Retinoic acid tiers mitochondrial metabolism to Sertoli Cell-Mediated efferocytosis via a non-RAR-dependent mechanism.

Efferocytosis of massive non-viable germ cells by Sertoli cells (SCs), the specialized phagocytes, is essential for maintaining testis homeostasis. What elusive is the contribution of mitochondrial metabolism to this energy-consuming process, as SC has a preference of aerobic glycolysis. All-trans retinoic acid (ATRA, hereafter referred to as RA) is a well-known morphogen that primarily acts through the nuclear RA receptor (RAR). It sustains SC blood-testisbarrier integrity, and it's SC-derived RA sets the timing of meiotic commitment. In this study, we revisited RA in SC biology, from the perspective of SC-mediated efferocytosis. We provide evidence that RA induces transcriptional programming of multiple regulators involved in efferocytosis, which thereby represses SC-mediated efferocytosis, via a RAR-independent mechanism, as blocking pan-RAR activity fails to rescue RA-induced defective efferocytosis. RA-treated SCs exhibit alternations in mitochondrial dynamics and metabolism, and the hindered efferocytosis can be rescued by stimulating mitochondrial OXPHOS via pharmacological targeting of AMPK and PDK. We thus prefer to propose a signaling axis of RA-mitochondrial metabolism-efferocytosis. Our study uncovers a hitherto unappreciated role of RA in SC biology and tiers mitochondria metabolism to SC-mediated efferocytosis, contributing a deeper understanding of SC in male reproduction.

Future in the past: paternal reprogramming of offspring phenotype and the epigenetic mechanisms.

That certain preconceptual paternal exposures reprogram the developmental phenotypic plasticity in future generation(s) has conceptualized the "paternal programming of offspring health" hypothesis. This transgenerational effect is transmitted primarily through sperm epigenetic mechanisms-DNA methylation, non-coding RNAs (ncRNAs) and associated RNA modifications, and histone modifications-and potentially through non-sperm-specific mechanisms-seminal plasma and circulating factors-that create 'imprinted' memory of ancestral information. The epigenetic landscape in sperm is highly responsive to environmental cues, due to, in part, the soma-to-germline communication mediated by epididymosomes. While human epidemiological studies and experimental animal studies have provided solid evidences in support of transgenerational epigenetic inheritance, how ancestral information is memorized as epigenetic codes for germline transmission is poorly understood. Particular elusive is what the downstream effector pathways that decode those epigenetic codes into persistent phenotypes. In this review, we discuss the paternal reprogramming of offspring phenotype and the possible underlying epigenetic mechanisms. Cracking these epigenetic mechanisms will lead to a better appreciation of "Paternal Origins of Health and Disease" and guide innovation of intervention algorithms to achieve 'healthier' outcomes in future generations. All this will revolutionize our understanding of human disease etiology.

From molecular pathogenesis to therapy: Unraveling non-coding RNAs/DNMT3A axis in human cancers.

Cancer is a comprehensive classification encompassing more than 100 forms of malignancies that manifest in diverse tissues within the human body. Recent studies have provided evidence that aberrant epigenetic modifications are pivotal indicators of cancer. Epigenetics encapsulates DNA methyltransferases as a crucial class of modifiers. DNMTs, including DNMT3A, assume central roles in DNA methylation processes that orchestrate normal biological functions, such as gene transcription, predominantly in mammals. Typically, deviations in DNMT3A function engender distortions in factors that drive tumor growth and progression, thereby exacerbating the malignant phenotype of tumors. Consequently, such abnormalities pose significant challenges in cancer therapy because they impede treatment efficacy. Non-coding RNAs (ncRNAs) represent a group of RNA molecules that cannot encode functional proteins. Recent investigation attests to the crucial significance of regulatory ncRNAs in epigenetic regulation. Notably, recent reports have illuminated the complex interplay between ncRNA expression and epigenetic regulatory machinery, including DNMT3A, particularly in cancer. Recent findings have demonstrated that miRNAs, namely miR-770-5p, miR-101, and miR-145 exhibit the capability to target DNMT3A directly, and their aberration is implicated in diverse cellular abnormalities that predispose to cancer development. This review aims to articulate the interplay between DNMT3A and the ncRNAs, focusing on its impact on the development and progression of cancer, cancer therapy resistance, cancer stem cells, and prognosis. Importantly, the emergence of such reports that suggest a connection between DNMT3A and ncRNAs in several cancers indicates that this connecting axis offers a valuable target with significant therapeutic potential that might be exploited for cancer management.

A comprehensive review on signaling attributes of serine and serine metabolism in health and disease.

Serine is a metabolite with ever-expanding metabolic and non-metabolic signaling attributes. By providing one­carbon units for macromolecule biosynthesis and functional modifications, serine and serine metabolism largely impinge on cellular survival and function. Cancer cells frequently have a preference for serine metabolic reprogramming to create a conducive metabolic state for survival and aggressiveness, making intervention of cancer-associated rewiring of serine metabolism a promising therapeutic strategy for cancer treatment. Beyond providing methyl donors for methylation in modulation of innate immunity, serine metabolism generates formyl donors for mitochondrial tRNA formylation which is required for mitochondrial function. Interestingly, fully developed neurons lack the machinery for serine biosynthesis and rely heavily on astrocytic l-serine for production of d-serine to shape synaptic plasticity. Here, we recapitulate recent discoveries that address the medical significance of serine and serine metabolism in malignancies, mitochondrial-associated disorders, and neurodegenerative pathologies. Metabolic control and epigenetic- and posttranslational regulation of serine metabolism are also discussed. Given the metabolic similarities between cancer cells, neurons and germ cells, we further propose the relevance of serine metabolism in testicular homeostasis. Our work provides valuable hints for future investigations that will lead to a deeper understanding of serine and serine metabolism in cellular physiology and pathology.

Retinoic acid signaling in development and differentiation commitment and its regulatory topology.

Retinoic acid (RA), the derivative of vitamin A/retinol, is a signaling molecule with important implications in health and disease. It is a well-known developmental morphogen that functions mainly through the transcriptional activity of nuclear RA receptors (RARs) and, uncommonly, through other nuclear receptors, including peroxisome proliferator-activated receptors. Intracellular RA is under spatiotemporally fine-tuned regulation by synthesis and degradation processes catalyzed by retinaldehyde dehydrogenases and P450 family enzymes, respectively. In addition to dictating the transcription architecture, RA also impinges on cell functioning through non-genomic mechanisms independent of RAR transcriptional activity. Although RA-based differentiation therapy has achieved impressive success in the treatment of hematologic malignancies, RA also has pro-tumor activity. Here, we highlight the relevance of RA signaling in cell-fate determination, neurogenesis, visual function, inflammatory responses and gametogenesis commitment. Genetic and post-translational modifications of RAR are also discussed. A better understanding of RA signaling will foster the development of precision medicine to improve the defects caused by deregulated RA signaling.

Unlocking gut microbiota potential of dairy cows in varied environmental conditions using shotgun metagenomic approach.

Food security and environmental pollution are major concerns for the expanding world population, where farm animals are the largest source of dietary proteins and are responsible for producing anthropogenic gases, including methane, especially by cows. We sampled the fecal microbiomes of cows from varying environmental regions of Pakistan to determine the better-performing microbiomes for higher yields and lower methane emissions by applying the shotgun metagenomic approach. We selected managed dairy farms in the Chakwal, Salt Range, and Patoki regions of Pakistan, and also incorporated animals from local farmers. Milk yield and milk fat, and protein contents were measured and correlated with microbiome diversity and function. The average milk protein content from the Salt Range farms was 2.68%, with an average peak milk yield of 45 litters/head/day, compared to 3.68% in Patoki farms with an average peak milk yield of 18 litters/head/day. Salt-range dairy cows prefer S-adenosyl-L-methionine (SAMe) to S-adenosyl-L-homocysteine (SAH) conversion reactions and are responsible for low milk protein content. It is linked to Bacteroides fragilles which account for 10% of the total Bacteroides, compared to 3% in the Patoki region. The solid Non-Fat in the salt range was 8.29%, whereas that in patoki was 6.34%. Moreover, Lactobacillus plantarum high abundance in Salt Range provided propionate as alternate sink to [H], and overcoming a Methanobrevibacter ruminantium high methane emissions in the Salt Range. Furthermore, our results identified ruminant fecal microbiomes that can be used as fecal microbiota transplants (FMT) to high-methane emitters and low-performing herds to increase farm output and reduce the environmental damage caused by anthropogenic gases emitted by dairy cows.

Circular RNAs in renal cell carcinoma: from mechanistic to clinical perspective.

CircRNAs, a special type of noncoding RNAs characterized by their stable structure and unique abilities to form backsplicing loops, have recently attracted the interest of scientists. These RNAs are abundant throughout the body and play important roles such as microRNA sponges, templates for transcription, and regulation of protein translation and RNA-binding proteins. Renal cancer development is highly correlated with abnormal circRNA expression in vivo. CircRNAs are currently considered promising targets for novel therapeutic approaches as well as possible biomarkers for prognosis and diagnosis of various malignancies. Despite our growing understanding of circRNA, numerous questions remain unanswered. Here, we address the characteristics of circRNAs and their function, focusing in particular on their impact on drug resistance, metabolic processes, metastasis, cell growth, and programmed cell death in renal cancer. In addition, the application of circRNAs as prognostic and diagnostic biomarkers will be discussed.

Non-coding RNAs/DNMT3B axis in human cancers: from pathogenesis to clinical significance.

Cancer is a complex disease with many contributing factors, and researchers have gained extensive knowledge that has helped them understand the diverse and varied nature of cancer. The altered patterns of DNA methylation found in numerous types of cancer imply that they may play a part in the disease's progression. The human cancer condition involves dysregulation of the DNA methyltransferase 3 beta (DNMT3B) gene, a prominent de novo DNA methyltransferase, and its abnormal behavior serves as an indicator for tumor prognosis and staging. The expression of non-coding RNAs (ncRNAs), which include microRNAs (miRNA), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), is critical in controlling targeted gene expression and protein translation and their dysregulation correlates with the onset of tumors. NcRNAs dysregulation of is a critical factor that influences the modulation of several cellular characteristics in cancerous cells. These characteristics include but are not limited to, drug responsiveness, angiogenesis, metastasis, apoptosis, proliferation, and properties of tumor stem cell. The reciprocal regulation of ncRNAs and DNMT3B can act in synergy to influence the destiny of tumor cells. Thus, a critical avenue for advancing cancer prevention and treatment is an inquiry into the interplay between DNMT3B and ncRNAs. In this review, we present a comprehensive overview of the ncRNAs/DNMT3B axis in cancer pathogenesis. This brings about valuable insights into the intricate mechanisms of tumorigenesis and provides a foundation for developing effective therapeutic interventions.

The emerging era of lactate: A rising star in cellular signaling and its regulatory mechanisms.

Cellular metabolites are ancient molecules with pleiotropic implications in health and disease. Beyond their cognate roles, they have signaling functions as the ligands for specific receptors and the precursors for epigenetic or posttranslational modifications. Lactate has long been recognized as a metabolic waste and fatigue product mainly produced from glycolytic metabolism. Recent evidence however suggests lactate is an unique molecule with diverse signaling attributes in orchestration of numerous biological processes, including tumor immunity and neuronal survival. The copious metabolic and non-metabolic functions of lactate mediated by its bidirectional shuttle between cells or intracellular organelles lead to a phenotype called "lactormone." Importantly, the mechanisms of lactate signaling, via acting as a molecular sensor and a regulator of NAD+ metabolism and AMP-activated protein kinase signaling, and via the newly identified lactate-driven lactylation, have been discovered. Further, we include a brief discussion about the autocrine regulation of efferocytosis by lactate in Sertoli cells which favoraerobic glycolysis. By emphasizing a repertoire of the most recent discovered mechanisms of lactate signaling, this review will open tantalizing avenues for future investigations cracking the regulatory topology of lactate signaling covered in the veil of mystery.

Recent advances in chromosome capture techniques unraveling 3D genome architecture in germ cells, health, and disease.

In eukaryotes, the genome does not emerge in a specific shape but rather as a hierarchial bundle within the nucleus. This multifaceted genome organization consists of multiresolution cellular structures, such as chromosome territories, compartments, and topologically associating domains, which are frequently defined by architecture, design proteins including CTCF and cohesin, and chromatin loops. This review briefly discusses the advances in understanding the basic rules of control, chromatin folding, and functional areas in early embryogenesis. With the use of chromosome capture techniques, the latest advancements in technologies for visualizing chromatin interactions come close to revealing 3D genome formation frameworks with incredible detail throughout all genomic levels, including at single-cell resolution. The possibility of detecting variations in chromatin architecture might open up new opportunities for disease diagnosis and prevention, infertility treatments, therapeutic approaches, desired exploration, and many other application scenarios.

Cytoskeletal orchestration of glucose uptake in Sertoli cell to support efferocytosis of apoptotic germ cells.

Efferocytosis of non-viable germ cells by Sertoli cells (SCs) constitutes a sentinel for testis homeostasis, yet how SCs signal for the metabolic and cytoskeletal adaption to this energetically costly process remains unexplored. Spectrin is membrane-associated periodic skeleton assembled into an actin-spectrin-based cytoskeletal structure with an interaction with glucose transporter Glut1. The contribution of spectrin to glucose uptake and efferocytosis is unknown. In this study, we identified a cross-regulation between glucose metabolism and efferocytosis in SCs. Pharmacological or genetic inhibition of glucose uptake or glycolysis compromises efferocytosis activity. We further found that ßII-spectrin is a hitherto unappreciated regulator of glucose metabolism and cytoskeletal architecture. ßII-spectrin deficiency impairs glucose uptake and lactate production in SCs. Moreover, a defective assembly of cytoskeleton and a loss of blood-testis barrier integrity are also featured by SCs deficient in ßII-spectrin. The disruption in glucose metabolism and cytoskeletal organization synergistically lead to a defective efferocytosis. In vivo siRNA-mediated targeting of ßII-spectrin in testis causes an obvious morphological aberration in seminiferous epithelium with the presence of exfoliated germ cells and multinucleated giant cells. Importantly, a decrease in expression of αII/ßII-spectrin was observed in testes of Adjudin-induced infertility model. By exploring the functional relevance of ßII-spectrin to the metabolic and cytoskeletal regulation of efferocytosis, our study proposes a potential link between ßII-spectrin deregulation and male infertility.

Smtnl2 regulates apoptotic germ cell clearance and lactate metabolism in mouse Sertoli cells.

Smtnl2 is an epithelial Smoothelin that binds to actin filaments and is crucial for epithelial morphogenesis. We examined the role of Smtnl2 in Sertoli cells, which undergo dynamic cytoskeleton reorganization to phagocytose apoptotic germ cells, a process known as efferocytosis. We observed Smtnl2 expression in primary mouse Sertoli cells and the 15P1 Sertoli cell line. Smtnl2 expression increased in 15P1 cells committing efferocytosis. Smtnl2-deficient Sertoli cells exhibited defective ability to engulf apoptotic germ cells and importantly, the phenomenon occurred in the setting of an unaffected maturation of phagosome. We demonstrated that Smtnl2 regulates the engulfment process through the function of branched actin nucleation protein ARP3, an actin assembly dictator. Intriguingly, a shift in glucose metabolism that restricts lactate production in Sertoli cells was induced upon Smtnl2 depletion, leading to the activation of downstream AMPK and AKT signaling. Using an in vivo RNAi approach, we found that silencing of Smtnl2 in testis triggers an obvious disruption in cytoskeleton architecture and blood-testis barrier integrity across seminiferous epithelium, causing the detachment of massive germ cells from their nest, as evidenced by their exfoliation into the lumen. Overall, our study identifies Smtnl2 as a determinant for Sertoli cells' functioning in supporting spermatogenesis.

Perfluorooctanoic acid alters the developmental trajectory of female germ cells and embryos in rodents and its potential mechanism.

The epidemiological studies regarding perfluorooctanoic acid (PFOA) suggests that its exposure causes reproductive health issues, the underlying mechanisms of which are still in its infancy. Here, we report that PFOA deteriorates female reproduction at multiple development stages. Oocyte meiosis and preimplantation development are severely impaired by PFOA with oxidative stress being a contributor. Supplementing with antioxidant melatonin partially rescues oocyte meiotic maturation and non-apoptotic demise. The attenuation in ovarian follicle development however can be improved by metformin but not melatonin. Importantly, metformin blunts PFOA-induced fetal growth retardation (FGR) and such protective effect could be recapitulated by transplantation of fecal material and pharmacological activation of AMPK. Mechanistically, PFOA causes gut microbiota dysbiosis, which might thereby rewire host metabolism of L-phenylalanine, histamine and L-palmitoylcarnitine that triggers hyperphenylalaninaemia, inflammation and ferroptosis to initiate FGR. Deregulated serine metabolism by the gut microbe constitutes an alternative mechanism underlying PFOA-induced FGR in that modulation of serine in dam's diet phenocopied the FGR. Our study expands the understanding of risk factors that impair human reproductive health, and proposes restoration of gut microbiota diversity and intervention of metabolism as therapeutics mitigating health risks predisposed by environmental perturbation.

Temperature-Reliable Low-Dimensional Perovskites Passivated Black-Phase CsPbI3 toward Stable and Efficient Photovoltaics.

Low-dimensional (LD) perovskites can effectively passivate and stabilize 3D perovskites for high-performance perovskite solar cells (PSCs). Regards CsPbI3 -based PSCs, the influence of high-temperature annealing on the LD perovskite passivation effect has to be taken into account due to fact the black-phase CsPbI3 crystallization requires high-temperature treatment, however, which has been rarely concerned so far. Here, the thermal stability of LD perovskites based on three hydrophobic organic ammonium salts and their passivation effect toward CsPbI3 and the whole device performance, have been investigated. It is found that, phenyltrimethylammonium iodide (PTAI) and its corresponding LD perovskites exhibit excellent thermal stability. Further investigation reveals that PTAI-based LD perovskites are mainly distributed at grain boundaries, which not only enhances the phase stability of CsPbI3 but also effectively suppresses non-radiative recombination. As a consequence, the champion PSC device based on CsPbI3 exhibits a record efficiency of 21.0 % with high stability.

Alternative splicing and MicroRNA: epigenetic mystique in male reproduction.

Infertility is rarely life threatening, however, it poses a serious global health issue posing far-reaching socio-economic impacts affecting 12-15% of couples worldwide where male factor accounts for 70%. Functional spermatogenesis which is the result of several concerted coordinated events to produce sperms is at the core of male fertility, Alternative splicing and microRNA (miRNA) mediated RNA silencing (RNAi) constitute two conserved post-transcriptional gene (re)programming machinery across species. The former by diversifying transcriptome signature and the latter by repressing target mRNA activity orchestrate a spectrum of testicular events, and their dysfunctions has several implications in male infertility. This review recapitulates the knowledge of these mechanistic events in regulation of spermatogenesis and testicular homoeostasis. In addition, miRNA payload in sperm, vulnerable to paternal inputs, including unhealthy diet, infection and trauma, creates epigenetic memory to initiate intergenerational phenotype. Naive zygote injection of sperm miRNAs from stressed father recapitulates phenotypes of offspring of stressed father. The epigenetic inheritance of paternal pathologies through miRNA could be a tantalizing avenue to better appreciate 'Paternal Origins of Health and Disease' and the power of tiny sperm.

Zinc oxide nanoparticle causes toxicity to the development of mouse oocyte and early embryo.

Zinc oxide nanoparticle (ZnO NP) is one of the most widely used nanomaterial in industrial and commercial products. Here, we reported hazardous effects of ZnO NP on the development of mouse oocyte and pre-implantation embryo. ZnO NP compromises meiosis partially by induction of oxidative stress as antioxidant rescues the development of ZnO NP-exposed oocytes, albeit with limited efficiency. It causes mitochondrial- and endoplasmic reticulum stresss which thereby activates autophagy and apoptosis to trigger oocyte demise. Examining ZnO NP-exposed oocytes that complete M-phase entry witnesses a disruption in meiotic cytoskeleton architecture. Intriguingly, loss of Grp78, a chaperone in the ER, phenocopies ZnO NP-induced meiotic defects and cytoskeleton disorganization. Importantly however, ZnO NP commences cytotoxicity by more than releasing of Zn2+ in that ZnCl2 to a much less extent recapitulates ZnO NP-induced phenomena. The prevailing DNA damage is another causative to developmental arrest and degeneration of oocytes and early embryos, but compared with oocytes, embryos are more sensitive to ZnO NP and succumb to death. ZnO NP is demonstrated in this study to be toxic for oocytes and enbryos in mammals, which warrants careful evaluation of human exposure with regard to its influence on reproductive health.

Bisphenol AF compromises blood-testis barrier integrity and sperm quality in mice.

The profound influence of environmental chemicals on human health including inducing life-threatening gene mutation has been publicly recognized. Being a substitute for the extensively used endocrine-disrupting chemical BPA, Bisphenol AF (BPAF) has been known as teratogen with developmental toxicities and therefore potentially putting human into the risk of biological hazards. Herein, we deciphered the detrimental effects of BPAF on spermatogenesis and spermiotiliosis in sexual maturity of mice exposing to BPAF (5, 20, 50 mg/kg/d) for consecutive 28 days. BPAF exposure significantly compromises blood-testis barrier integrity and sperm quantity and quality in a dose-dependent manner. Sperms from BPAF exposure mice are featured by severe DNA damage, altered SUMOylation and ubiquitination dynamics and interfered epigenetic inheritance with hypermethylation of H3K27me3 presumably due to the aggregation of cellular reactive oxygen species (ROS). Furthermore, BPAF treatment (50 µM for 24 h) compromises cytoskeleton architecture and tight junction permeability in primary cultured Sertoli cells evidenced by dysfunction of actin regulatory proteins (e.g. Arp3 and Palladin) via activation of ERK signaling, thereby perturbing the privilege microenvironment created by Sertoli cells for spermatogenesis. Overall, our study determines BPAF is deleterious for male fertility, leading to a better appreciation of its toxicological features in our life.

Graphene platelet reinforced copper composites for improved tribological and thermal properties.

In this work, investigations were conducted to evaluate a type of graphene platelet-reinforced copper (GPL/Cu) composite for enhanced tribological and thermal properties. The pin-on-disc (steel) results show that the wear loss and the friction coefficient of the composites decrease by nearly 80% and 70%, respectively, in comparison with those of pure Cu. Thermal conductivity of the composites initially improves substantially by approximately 30% with a slight loading of 0.25 vol% GPLs and decreases gradually with a higher content of GPLs. Microstructural analysis reveals that the enhancement in the tribological property is attributed to both the self-lubricating property of GPLs and grain refinement while the improvement in the thermal property is closely associated with the uniform dispersion of GPLs.

Bisphenol AF negatively affects oocyte maturation of mouse in vitro through increasing oxidative stress and DNA damage.

Bisphenol AF (BPAF) is commonly used in industry production as a substitute for Bisphenol A (BPA). Many studies showed that BPAF negatively affect some physiological processes in humans and animals. However, the effects of BPAF on oocyte maturation and its possible mechanisms are sparsely understood. In the present study, we found that 100 µM BPAF exposure affect oocyte maturation with a decreased first polar body extrusion (PBE) rate. Immunofluorescence study displayed that BPAF exposure disrupt the spindle morphology through affecting the function of microtubule organizing centers (MTOCs), which was confirmed by the dysfunction of γ-tubulin and phosphorylated mitogen-activated protein kinase (p-MAPK). As shown by reactive oxygen species (ROS) accumulation, BPAF exposure also induced oxidative stress. Moreover, DNA damage was significantly increased after BPAF exposure, which may be caused by oxidative stress. In addition, histone modification statuses were changed after BPAF exposure, as shown by western blot with decreased expression of H3K9me3 and H3K27ac. Collectively, our current work demonstrated the possibility of BPAF to negatively impact female fertility and revealed the mechanisms that BPAF disrupted mouse oocyte maturation by affecting cytoskeletal dynamics, inducing oxidative stress, increasing DNA damage, and changing the status of epigenetic modifications. This finding can help develop the potential therapies to alleviate oxidative damage to preserve fertility in people who are often exposed to BPAF environment.