Roles of Thermosensitive Transient Receptor Channels TRPV1 and TRPM8 in Paclitaxel-Induced Peripheral Neuropathic Pain.

Paclitaxel, a microtubule-stabilizing chemotherapy drug, can cause severe paclitaxel-induced peripheral neuropathic pain (PIPNP). The roles of transient receptor potential (TRP) ion channel vanilloid 1 (TRPV1, a nociceptor and heat sensor) and melastatin 8 (TRPM8, a cold sensor) in PIPNP remain controversial. In this study, Western blotting, immunofluorescence staining, and calcium imaging revealed that the expression and functional activity of TRPV1 were upregulated in rat dorsal root ganglion (DRG) neurons in PIPNP. Behavioral assessments using the von Frey and brush tests demonstrated that mechanical hyperalgesia in PIPNP was significantly inhibited by intraperitoneal or intrathecal administration of the TRPV1 antagonist capsazepine, indicating that TRPV1 played a key role in PIPNP. Conversely, the expression of TRPM8 protein decreased and its channel activity was reduced in DRG neurons. Furthermore, activation of TRPM8 via topical application of menthol or intrathecal injection of WS-12 attenuated the mechanical pain. Mechanistically, the TRPV1 activity triggered by capsaicin (a TRPV1 agonist) was reduced after menthol application in cultured DRG neurons, especially in the paclitaxel-treated group. These findings showed that upregulation of TRPV1 and inhibition of TRPM8 are involved in the generation of PIPNP, and they suggested that inhibition of TRPV1 function in DRG neurons via activation of TRPM8 might underlie the analgesic effects of menthol.

microRNA-486-5p is implicated in the cisplatin-induced apoptosis and acute inflammation response of renal tubular epithelial cells by targeting HAT1.

The proinflammatory property of cisplatin is potentially destructive and contributes to the pathogenesis of acute kidney injury (AKI). The role and upstream regulatory mechanism of histone acetyltransferase 1 (HAT1) in acute kidney inflammation are still unknown. We performed RNA sequencing to filter differentially expressed microRNAs (miRNAs) in the kidney tissue of mice with AKI induced by cisplatin and ischemia-reperfusion. Here, we found that miR-486-5p was upregulated and that the expression of HAT1 was reduced in AKI mouse models and injured human renal proximal tubular epithelial cell (HK-2) model induced by cisplatin. miR-486-5p is implicated in cisplatin-induced kidney damage in vivo. Bioinformatics analysis predicted a potential binding site between miR-486-5p and HAT1. The Luciferase reporter assay and Western blot confirmed that miR-486-5p directly targeted the 3'-untranslated region of HAT1 mRNA and inhibited its expression in the cytoplasm of HK-2 cells. In the in vitro study, inhibiting miR-486-5p reduced apoptosis, and the expression of proinflammatory mediators was induced by cisplatin in HK-2 cells. Simultaneously, the downregulation of miR-486-5p inhibited the activation of the toll-like receptor 4 (TLR4) and nuclear factor-kappa B (NF-κB). We further found that HAT1 could inhibit apoptosis and the activation of cisplatin on the TLR4/NF-κB pathway and that the upregulation of miR-486-5p reversed this effect. Therefore, the upregulation of miR-486-5p targeting HAT1 promoted the cisplatin-induced apoptosis and acute inflammation response of renal tubular epithelial cells by activating the TLR4/NF-κB pathway, providing a new basis to highlight the potential intervention of regulating the miR-486-5p/HAT1 axis.

[Novel coronavirus induces testicular injury: Analysis of causes and follow-up monitoring].

The outbreak of coronavirus disease 2019 (COVID-19) caused by 2019 novel coronavirus has become a global public health challenge. In addition to the typical respiratory symptoms, COVID-19 can induce damage to testicular spermatogenesis. This study focuses on the possible causes and follow-up monitoring of testicular injury induced by COVID-19.

[Effect of testicular autophagy on spermatogenic cells in varicocele rats].

OBJECTIVE: To study the effect of different levels of autophagy in the testis on the apoptosis of spermatogenic cells in the rat model of varicocele (VC). METHODS: We randomly divided 54 SD male rats into six groups, blank control (n = 6), rapamycin control (n = 6), chloroquine control (n = 6), VC model control (n = 12), VC + rapamycin (n = 12), and VC + chloroquine (n = 12). We observed the histomorphological changes of the testis and epididymis by HE staining, obtained the scores on spermatogenesis in the testis and epididymis, calculated the apoptosis index (AI) of the testicular spermatogenic cells by TUNEL, and determined the expressions of LC3-Ⅱ, LC3-Ⅰ, p62, Bax and Bcl-2 proteins in the testis tissue by Western blot. RESULTS: There were no significant morphological changes in the testis and epididymis of the rats in the blank control, rapamycin control and chloroquine control groups, or significant differences in the scores on testicular and epididymal spermatogenesis and AI of the testicular spermatogenic cells (P>0.05). The animals in the VC model control group exhibited significant pathological damage in the testicular and epididymal tissues, with remarkably decreased scores on spermatogenesis (P<0.01) and increased AI (P<0.01), which were markedly improved in the VC + rapamycin group and slightly aggravated in the VC + chloroquine group compared with the VC model controls. In comparison with the rats in the blank control group, those in the VC model control group showed significantly up-regulated expressions of the autophagy-related protein LC3 (including the LC3-Ⅱ/LC3-Ⅰ ratio) and the pro-apoptotic protein Bax in testicular tissue (P<0.01) but down-regulated expression of the anti-apoptotic protein Bcl-2 (P<0.01). The expressions of LC3 and Bcl-2 in the testis tissue were significantly higher in the VC + rapamycin (P<0.01) but lower in the VC + chloroquine group (P<0.01), while those of p62 and Bax remarkably lower in the VC + rapamycin (P<0.01) but higher in the VC + chloroquine group than in the VC model controls (P<0.01). CONCLUSIONS: Varicocele induces autophagy in the testis and apoptosis of spermatogenic cells in rats. Up-regulating autophagy can inhibit while blocking autophagy can promote the apoptosis of spermatogenic cells.

Overexpression of sirtuin 1 attenuates calcium oxalate-induced kidney injury by promoting macrophage polarization.

Sirtuin 1 (SIRT1) protein is involved in macrophage differentiation, while NOTCH signaling affects inflammation and macrophage polarization. Inflammation and macrophage infiltration are typical processes that accompany kidney stone formation. However, the role and mechanism of SIRT1 in renal tubular epithelial cell injury caused by calcium oxalate (CaOx) deposition and the relationship between SIRT1 and the NOTCH signaling pathway in this urological disorder are unclear. This study investigated whether SIRT1 promotes macrophage polarization to inhibit CaOx crystal deposition and reduce renal tubular epithelial cell injury. Public single-cell sequencing data, RT-qPCR, immunostaining approaches, and Western blotting showed decreased SIRT1 expression in macrophages treated with CaOx or exposed to kidney stones. Macrophages overexpressing SIRT1 differentiated towards the anti-inflammatory M2 phenotype, significantly inhibiting apoptosis and alleviating injury in the kidneys of mice with hyperoxaluria. Conversely, decreased SIRT1 expression in CaOx-treated macrophages triggered Notch signaling pathway activation, promoting macrophage polarization towards the pro-inflammatory M1 phenotype. Our results suggest that SIRT1 promotes macrophage polarization towards the M2 phenotype by repressing the NOTCH signaling pathway, which reduces CaOx crystal deposition, apoptosis, and damage in the kidney. Therefore, we propose SIRT1 as a potential target for preventing disease progression in patients with kidney stones.

[Advances in proteomic research on plant responses to metal-based nanomaterial stress]. / æ¤ç‰©å¯¹é‡‘å±žçº³ç±³ææ–™èƒè¿«å“åº”çš„è›‹ç™½è´¨ç»„å­¦ç ”ç©¶è¿›å±•.

Soil is gradually becoming the main sink of metal-based nanomaterials (MNMs) in the environment. Plants, as a vital component in the ecosystem, play a critical role in determining the fate of nanomaterials. Previous studies showed that MNMs could affect the growth and development of various plant species via altering protein expression. In this review, we described the differences in plant protein expression caused by various typical MNM stresses, and summarized the impact factors including physicochemical properties of MNMs, plant characteristics and stress conditions on plant protein response under the stress of MNMs. Moreover, the response mechanisms of plant protein to MNMs stress were reviewed, including energy synthesis and metabolic response, amino acid synthesis and information transmission response, and oxidative stress and defense response. Finally, further research directions were proposed.

GYY4137 a H2S donor, attenuates ipsilateral epididymis injury in experimentally varicocele-induced rats via activation of the PI3K/Akt pathway.

OBJECTIVES: The current study was aimed to investigate the effect of morpholin-4-ium 4 methoxyphenyl (morpholino) phosphinodithioate (GYY4137) on ipsilateral epididymis injury in a rat model of experimental varicocele (VC). MATERIALS AND METHODS: Sixty Wistar rats were randomly assigned to sham, sham plus GYY4137, VC and VC plus GYY4137 groups. Sperm quality parameters, including sperm count, motility and viability were evaluated after 4 weeks. Histological changes were measured by hematoxylin and eosin staining between the groups. The oxidative stress levels were estimated by determining epididymal superoxide dismutase (SOD) and malondialdehyde (MDA). The apoptosis status and the expression of phosphatidylinositol 3'-OH kinase (PI3K)/Akt were analyzed by immunohistochemical analysis, western blot and RT-qPCR. RESULTS: VC resulted in the decrease of sperm parameters, significant histological damage and higher levels of oxidative stress and apoptosis. Compared to the VC group, GYY4137 markedly ameliorated these observed changes. In addition, treatment with GYY4137 obviously reduced the levels of caspase-3 and Bax and increased the levels of the phosphorylation of PI3K p85 and Akt. CONCLUSION: Our data demonstrated that GYY4137 may alleviate the sperm damage and epididymis injury in experimentally VC-induced rats by activation of the PI3K/Akt pathway.