搜索结果：The Journal of steroid biochemistry and molecular biology

We aimed to estimate the prevalence of vitamin D deficiency in Mongolian pregnant women at the National level as part of the Fifth National Nutrition Survey 2016. This was a cross - sectional survey, conducted between September and November in 21 Aimags of 4 economic regions of the country, and in Ulaanbaatar. Given the regional differences in lifestyle and nutritional status, the target populations were stratified into 5 strata based on their economic region and in Ulaanbaatar, with equal samples drawn from each stratum using a cluster - randomized sampling design. A representative sample of 30 clusters was randomly selected using Probability Proportional to Size [PPS] methodology in each of the 4 regions and Ulaanbaatar for a total of 150 cluster units. The selection of survey participants differed for the three sampling regions. Household eligibility was based on having a child 0-59 months of age, living in the household which was randomly selected from each cluster for a total of 450 households in each region. Households with a child 0-59 months of age were selected from household lists available at the kheseg or Bagh level. All pregnant women were selected randomly from Soum and Khoroo family health center antenatal care registries who were mothers of a family with children aged from 0 to 5 years old. We conducted a cross - sectional survey evaluation of 924 pregnant women who were mothers of a family with children 0-5 years old. Serum concentration of 25 - hydroxyvitamin D [25(OH)D] were measured using an enzyme-linked fluorescence assay. The overall prevalence of vitamin D deficiency was 75.4% (95% CI 72.2-78.4) with no significant difference in the prevalence of vitamin D deficiency by age group, economic region, area, location, education, ethnicity and body height statuses. Also, prevalence of vitamin D deficiency was 71.9% (95% CI 60.3-81.1), 77.5% (95% CI 60.3-81.6) and 74.2% (95% CI 69.2-78.7) in the first trimester, second trimester and third trimester of pregnancy with no significant difference in the prevalence of vitamin D deficiency between the trimesters of pregnancy. Only 7.3% of pregnant women took a specific vitamin D supplement, with 31.5% of these starting in the first trimester and 60.9% of pregnant women starting supplementation in the second trimester. There is currently no vitamin D food fortification in Mongolia, and oral vitamin D intake across the whole population is very low. The findings of this survey showed that vitamin D deficiency in pregnant women is a public health problem in Mongolia. In conclusion, vitamin D deficiency and low vitamin D status are common in Mongolian pregnant women, which indicated the essential need to include vitamin D screening with adverse maternal and fetal outcomes, and a requirement needed to implement empirical vitamin D supplementation programs before food fortification with vitamin D.

Neuroactive steroids (NASs) have attracted considerable interest as novel treatments for various central nervous system (CNS) disorders and as new intravenous general anesthetics. Herein, we report the synthesis, biological evaluation, and in silico studies of a series of promising NASs, 17-imidazo[1,2-a]pyridinyl-3α-hydroxy-5α-androstanes (17IPAs). It was shown that 17IPAs can be synthesized by the condensation of 21-bromo-3α-hydroxy-5α-androstan-20-one with substituted 2-aminopyridines under mild conditions. A representative series of 17IPAs was evaluated for their ability to alter the amplitude of currents evoked by 1 µM γ-aminobutyric acid (GABA) in isolated rat cerebellar Purkinje neurons. The compounds were found to be potent and efficacious positive allosteric modulators of GABA type A receptors (GABAARs), with EC50 values ranging from 0.34 to 3.2 µM. Interactions of the most potent compound (EC50 = 0.34 ± 0.1 µM) with the GABAAR were investigated using molecular docking calculations. Our model predicts that the imidazo[1,2-a]pyridine moiety at the C17 position of the 5α-androstan-3α-ol core does not prevent the binding of the compound to the neurosteroid site at the β(+)/α(-) intersubunit interfaces. We conclude that 17IPAs retain their ability to potentiate α1β2γ2 GABAARs despite the changes in the profile of interacting residues. Experiments with [3H]flunitrazepam displacement in rat cortical membranes excluded any possible competitive binding of 17IPAs to the benzodiazepine binding site of GABAAR. Overall, 17-imidazo[1,2-a]pyridinyl-5α-androstanes may serve as the starting point for the rational design of novel selective NASs for CNS indications and anesthesia.

Polycystic ovary syndrome (PCOS) is the most prevalent endocrine-metabolic disorder in women of reproductive age, and is characterized by hyperandrogenism, anovulation, and polycystic ovarian morphology. Emerging molecular evidence has identified dysregulated ovarian steroidogenesis as a major contributing mechanism linking reproductive and metabolic phenotypes in PCOS, acting in concert with neuroendocrine and metabolic dysfunction. This review synthesizes current knowledge on enzymatic and regulatory perturbations driving androgen excess and estrogen deficiency in PCOS, emphasizing their mechanistic, diagnostic, and therapeutic implications. Dysregulated steroidogenic enzymes and associated signaling pathways contribute to androgen excess, impaired folliculogenesis, and metabolic dysfunction in PCOS. Importantly, these steroidogenic alterations are not uniform across all patients with PCOS but vary according to hyperandrogenic, anovulatory, ovulatory, lean, obese, reproductive, and metabolic phenotypes. Particular focus is placed on how these molecular derangements disrupt theca-granulosa cell communication, impair folliculogenesis, and promote hyperandrogenism, oxidative stress, and insulin resistance in the ovaries. This review also discusses therapeutic strategies according to evidence level, distinguishing established PCOS treatments such as lifestyle intervention, insulin sensitizers, ovulation-induction agents, hormonal regulators, and anti-androgens from investigational enzyme-specific inhibitors and speculative precision approaches such as gene editing and exosome-based delivery systems. Collectively, these insights underscore that the pathophysiology of PCOS extends beyond endocrine imbalance to encompass multi-omic alterations in metabolism and signaling. Understanding enzyme-level dysregulation offers opportunities for mechanism-based interventions that can restore steroidogenic homeostasis, improve fertility outcomes, and mitigate long-term metabolic risk. Future research should prioritize enzyme-signal interdependencies and develop personalized therapeutic strategies targeting the biochemical dysfunctions of PCOS.

Androgens and the androgen receptor (AR) play critical roles in prostate cancer (PCa) development and progression. Consequently, primary treatment strategies target either androgen synthesis or androgen-AR interactions. Although initially effective, tumors frequently recur as androgen-independent and more aggressive disease. In recurrent tumors, AR signaling often remains active through AR mutations or activation of alternative signaling pathways. Earlier studies from our laboratory had identified GPR56 (ADGRG1/GPCR205), an adhesion GPCR, as a possible membrane androgen receptor. Here, we demonstrate that GPR56, is significantly overexpressed in PCa tissues at both the transcript and protein levels and is associated with poor patient survival. Functional studies revealed that GPR56 promotes PCa cell proliferation and migration. Furthermore, GPR56 regulates the expression of key androgen-responsive genes, including KLK3 (PSA), FOXA1, TMPRSS2, and NKX3.1 and many others, across multiple prostate cell models. This study demonstrates that Testosterone (T) stimulation of cells expressing GPR56, activates the G13-RhoA-PKN1 signaling pathway, resulting in enhanced PKN1 expression and activation. This leads to AR-PKN1 interaction and increased transcriptional activity of AR target genes. Further T-stimulation activates serum response factor (SRF)-dependent transcription activating the RhoA-ROCK1-MLCK axis, leading to robust actin polymerization, a process associated with increased tumor cell motility and metastatic potential. Collectively, these findings shed light on the role of GPR56 in AR signaling and PCa. Further, the identification of a previously unrecognized GPR56-G13-PKN1 axis which interacts with AR and possibly SRF to enhance AR target gene activity, presents GPR56 as a promising therapeutic target especially in case of advanced PCa.

The Vitamin D External Quality Assessment Scheme (DEQAS) evaluates participants' performance of analytical methods for vitamin D metabolites, including 1,25dihydroxyvitamin D (1,25(OH)2D), by distributing samples globally on a quarterly basis. In this review an assessment of the performance of current 1,25(OH)2D methods is presented. Data submitted by scheme participants for the 2024/25 DEQAS distribution cycle was analysed and trends between assays were compared. The four distributions across the 2024/25 DEQAS cycle covered a wide concentration range, challenging participants to report results across the full reference interval. Analytical performance is improving; however, variation persists between the major method groups. Participation in an accuracy-based scheme is considered the gold standard, but there is currently no reference measurement procedure available for 1,25(OH)2D. Participant performance is therefore assessed against the Method Laboratory Trimmed Mean (MLTM). To evaluate the validity of this approach, measurement uncertainty was calculated for each method and for the All Laboratory Trimmed Mean (ALTM) across all of the distributions of the 2024/25 cycle. Calculated measurement uncertainty fell within the limits of acceptability (less than 30% of standard deviation) for the ALTM, and for the MTLM of DiaSorin Liaison XL group. For method groups with fewer participants, the uncertainty of the MLTM as a target value fell outside the limits of acceptability, confirming that the ALTM offers a more robust target value. This finding supports the use of the ALTM for assessing participants' performance, with acceptable performance being defined as the ALTM ± 30%, in at least 80% of distributed samples. This performance target represents what can be achieved with the current 'state of the art' of methods for 1,25(OH)2D measurement.

Neurodegenerative disorders such as Alzheimer's and Parkinson's diseases arise from complex interactions among oxidative stress, neuroinflammation, metabolic dysfunction, and dysregulated signaling networks. This review aim of the synthesize mechanistic evidence on β-sitosterol as a multi-target phytochemical and clarify how its actions connect to gut-brain axis modulation in neurodegeneration. The integrated mechanistic framework linking β-sitosterol's effects on cholesterol homeostasis, neuroinflammation, mitochondrial function, cholinergic signaling, and microbiota-barrier integrity to cognitive outcomes. Scope: preclinical and early translational evidence on β-sitosterol alone and with complementary phytochemicals, including nano-delivery strategies. Increasing evidence highlights phytochemicals as promising multi-target therapeutic agents capable of modulating these interconnected pathological processes. β-Sitosterol exhibits broad activity by regulating cholesterol metabolism, suppressing neuroinflammation, restoring redox balance, preserving mitochondrial function, and inhibiting important Alzheimer's diseases targets, including acetylcholinesterase and butyrylcholinesterase. The mechanisms action of β-sitosterol may (i) dampen microglial activation via TLR4/NF-κB signaling, (ii) activate Nrf2-dependent antioxidant responses (Nrf2/HO-1), (iii) support mitochondrial function and reduce ROS, (iv) stabilize membrane cholesterol and modulate amyloidogenic processing, and (v) inhibit acetylcholinesterase/butyrylcholinesterase to restore cholinergic tone. Complementary showing a neuroprotective effect actions of other phytochemicals such as curcumin, resveratrol, sulforaphane, and sinapic acid further enhance neuroprotection by modulating pathways like Nrf2/HO-1, TLR4/NF-κB, PI3K/Akt, and autophagy. Collectively, preclinical studies demonstrate that diverse botanical extracts significantly improve cognitive performance, reduce amyloid burden, restore cholinergic function, and attenuate neuroinflammation and oxidative damage. Emerging preclinical evidence suggests in rodent models of amyloid pathology, β-sitosterol (5-50 mg/kg) has been reported to improve memory in behavioral tests and reduce markers of neuroinflammation and oxidative stress; gut-brain effects include microbiota remodeling and enhanced barrier integrity, which correlate with reduced neuroimmune activation. Advances in nano-delivery systems and functional food formulations substantially improve phytochemical stability, bioavailability, and brain targeting. Available evidence is chiefly preclinical; clinical translation will require standardized dosing, pharmacokinetic and blood-brain barrier penetration studies, and randomized trials with microbiome and cognitive endpoints. Collectively, these findings position phytochemicals as promising candidates for multi-target disease modification and the development of next-generation neurotherapeutic strategies.

This study investigated the impact of prepubertal L-arginine on prepubertal and maternal codeine-induced testicular toxicity in F1 male offspring. Forty female rats were randomized at weaning into either vehicle-treated control or codeine-treated groups (n = 20 rats/group). After 8 weeks of treatment, the animals were matched with healthy, sexually developed male rats. During pregnancy and lactation, the female rats continued their pre-pregnancy treatments. The female rats delivered at term and 20 male FI offspring from each group (the control and codeine-treated groups) were divided into four groups by randomization after weaning: the control, codeine-treated, L-arginine-treated, and codeine + L-arginine-treated groups (n = 10 rats per group). Prepubertal codeine use significantly reduced testicular weight and gamma-glutamyl transferase and sorbitol dehydrogenase activities, increased testicular injury markers (lactate dehydrogenase and lactate), and distorted testicular histoarchitecture. These findings were associated with decreased activities of steroidogenic proteins (StAR, 3β-HSD, and 17β-HSD) and male reproductive hormones (LH, FSH, and testosterone). More so, codeine increased pro-inflammatory (myeloperoxidase, TNF-α, IL-1β) and pro-apoptotic (Bax and caspase 3 activity) genes and proteins, and reduced antioxidant cytoprotective genes and proteins. These negative effects were associated with the modulation of transcription factors (Nrf2 and NF-kB) and were more profound in animals whose dams were also exposed to codeine compared with those whose dams were not exposed to codeine. Nonetheless, codeine-induced perturbations were attenuated by prepubertal L-arginine administration. Our results revealed that L-arginine protected the testis and preserved testicular steroidogenesis in codeine-exposed rats by suppressing oxidative stress, inflammation, and apoptosis.

Progestin signaling in teleosts is mediated by a diverse receptor repertoire that has been further expanded after genome duplication. However, how these receptors are organized and respond to exogenous stimulation within a single species remains poorly understood. Here, we characterized the progestin receptor system (PRS) in Spinibarbus hollandi through genome-wide identification, evolutionary analysis, basal expression profiling, molecular docking, and levonorgestrel (LNG) treatment experiments. We identified 14 PRS genes, including lineage-specific loss of paqr5b and retention of duplicated paqr6, indicating uneven post-duplication trajectories within this receptor family. Basal expression profiling further revealed tissue-specific patterns of PRS components across the gonad, liver, and brain. Under LNG treatment, somatic growth remained largely stable, whereas gonadal development showed clear sex-biased responses. Females exhibited ovarian regression and reduced gonadosomatic index across all treatment groups, whereas males retained active spermatogenesis at low and medium concentrations and developed degenerative lesions mainly at the highest concentration. These phenotypic differences were accompanied by tissue-specific shifts in the overall PRS expression landscape and by non-uniform transcriptional responses among selected PRS members, including shared downregulation of paqr7a, a female-specific decline but relative male stability of paqr7b, inducible hepatic expression of pgr1, and brain upregulation of pgrmc1. Together, these findings indicate that the PRS of S. hollandi has diverged at both the repertoire and expression levels and responds to exogenous progestin treatment in a tissue- and sex-dependent manner.

This study investigates the regulatory role of p21-activated protein kinase 1 (PAK1) in estrogen secretion during ovulation induction in Bactrian camels, along with the associated molecular mechanisms. We evaluated the morphological differences of follicles between ovulatory and non-ovulatory camels through rectal examinations and B-ultrasound imaging. Using iTRAQ quantitative proteomics, we identified a significant upregulation of PAK1 protein in the ovarian tissues of the ovulatory group, followed by a bioinformatics analysis to explore its biological functions. Our results revealed distinct tissue-specific expression and distribution patterns of PAK1 within the hypothalamic-pituitary-gonadal (HPG) axis. In in vitro cultured ovarian granulosa cells, FTY720-induced activation of PAK1 significantly increased cell viability, reduced apoptosis rates, and decreased the expression of apoptosis-related molecules. Additionally, PAK1 activation enhanced the expression of key enzymes and receptors involved in estrogen synthesis, promoting estradiol secretion. Conversely, inhibiting PAK1 with IPA-3 resulted in opposing effects, exacerbating granulosa cell apoptosis and reducing estrogen synthesis. Overall, this study demonstrates that PAK1 is essential for regulating estrogen secretion by modulating granulosa cell apoptosis and the expression of key steroidogenic enzymes, ultimately influencing ovulation induction in Bactrian camels. These findings improve our understanding of the reproductive regulatory mechanisms in camels and provide a molecular framework for further investigations into ovulation induction and enhancements in reproductive performance.

Calcium (Ca²⁺) homeostasis is tightly regulated by the coordinated actions of the intestine, kidneys and bone. Ca²⁺ transport occurs via either a paracellular pathway, which depends on the expression of select claudins, including claudin-12 (CLDN12) in the tight junction, or a transcellular pathway, involving apical influx through TRPV6. While disruption of paracellular or transcellular pathways impairs transepithelial Ca²⁺ flux, Cldn12-deficient mice and Trpv6 mutant (Trpv6D541A/D541A) mice do not display alterations in Ca²⁺ balance as reported previously, perhaps because one pathway compensates for the other. To test this hypothesis, we generated a double knockout mouse (DKO, Cldn12-/-/ Trpv6D541A/D541A) to assess Ca²⁺ homeostasis using metabolic cage balance studies, quantitative real-time PCR, and micro-computed tomography (Micro-CT). Despite lacking these key Ca²⁺ transport mechanisms, DKO mice maintained normal blood Ca²⁺. However, PTH and calcitriol were significantly elevated, as were renal Cyp27b1 and Cyp24a1 expression, consistent with hormonal compensation. The proximal colon and cecum exhibited significant compensatory changes in Ca²⁺-regulatory gene expression, including upregulation of the Ca²⁺ buffer S100g and basolateral extrusion mechanism Atp2b1. Notably, the Ca²⁺ channel Trpv5, which is absent from the intestine, became detectable in the proximal colon and cecum, but not in the distal colon or small intestine of DKO mice. Micro-CT of bone revealed reduced trabecular bone volume and thickness, indicating increased bone resorption as a secondary compensatory mechanism. This study highlights the adaptive plasticity of Ca²⁺-regulatory mechanisms and suggests a role for TRPV5 in reabsorbing Ca²⁺ from the proximal colon and cecum when upstream mechanisms of Ca²⁺ absorption are impaired.

Exemestane (EMT) is a third-generation steroidal aromatase inhibitor extensively used in hormone receptor (HR)-positive breast cancer therapy and has been known to exert cardiovascular effects during prolonged treatment. The current study was planned to investigate the dose-dependent cardiotoxic effects of EMT. Thirty-two Sprague Dawley rats were randomly divided into four groups i.e., control group, EMT (5 mg/kg), EMT (15 mg/kg) and EMT (25 mg/kg) groups. Gene expression analysis showed downregulated expression of ATP2A2 (SERCA2a), CACNA1C, NOS3 (eNOS) and KLF2 coupled with marked upregulation in the expression of RYR2, PLN, CAMK2D, VEGFA, EDN1 and ICAM1, suggesting impaired calcium handling and endothelial dysfunction. The antioxidant enzymes (CAT, SOD, GPx, GST, GSR, HO-1 and GSH) were decreased significantly while the concentrations of ROS and MDA were increased in dose-dependent manner after EMT intoxication. Cardiac function assessment by echocardiography showed that EMT caused dose-dependent cardiac dysfunction as evidenced by reduced heart rate, wall thickness and cardiac chamber volumes of the ventricles thereby suggesting progressive ventricular remodeling, myocardial hypertrophy, and chamber enlargement particularly at 25 mg/kg EMT administration. Furthermore, EMT intoxication caused elevation in the levels of CK-MB, CPK, troponins, LDH, BNP, NT-proBNP and CRP. Significant upregulation observed in the levels of NF-κB, TNF-α, IL-1β, IL-6 and COX-2 after EMT administration. Moreover, EMT exposure promoted the levels of Bax, Caspase-3 and Caspase-9 while suppressing the levels of Bcl-2. Histopathological analysis demonstrated progressive myocardial degeneration, edema, inflammatory infiltration and peripheral necrosis. Overall, chronic EMT exposure leads to severe, dose-dependent cardiotoxicity, characterized by calcium dysregulation, oxidative stress, inflammatory responses, endothelial dysfunction and apoptosis, and thus warrants cardiac monitoring during prolonged EMT therapy.

Estrogen operates as a pleiotropic steroidal, neuroendocrine modulator to combat accelerated brain ageing and neurodegeneration by addressing a convergent inflammatory-metabolic trio. Estrogen receptor-dependent neural cellular signalling reduces TLR4-mediated immune priming and NF-κB activation, preventing NLRP3 inflammasome assembly and pro-inflammatory cytokine release. Concurrently, estrogen increases SIRT1 activity, restoring metabolic and epigenetic equilibrium while inhibiting HMGB1 acetylation, translocation, extracellular release, and activation of the stress-response pathway. Coordinated regulation of the TLR4-NFκB-NLRP3 and SIRT1-HMGB1 molecular triad reduces chronic neuroinflammation, preserves neuronal integrity, metabolic resilience, and slows persistent inflammation-driven brain ageing. This highlights estrogen and estrogen-based steroidal modulators as promising therapeutic candidates for reversing accelerated cognitive ageing and neurodegenerative disorders. However, a crucial research gap persists in the absence of a systems-level assessment of neurosteroids as a multi-target regulator of convergent innate immunological and metabolic signalling networks. The control of the TLR4-NFκB-NLRP3 inflammasome axis and the SIRT1-HMGB1 metabolic-epigenetic checkpoint has not been well studied as an interrelated, steroidal druggable trifecta driving brain homeostasis and neurodegeneration. These pathways are often studied in isolation, despite overwhelming evidence that their bidirectional interplay contributes to persistent neuroinflammation, immunometabolic dysfunction, and cellular senescence. This review synthesises evidence from molecular endocrinology, biochemical, pre-clinical, and clinical models to advance a mechanistically integrated and therapeutically actionable framework that aligns into a unified endocrine, metabolic, and immune target-driven framework relevant to complex, inflammation-driven brain ageing, thereby offering a strong foundation and paving the way for future molecular target validation and disease-modifying, steroid-mimetic interventions against neurodegeneration.

Organ transplantation has evolved significantly since the first successful kidney transplant in the 1950s, but corticosteroids remain a mainstay of immunosuppressive therapy. This review addresses the emerging and expanding role of corticosteroids as adjunct therapeutic agents in transplantation with particular emphasis on their immunosuppressive and tolerance inducing properties. The progression of current immunosuppressive strategies, including the combined use of steroids, calcineurin inhibitors, and mTOR inhibitors have also been discussed. The review highlights the mechanisms underlying glucocorticoid activity, including receptor interactions, gene regulation, and modulation of inflammatory responses. The clinical significance of corticosteroids is discussed across different stages of transplant therapy, including induction, long-term maintenance, and management of acute rejection episodes. Special attention is given to their ability to promote immune tolerance by enhancing regulatory T-cell activity, thereby contributing to immune homeostasis and graft survival. Finally, review addresses future perspectives focused on minimizing steroid exposure through more individualized immunosuppressive approaches while evaluating the continuing central role of corticosteroids in the induction of transplant tolerance.

Parkinson's disease (PD) is a progressive neurodegenerative disease due to degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The fundamental cause of PD is not completely confirmed. However, genetic, epigenetic, and environmental factors are intricate in the progressive accumulation of mutant α-synuclein (α-Syn) in the dopaminergic neurons of the SNpc. PD is frequently linked with other age-related diseases such as benign prostatic hypertrophy, which is treated by the 5α-reductase inhibitor finasteride. Particularly, 5α-reductase, which is expressed in the prostate, is also expressed in the brain for the biosynthesis of the neuroprotective neurosteroids. Thus, 5α-reductase inhibitors such as finasteride may adversely affect the pathogenesis of PD. Nevertheless, numerous preclinical and clinical investigations highlight that finasteride may have a neuroprotective effect against the development and progression of PD. Despite this effect of finasteride, prolonged use of a 5α-reductase inhibitor is associated with the development of dementia in the initial periods after starting treatment. However, reducing the magnitude of the association over time suggested that the risk may be completely or in part due to increased dementia detection among patients with benign prostate enlargement. The fundamental mechanism by which 5α-reductase inhibitors are related to cognitive impairment is indistinct. Therefore, the possible role of finasteride in PD is not completely clarified. Consequently, the objective of the present review was to explain and discuss the precise role of finasteride in PD.

Luteinizing hormone (LH), a pivotal gonadotropin, governs the physiological functions of Leydig cells (LCs) and testicular testosterone biosynthesis, and plays an indispensable role in regulating reproductive capacity and gonadal function in male animals. Tibetan sheep are domestic animals endemic to the Qinghai-Tibet Plateau. Improving testosterone biosynthesis in rams is critical for sustaining their reproductive performance. Nevertheless, the molecular mechanism by which LH regulates steroid hormone synthesis in Tibetan sheep LCs remains unclear. In this study, primary LCs isolated from Tibetan sheep were cultured and treated with LH for different durations. We subsequently detected testosterone secretion, the expression of key steroidogenic enzymes, cell proliferation and apoptosis, as well as the levels of molecules related to the cAMP (cyclic adenosine monophosphate)/PKA (protein kinase A) signaling pathway. The experimental results revealed that LH could promote testosterone secretion in LCs, with the optimal effect observed at 24h. Alongside elevated testosterone biosynthesis, the expression levels of key steroidogenic proteins were significantly upregulated. These findings verified that LH activates the androgen biosynthetic pathway in LCs, facilitates LCs proliferation and suppresses cellular apoptosis. In addition, LH activates the cAMP/PKA-CREB (cAMP response element-binding protein) signaling pathway to facilitate testosterone biosynthesis. Collectively, LH regulates testosterone production in Tibetan sheep LCs through the cAMP/PKA-CREB cascade. This study lays a theoretical foundation for enhancing ram reproductive performance and provides strategies to optimize Tibetan sheep reproductive cycles.

Iron deficiency (ID) and vitamin D deficiency (VDD) often occur together in Saudi Arabia and across the Middle East, influenced by shared cultural, dietary, and environmental factors. This narrative review compiles evidence on this dual issue, exploring epidemiology, mechanisms, clinical effects, and public health strategies. Data confirm significant overlap: VDD affects 60-88% of Saudi adults and 60-81% of children, while ID impacts 23-36% of adults and 20-49% of children. Throughout this review, vitamin D deficiency (VDD) is defined per original study criteria, most commonly as 25-hydroxyvitamin D [25(OH)D] <&#x202f;20&#x202f;ng/mL (<50 nmol/L), consistent with pre-2024 Endocrine Society guidelines. We acknowledge the 2024 Endocrine Society revised guideline, which defines deficiency as <&#x202f;12&#x202f;ng/mL (<30 nmol/L) and eliminates the 'insufficiency' category; prevalence estimates would be substantially lower under this newer threshold. Their co-occurrence may be linked through common inflammatory pathways affecting hepcidin regulation and vitamin D activation, although human data are inconsistent. Combined deficiencies worsen health outcomes, including impaired growth, neurocognitive issues, immune problems, and adverse effects on maternal and child health. Diagnosis is difficult due to nonspecific symptoms and biomarker limitations during inflammation. Current interventions such as food fortification and supplementation, are hampered by isolated approaches and a lack of nationally representative combined prevalence data. The top priority is conducting a national survey to measure the prevalence of concurrent ID and VDD. Once this data is available, integrated strategies such as dual fortification, combined supplementation protocols, and culturally-sensitive public health campaigns can be effectively implemented. This framework offers an evidence-based approach to translating epidemiological and mechanistic insights into measurable public health improvements in Saudi Arabia and the wider Middle East.

Finasteride clinically approved for the treatment of benign prostatic hyperplasia exerts its therapeutic effect by inhibiting type II 5&#x3b1;-reductase, thereby reducing dihydrotestosterone levels, leading to prostate shrinkage and symptomatic relief. However, finasteride also influences the levels of neurosteroids (allopregnanolone) and has been linked to depression-like behavior and impaired neurogenesis. Preclinical and clinical studies have shown that finasteride can robustly induce depressive behavior and can inhibit hippocampal neurogenesis in mice attributed to altered neurosteroids levels. Hence discovery and development of 5&#x3b1;-reductase inhibitors that are effective and devoid of depressionlike effect is essential. The aim of the present study is to assess the safety profile of newly synthesised steroidal 5&#x3b1;-reductase inhibitors. Six compounds from two series were synthesized and screened. Based on in silico docking against human 5&#x3b1;-reductase type II and reduction of serum DHT levels, ND-1 and ND-5 were identified as lead candidates. Both showed strong binding affinities (ND-1: -10.2&#x202f;kcal/mol; ND-5: -9.8&#x202f;kcal/mol) comparable to finasteride (-10.5&#x202f;kcal/mol) and significantly reduced serum DHT in vivo. ND-1 and ND-5 were further evaluated in a testosterone-induced BPH rat model and assessed for depression-like effects following chronic treatment using locomotor activity, sucrose splash, and forced swim tests, along with serum allopregnanolone estimation. In the BPH model, both compounds markedly decreased prostate weight, seminal vesicle weight, demonstrating efficacy comparable to finasteride. Importantly, unlike finasteride, they did not induce depression-like behaviour and preserved serum allopregnanolone levels, highlighting their potential as safer alternatives. However, further studies are required to understand the underlying molecular mechanisms.

Ketosis is a common metabolic disorder in dairy cows, typically occurring during early postpartum negative energy balance and characterized by hyperketonemia, hepatic lipid accumulation, and oxidative stress. Although acetoacetyl-CoA synthetase (AACS) plays a key role in ketone body metabolism, its association with acetoacetate (AcAc) utilization during ketosis remains unclear. This study aimed to assess the effects of AACS on fatty acid and cholesterol metabolic pathways in neonatal bovine hepatocytes exposed to high concentrations of non-esterified fatty acids (NEFA). Liver tissues were collected from healthy (n&#x202f;=&#x202f;6; BHBA < 1.0&#x202f;mM) and ketotic (n&#x202f;=&#x202f;6; BHBA > 3.0&#x202f;mM) dairy cows. Additionally, hepatocytes isolated from neonatal calves were treated with 1.2&#x202f;mM NEFA to establish an in vitro ketotic model. To evaluate the role of AACS, two separate experimental approaches were employed using NEFA-challenged hepatocytes: siRNA-mediated AACS knockdown and exogenous AcAc supplementation. Results demonstrated that liver tissues from ketotic cows and NEFA-treated cells exhibited upregulation of AACS and HMGCS2, along with key lipogenic proteins (SREBF1, ACACA, and FASN). In contrast, the expression of cholesterol synthesis and efflux factors (SREBF2, HMGCR, ABCA1, ABCG5, and ACAT2) was downregulated. NEFA challenge also reduced BDH1 and CPT1A levels, decreased intracellular total cholesterol, increased TAG accumulation, and induced oxidative stress and mitochondrial dysfunction. Silencing AACS partially attenuated NEFA-induced lipid accumulation but further suppressed cholesterol synthesis and efflux-related gene expression. Conversely, AcAc supplementation upregulated the expression of cholesterol synthesis and efflux-related genes but exacerbated lipid deposition, oxidative stress, and mitochondrial dysfunction. Overall, these findings indicate that NEFA-induced upregulation of AACS abundance in hepatocytes may modulate the partitioning of acetoacetate toward de novo lipogenesis and alter cholesterol synthesis and efflux-related gene expression.

Soluble epoxide hydrolase (sEH) is a key enzyme in epoxy fatty acid (EpFA) metabolism, significantly affecting the balance of lipid mediators and the health of the central nervous system (CNS). This review explains the molecular biology, enzymatic activity, and clinical importance of sEH, emphasizing its role in converting anti-inflammatory epoxygenase metabolites into less active diols. Blocking sEH increases EpFA availability, leading to protective effects in experimental models of neuroinflammation, oxidative stress, and vascular failure linked to Alzheimer's, Parkinson's, and traumatic brain injury. The pharmacokinetics and chemistry of urea- and amide-based sEH inhibitors are also reviewed to highlight their development as potential CNS-targeted treatments. Recent preclinical and early clinical studies indicate that sEH inhibition may slow neurodegeneration and improve synaptic plasticity, thereby enhancing cognitive and behavioral functions. Overall, this review combines biochemical and pharmacological insights to support sEH as a promising target for treating neuroinflammation and neurodegenerative diseases characterized by disrupted lipid mediator signaling.