Aging induced testicular damage: analyzing the ameliorative potential of Mucuna pruriens seed extract.

Mucuna pruriens Linn. (M. pruriens), a leguminous plant, was used extensively in Ayurveda, to treat male-related infertility. Previous studies have demonstrated antioxidant, androgenic, aphrodisiac, and spermatogenic properties of M. pruriens seed extract. Surprisingly, the biological activities of M. pruriens on aging-induced pathological changes in the testis microenvironment have never been explored and the present study was focused on the testing therapeutic efficacy of M. pruriens on aged rat testis. Male Wistar albino rats were grouped as; adult (3 months), aged (24 months), aged + M. pruriens and adult + M. pruriens (N = 6/group). The extract was administrated at a dose of 200 mg/kg body weight (dosage determined in our previous study) daily by gavage for 60 days. The total and free testosterone, FSH and LH levels were considerably increased in aged + M. pruriens. The diameter & volume of the seminiferous tubules, the height & volume of the epithelium, and the number of Leydig cells number were significantly decreased in aged rat testis, concomitantly connective tissue proportion was increased compared to adult rats. The seminiferous epithelium indicates significant rejuvenation or restoration of spermatogenic cells in aged + M. pruriens rat testis. The highlighting observations in aged + M. pruriens was increased in the following parameters i.e., tubular diameter (25%), number of tubules (35%), epithelial height (25%) & volume (20%), and number of Leydig cells (35%) when compared to untreated aged rat testis. The TNFα, NF-κB, cytochrome c, Caspase-9, Caspase-3, Bcl-2, Bax, PARP iNOS, and inflammatory and apoptotic factors were downregulated in aged + M. pruriens. M. pruriens was able to restore spermatogenesis and enhance the activity of Sertoli cells and Leydig cells and improve the pituitary-gonadal axis in aged rat testis and observations indicate the therapeutic activity of M. pruriens in aged rat testis.

Testosterone Influence on Microtubule-Associated Proteins and Spine Density in Hippocampus: Implications on Learning and Memory.

The thorny protrusions or spines increase the neuronal surface area, facilitate synaptic interconnections among neurons, and play an essential role in the hippocampus. Increasing evidence suggests that testosterone, the gonadal hormone, plays an important role in neurogenesis and synaptic plasticity. The role of testosterone on microtubule-associated proteins on dendritic neurite stability in the hippocampus and its impact on learning disability is not elucidated. Adult male Wistar albino rats were randomly selected for the control, castrated, castrated + testosterone, and control + testosterone groups. Bilateral orchidectomy was done, and the testosterone propionate was administered during the entire trial period, i.e., 14 days. The learning assessments were done using working/reference memory versions of the 8-arm radial maze and hippocampal tissues processed for histological and protein expressions. There were reduced expressions of microtubule-associated protein 2 (MAP2), postsynaptic density protein 95 (PSD95), and androgen receptor (AR) and increased expression of pTau in the castrated group. Conversely, the expression of MAP2, PSD95, and AR was increased, and the pTau expression was reduced in the hippocampus of the castrated rat administrated with testosterone. Androgen-depleted rats showed impaired synaptic plasticity in the hippocampus associated with contracted microtubule dynamics. Along with learning disability, there was an increased number of reference memory errors and working memory errors in castrated rats. Observations suggest that androgen regulates expression of neural tissue-specific MAPs and plays a vital role in hippocampus synaptic plasticity and that a similar mechanism may underlie neurological disorders in aging and hypogonadal men.

Influence of Testosterone Depletion on Neurotrophin-4 in Hippocampal Synaptic Plasticity and Its Effects on Learning and Memory.

Sex steroids are neuromodulators that play a crucial role in learning, memory, and synaptic plasticity, providing circuit flexibility and dynamic functional connectivity in mammals. Previous studies indicate that testosterone is crucial for neuronal functions and required further investigation on various frontiers. However, it is surprising to note that studies on testosterone-induced neurotrophin-4 (NT-4) expression and its influence on synaptic plasticity and learning and memory moderation are scanty. The present study is focused on analysing the localized influence of NT-4 on hippocampal synaptic plasticity and associated moderation in learning and memory under testosterone deprivation. Adult Wistar albino rats were randomly divided into various groups, control (Cont), orchidectomy (ORX), ORX + testosterone supplementation (ORX + T), and Cont + testosterone (Cont + T). After 2 weeks, the serum testosterone level was undetectable in ORX rats. The behavioural assessment showed a decline in the learning ability of ORX rats with increased working and reference memory errors in the behavioural assessment in the 8-arm radial maze. The mRNA and protein expressions of NT-4 and androgen receptors (ARs) were significantly reduced in the ORX group. In addition, there was a decrease in the number of neuronal dendrites in Golgi-Cox staining. These changes were not seen in ORX + T rats with improved learning behaviour indicating that testosterone exerts its protective effect on hippocampal synaptic plasticity through AR-dependent NT-4 regulation in learning and memory upgrade.

Identification of miR-802-5p and its involvement in type 2 diabetes mellitus.

MicroRNAs (miRNA) are recently discovered endogenous, small noncoding RNAs (of 22 nucleotides) that play pivotal roles in gene regulation. They are involved in post-transcriptional control of gene expression. miRNAs are emerging as important regulators of cell proliferation, development, cancer formation, stress responses, cell death and physiological conditions. Increasing evidence has demonstrated the human miRNAs bind to their target mRNA sequences with perfect or near-perfect sequence complementarily. This provides a powerful strategy for discovering potential type 2 diabetes mellitus (T2DM) targets and gives the probability to exploit them for diagnostic and therapeutic causes. About 6% of the world population is affected by T2DM, and it is recognized as a global epidemic by the World Health Organization. At present there is no valid biomarker to control or manage T2DM. Therefore, the present study applied a mature sequence of miRNAs from publicly accessible databases to identify the miRNA from T2DM expressed sequence tags, and the results are detailed and discussed below.

Therapeutic potential of Mucuna pruriens (Linn.) on ageing induced damage in dorsal nerve of the penis and its implication on erectile function: an experimental study using albino rats.

OBJECTIVE: To study the effect of ethanolic seed extract of Mucuna pruriens on damaged dorsal nerve of the penis (DNP) in aged rat in relation to penile erection. METHODS: The rats were divided into four groups Young (3 months), Aged (24 - 28 months), Aged + M. pruriens, and Young + M. pruriens (200 mg/kg b.w/60 days) and were subjected to the hypophysial - gonadal axis, nerve conduction velocity (NCV), and penile reflex. DNP sections were stained with nitric oxide synthase (nNOS), nicotinamide adenine dinucleotide phosphate (NaDPH) diaphorase, androgen receptor (AR), and osmium tetroxide. Terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling (TUNEL) staining, electron microscopy(EM) and histometric analyses were done. RESULTS: Significant disturbance in hypophysial - gonadal axis was noted in aged rat. With reduced number of myelinated fibers, diameter, vacuolization, indentation of the myelin sheath, and degeneration. nNOS and its cofactor (NaDPH diaphorase) were reduced in aged rat DNP. NCV was slow in aged rats and concomitant poor penile reflex was also noted. AR showed reduced expression in aged rat DNP when compared to young and control groups. TUNEL positive cells were increased in aged rat DNP. These pathological changes were remarkably reduced or recovered in M. pruriens treated aged rats. CONCLUSIONS: The results indicate a multi-factorial therapeutic activity in penile innervations towards sustaining the penile erection in the presence of the extract in aged rats and justifying the claim of traditional usage.

Expression of adenosine receptors and vegf during angiogenesis and its inhibition by pentoxifylline-A study using zebrafish model.

Angiogenesis, formation of new blood vessels is an important process involved in neovascular diseases and tumor progression. Understanding and defining novel therapeutic targets of neovascular diseases like retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration have been hindered by a lack of appropriate animal models. Zebrafish provides an excellent vertebrate model to study above disorders since its circulatory system and retinal layers are similar to mammals. Adenosine is a known mediator of angiogenesis in hypoxic condition and adenosine receptor antagonists such as theophylline, theobromine are known to exert antiangiogenic properties. We evaluated the anti-angiogenic potential of a methylxanthine pentoxifylline (PTX) with various concentrations (0.1-1mM) at 50% epiboly stage (5.2 hpf) of zebrafish embryos and studied the mRNA expression of major angiogenic factors like vegfaa and its receptors under normal conditions and when treated with an adenosine analog NECA (5'-N-ethylcarboxamidoadenosine). Upregulation of adenosine receptors, hif-1α and vegfaa by NECA could possibly mimic hypoxic condition, but PTX downregulated vegfaa and other growth factors at 1mM concentration. Vegfa protein expression was also downregulated by PTX in the retina and the compound did not damage the retinal cells. Embryos treated with PTX generated abnormal phenotypic variants with poor vasculature, tail bending and developmental delay at 1mM. Survival rates, heart rate and hatching rates were also significantly lower. Targeting the vegf signaling pathway with small molecules inhibiting adenosine receptors in addition to antagonizing vegf might be a promising approach to treat neovascular diseases of the retina and also tumors.