transplanted BMSCs down-regulated the expression of NF-κB-p65, MMP-9, TNF-α, and Bax, and up-regulated VEGF and Bcl-2 in myocardial tissue, which could be further enhanced by sh-VCAM-1 and rescued by PMA. Our study demonstrated that silencing VCAM-1 in BMSCs could inhibit inflammation and apoptosis, thus improving cardiac function in MI. [ABSTRACT FROM AUTHOR]