Poweromin X Ten, a polyherbal formulation improves male sexual function: In vivo and network pharmacology study.

Introduction: Poweromin X Ten (PXT) is a polyherbal formulation, traditionally used to enhance male sexual function. However, the safety and benefits of PXT have not been scientifically evaluated. Therefore, the present study investigated the toxicity and aphrodisiac potential of PXT in male rats and explored its principal mechanisms of action. Methods: Male Wistar rats were orally administered PXT (50 or 100 mg/kg) for 28 days, and sexual activity parameters, including latency and frequency of mounting and intromissions, were studied. The reproductive toxicity and spermatogenic potential were also examined. Furthermore, dopamine and serotonin levels in brain regions associated with sexual activity were assessed. Network analysis was used to identify the key bioactive compounds and their core targets involved in their beneficial actions. Results: Treatment with PXT improved sexual activity in male rats, as evidenced by reduced mounting and intromission latency and a significant increase in mount frequency. Moreover, PXT exhibited spermatogenic potential and did not induce reproductive toxicity. Notably, treatment with 50 mg/kg PXT elevated dopamine levels in median preoptic area and hypothalamus. Pathway analysis indicated that PXT primarily modulated the PI3K-Akt, calcium, and MAPK signalling pathways to enhance male sexual function. Network analysis identified macelignan, ß-estradiol, testosterone, and paniculatine as key bioactive components of PXT, which likely act through core targets, such as androgen receptor (AR), Mitogen-activated protein kinase 3 (MAPK3), epidermal growth factor receptor (EGFR), estrogen receptor 1 (ESR1), and vascular endothelial growth factor (VEGF) to facilitate the improvement of male sexual function. Conclusion: Study results suggest that PXT is a safer alternative with aphrodisiac and spermatogenic potential. These effects are partly attributed to the enhanced dopamine levels in the brain. Furthermore, this study provides insights into the specific signalling pathways and bioactive compounds that underlie the improvements in male sexual function associated with PXT.

Molecular Susceptibility and Treatment Challenges in Melanoma.

Melanoma is the most aggressive subtype of cancer, with a higher propensity to spread compared to most solid tumors. The application of OMICS approaches has revolutionized the field of melanoma research by providing comprehensive insights into the molecular alterations and biological processes underlying melanoma development and progression. This review aims to offer an overview of melanoma biology, covering its transition from primary to malignant melanoma, as well as the key genes and pathways involved in the initiation and progression of this disease. Utilizing online databases, we extensively explored the general expression profile of genes, identified the most frequently altered genes and gene mutations, and examined genetic alterations responsible for drug resistance. Additionally, we studied the mechanisms responsible for immune checkpoint inhibitor resistance in melanoma.

Spermidine as an epigenetic regulator of autophagy in neurodegenerative disorders.

Autophagy is an abnormal protein degradation and recycling process that is impaired in various neurological diseases like Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease. Spermidine is a natural polyamine found in various plant- and meat-based diets that can induce autophagy, and is decreased in various neurodegenerative diseases. It acts on epigenetic enzymes like E1A-binding protein p300, HAT enzymes like Iki3p and Sas3p, and α-tubulin acetyltransferase 1 that modulate autophagy. Histone modifications like acetylation, phosphorylation, and methylation could influence autophagy. Autophagy is epigenetically regulated in various neurodegenerative disorders with many epigenetic enzymes and miRNAs. Polyamine regulation plays an essential role in the disease pathogenesis of AD and PD. Therefore, in this review, we discuss various enzymes and miRNAs involved in the epigenetic regulation of autophagy in neurodegenerative disorders and the role of spermidine as an autophagy enhancer. The alterations in spermidine-mediated regulation of Beclin-1, LC3-II, and p62 genes in AD and other PD-associated enzymes could impact the process of autophagy in these neurodegenerative diseases. With the ever-growing data and such promising effects of spermidine in autophagy, we feel it could be a promising target in this area and worth further detailed studies.

Moonlighting functions of the ubiquitin-like protein, Hub1/UBL-5.

The faithful splicing of pre-mRNA is critical for accurate gene expression. Dysregulation of pre-mRNA splicing has been associated with several human diseases including cancer. The ubiquitin-like protein Hub1/UBL5 binds to the substrates non-covalently and promotes pre-mRNA splicing. Additionally, UBL5 promotes the common fragile sites stability and the Fanconi anemia pathway of DNA damage repair. These functions strongly suggests that UBL5 could potentially be implicated in cancer. Therefore, we analyzed the UBL5 expression in TCGA tumor sample datasets and observed the differences between tumor and normal tissues among different tumor subtypes. We have noticed the alteration frequency of UBL5 in TCGA tumor samples. Altogether, this review summarizes the UBL5 functions and discusses its putative role in tumorigenesis.

The ubiquitin-like protein Hub1/UBL-5 functions in pre-mRNA splicing in Caenorhabditis elegans.

The ubiquitin-like protein Hub1/UBL-5 associates with proteins non-covalently. Hub1 promotes alternative splicing and splicing of precursor mRNAs with weak introns in yeast and mammalian cells; however, its splicing function has remained elusive in multicellular organisms. Here, we demonstrate the splicing function of Hub1/UBL-5 in the free-living nematode Caenorhabditis elegans. Hub1/UBL-5 binds to the HIND-containing splicing factors Snu66/SART-1 and PRP-38 and associates with other spliceosomal proteins. C. elegans hub1/ubl-5 mutants die at the Larval 3 stage and show splicing defects for selected targets, similar to the mutants in yeast and mammalian cells. UBL-5 complemented growth and splicing defects in Schizosaccharomyces pombe hub1 mutants, confirming its functional conservation. Thus, UBL-5 is important for C. elegans development and plays a conserved pre-mRNA splicing function.

What is the Role of Lithium in Epilepsy?

Lithium is a well-known FDA-approved treatment for bipolar and mood disorders. Lithium has been an enigmatic drug with multifaceted actions involving various neurotransmitters and intricate cell signalling cascades. Recent studies highlight the neuroprotective and neurotrophic actions of lithium in amyotrophic lateral sclerosis, Alzheimer's disease, intracerebral hemorrhage, and epilepsy. Of note, lithium holds a significant interest in epilepsy, where the past reports expose its non-specific proconvulsant action, followed lately by numerous studies for anti-convulsant action. However, the exact mechanism of action of lithium for any of its effects is still largely unknown. The present review integrates findings from several reports and provides detailed possible mechanisms of how a single molecule exhibits marked pro-epileptogenic as well as anti-convulsant action. This review also provides clarity regarding the safety of lithium therapy in epileptic patients.

Role of promoters in regulating alternative splicing.

Alternative splicing (AS) plays a critical role in enhancing proteome complexity in higher eukaryotes. Almost all the multi intron-containing genes undergo AS in humans. Splicing mainly occurs co-transcriptionally, where RNA polymerase II (RNA pol II) plays a crucial role in coordinating transcription and pre-mRNA splicing. Aberrant AS leads to non-functional proteins causative in various pathophysiological conditions such as cancers, neurodegenerative diseases, and muscular dystrophies. Transcription and pre-mRNA splicing are deeply interconnected and can influence each other's functions. Several studies evinced that specific promoters employed by RNA pol II dictate the RNA processing decisions. Promoter-specific recruitment of certain transcriptional factors or transcriptional coactivators influences splicing, and the extent to which these factors affect splicing has not been discussed in detail. Here, in this review, various DNA-binding proteins and their influence on promoter-specific AS are extensively discussed. Besides, this review highlights how the promoter-specific epigenetic changes might regulate AS.

Sde2 is an intron-specific pre-mRNA splicing regulator activated by ubiquitin-like processing.

The expression of intron-containing genes in eukaryotes requires generation of protein-coding messenger RNAs (mRNAs) via RNA splicing, whereby the spliceosome removes non-coding introns from pre-mRNAs and joins exons. Spliceosomes must ensure accurate removal of highly diverse introns. We show that Sde2 is a ubiquitin-fold-containing splicing regulator that supports splicing of selected pre-mRNAs in an intron-specific manner in Schizosaccharomyces pombe Both fission yeast and human Sde2 are translated as inactive precursor proteins harbouring the ubiquitin-fold domain linked through an invariant GGKGG motif to a C-terminal domain (referred to as Sde2-C). Precursor processing after the first di-glycine motif by the ubiquitin-specific proteases Ubp5 and Ubp15 generates a short-lived activated Sde2-C fragment with an N-terminal lysine residue, which subsequently gets incorporated into spliceosomes. Absence of Sde2 or defects in Sde2 activation both result in inefficient excision of selected introns from a subset of pre-mRNAs. Sde2 facilitates spliceosomal association of Cactin/Cay1, with a functional link between Sde2 and Cactin further supported by genetic interactions and pre-mRNA splicing assays. These findings suggest that ubiquitin-like processing of Sde2 into a short-lived activated form may function as a checkpoint to ensure proper splicing of certain pre-mRNAs in fission yeast.