Despite the advances in our understanding of the genetic and immunological basis of cancer, cancer remains a major public health burden with an ever-increasing incidence rate globally. Nevertheless, increasing evidence suggests that the components of the complement system could regulate the tumor microenvironment (TME) to promote cancer progression, recurrence, and metastasis. In the present study, we used an integrative multi-omics analysis of clinical data to explore the relationships between the expression levels of and genetic and epigenetic alterations in C3, C5, C3AR1, and C5AR1 and tumor immune evasion, therapy response, and patient prognosis in various cancer types. We found that the complements C3, C5, C3AR1, and C5AR1 have deregulated expression in human malignancies and are associated with activation of immune-related oncogenic processes and poor prognosis of cancer patients. Furthermore, we found that the increased expression levels of C3, C5, C3AR1, and C5AR1 were primarily predicted by copy number variation and gene methylation and were associated with dysfunctional T-cell phenotypes. Single nucleotide variation in the gene signature co-occurred with multiple oncogenic mutations and is associated with the progression of onco-immune-related diseases. Further correlation analysis revealed that C3, C5, C3AR1, and C5AR1 were associated with tumor immune evasion via dysfunctional T-cell phenotypes with a lesser contribution of T-cell exclusion. Lastly, we also demonstrated that the expression levels of C3, C5, C3AR1, and C5AR1 were associated with context-dependent chemotherapy, lymphocyte-mediated tumor killing, and immunotherapy outcomes in different cancer types. In conclusion, the complement components C3, C5, C3AR1, and C5AR1 serve as attractive targets for strategizing cancer immunotherapy and response follow-up.

Valproic acid (VPA), an anti-epileptic drug, reduces testosterone levels and sperm quality. However, the degree to which testosterone levels and sperm quality are decreased under VPA treatment needs to be clarified. The aim of the present study was to investigate the testicular proteins involved in testosterone synthesis and spermatogenesis, histopathology and sperm acrosome status in VPA-treated rats. Adult rats were divided into control and experimental groups (n = 8 in each). Rats in the experimental group were treated with 500 mg kg–1, i.p., VPA for 10 consecutive days. Expression of Ki-67, tyrosine phosphorylated proteins and testicular steroidogenic proteins was examined. As expected, VPA-treated rats exhibited adverse changes in almost all reproductive parameters, particularly an increase in precocious acrosome reactions, compared with the control group. In addition, fibrosis of the tunica albuginea and tubule basement membrane was observed in testes from VPA-treated rats. Moreover, the expression of testicular Ki-67, cholesterol side-chain cleavage enzyme (P450scc) and phosphorylated proteins (41, 51 and 83 kDa) was decreased significantly in VPA-treated rats compared with control. In contrast, the expression of steroidogenic acute regulatory proteins in the VPA-treated group was significantly higher than in the control group. In conclusion, VPA treatment changes the expression of testicular proteins responsible for spermatogenesis and testosterone production, resulting in male infertility.

To investigate male reproductive parameters via changes of potential testicular protein markers in restraint-stress rats. Male Sprague-Dawley rats were divided into two groups (non-immobilized control and restraint-immobilized/stress groups, n=8 each group). The stress animals were immobilized (12 h/d) by a restraint cage for 7 consecutive days. All reproductive parameters, morphology and histology were observed and compared between groups. In addition, the expression of steroidogenic acute regulatory (StAR) and phosphotyrosine proteins (previously localized in Sertoli and late spermatid cells) in testicular lysate was assayed by immuno-Western blotting. Testosterone level, sperm concentration and sperm head normality of stress rats were significantly decreased while the corticosterone level was increased as compared with the control (P<0.05). Histologically, stress rats showed low sperm mass in epididymal lumen and some atrophy of seminiferous tubules. Although the expression of testicular StAR protein was not significantly different between groups, changed patterns of the 131, 95, and 75 kDa testicular phosphorylated proteins were observed in the stress group compared with the control group. The intensity of a testicular 95-kDa phosphorylated protein was significantly decreased in stress rats. This study has demonstrated the alteration of testicular phosphorylated protein patterns, associated with adverse male reproductive parameters in stress rats. It could be an explanation of some infertility in stress males.

目的 探讨 Phyllanthus emblica L.(PE)叶提取物对慢性应激大鼠睾丸损伤和相关蛋白标志物变化的影响。

Chronic stress is a major common cause of male infertility. Many species of velvet beans are shown to be rich in l-DOPA. In Thai folklore medicine, seeds of Mucuna pruriens (L.) DC. var. pruriens (Thai Mhamui or T-MP) have been used for treating erectile dysfunction. This study aimed to determine l-DOPA levels in T-MP seed extract and investigate its preventive on sexual behaviors and reproductive parameter damages including essential proteins in chronic unpredictable mild stress (CUMS) mice. Mice were divided into 4 groups: (I) control, (II) CUMS, (III) T-MP300 + CUMS, and (IV) T-MP600 + CUMS. Groups I and II received DW while groups III and IV were pretreated with the seed extracts (300 and 600 mg/kg BW) for 14 consecutive days before co-treatment with a randomly different CUMS/day (from 12 mild stressors) for 43 days. T-MP seed extract contained l-DOPA approximately 10% of total dried weight. A dose of 600 mg/kg improved sexual performances and degenerative seminiferous epithelium in CUMS mice. Sperm qualities and testosterone level were elevated while corticosterone was decreased in co-treatment groups. T-MP-CUMS cotreated groups also improved expressions of AKAP4, AR, and TyrPho proteins in testis, epididymis, and sperm. T-MP increased StAR and CYP11A1 expressions in testis. It also suppressed testicular apoptosis via decreased expressions of Hsp70, caspases 3, and 9. T-MP seeds containing l-DOPA could improve sexual behaviors and essential reproductive proteins caused by CUMS. Natural Products; Traditional Herbal Medicine; Animal Model; Histopathology.