Methylation of histone H3 lysine 36 is a barrier for therapeutic interventions of head and neck squamous cell carcinoma.

Approximately 20% of head and neck squamous cell carcinomas (HNSCCs) exhibit reduced methylation on lysine 36 of histone H3 (H3K36me) due to mutations in histone methylase NSD1 or a lysine-to-methionine mutation in histone H3 (H3K36M). Whether such alterations of H3K36me can be exploited for therapeutic interventions is still unknown. Here, we show that HNSCC models expressing H3K36M can be divided into two groups: those that display aberrant accumulation of H3K27me3 and those that maintain steady levels of H3K27me3. The former group exhibits reduced proliferation, genome instability, and heightened sensitivity to genotoxic agents like PARP1/2 inhibitors. Conversely, H3K36M HNSCC models with constant H3K27me3 levels lack these characteristics unless H3K27me3 is elevated by DNA hypomethylating agents or inhibiting H3K27me3 demethylases KDM6A/B. Mechanistically, H3K36M reduces H3K36me by directly impeding the activities of the histone methyltransferase NSD3 and the histone demethylase LSD2. Notably, aberrant H3K27me3 levels induced by H3K36M expression are not a bona fide epigenetic mark because they require continuous expression of H3K36M to be inherited. Moreover, increased sensitivity to PARP1/2 inhibitors in H3K36M HNSCC models depends solely on elevated H3K27me3 levels and diminishing BRCA1- and FANCD2-dependent DNA repair. Finally, a PARP1/2 inhibitor alone reduces tumor burden in a H3K36M HNSCC xenograft model with elevated H3K27me3, whereas in a model with consistent H3K27me3, a combination of PARP1/2 inhibitors and agents that up-regulate H3K27me3 proves to be successful. These findings underscore the crucial balance between H3K36 and H3K27 methylation in maintaining genome instability, offering new therapeutic options for patients with H3K36me-deficient tumors.

Printing 3D Metallic Structures in Porous Matrix.

The fabrication of metallic micro/nanostructures has great potential for advancing optoelectronic microdevices. Over the past decade, femtosecond laser direct writing (FsLDW) technology has played a crucial role in driving progress in this field. In this study, silica gel glass is used as a supporting medium, and FsLDW is employed to reduce gold and palladium ions using 7-Diethylamino-3-thenoylcoumarin (DETC) as a two-photon sensitizer, enabling the printing of conductive multilayered and 3D metallic structures. How the pore size of the silica gel glass affects the electrical conductivity of printed metal wires is systematically examined. This 3D printing method is versatile and offers expanded opportunities for applying metallic micro/nanostructures in optoelectronic devices.

The Promising Seesaw Relationship Between Activity and Stability of Ru-Based Electrocatalysts for Acid Oxygen Evolution and Proton Exchange Membrane Water Electrolysis.

The development of electrocatalysts that are not reliant on iridium for efficient acid-oxygen evolution is a critical step towards the proton exchange membrane water electrolysis (PEMWE) and green hydrogen industry. Ruthenium-based electrocatalysts have garnered widespread attention due to their remarkable catalytic activity and lower commercial price. However, the challenge lies in balancing the seesaw relationship between activity and stability of these electrocatalysts during the acid-oxygen evolution reaction (OER). This review delves into the progress made in Ru-based electrocatalysts with regards to acid OER and PEMWE applications. It highlights the significance of customizing the acidic OER mechanism of Ru-based electrocatalysts through the coordination of adsorption evolution mechanism (AEM) and lattice oxygen oxidation mechanism (LOM) to attain the ideal activity and stability relationship. The promising tradeoffs between the activity and stability of different Ru-based electrocatalysts, including Ru metals and alloys, Ru single-atomic materials, Ru oxides, and derived complexes, and Ru-based heterojunctions, as well as their applicability to PEMWE systems, are discussed in detail. Furthermore, this paper offers insights on in situ control of Ru active sites, dynamic catalytic mechanism, and commercial application of PEMWE. Based on three-way relationship between cost, activity, and stability, the perspectives and development are provided.

Epigenetic mechanisms driving the pathogenesis of systemic lupus erythematosus, systemic sclerosis and dermatomyositis.

Autoimmune connective tissue disorders, including systemic lupus erythematosus, systemic sclerosis (SSc) and dermatomyositis (DM), often manifest with debilitating cutaneous lesions and can result in systemic organ damage that may be life-threatening. Despite recent therapeutic advancements, many patients still experience low rates of sustained remission and significant treatment toxicity. While genetic predisposition plays a role in these connective tissue disorders, the relatively low concordance rates among monozygotic twins (ranging from approximately 4% for SSc to about 11%-50% for SLE) have prompted increased scrutiny of the epigenetic factors contributing to these diseases. In this review, we explore some seminal studies and key findings to provide a comprehensive understanding of how dysregulated epigenetic mechanisms can contribute to the development of SLE, SSc and DM.

CircOGDH Is a Penumbra Biomarker and Therapeutic Target in Acute Ischemic Stroke.

BACKGROUND: Acute ischemic stroke (AIS) is a leading cause of disability and mortality worldwide. Prediction of penumbra existence after AIS is crucial for making decision on reperfusion therapy. Yet a fast, inexpensive, simple, and noninvasive predictive biomarker for the poststroke penumbra with clinical translational potential is still lacking. We aim to investigate whether the CircOGDH (circular RNA derived from oxoglutarate dehydrogenase) is a potential biomarker for penumbra in patients with AIS and its role in ischemic neuronal damage. METHODS: CircOGDH was screened from penumbra of middle cerebral artery occlusion mice and was assessed in plasma of patients with AIS by quantitative polymerase chain reaction. Magnetic resonance imaging was used to examine the penumbra volumes. CircOGDH interacted with miR-5112 (microRNA-5112) in primary cortical neurons was detected by fluorescence in situ hybridization, RNA immunoprecipitation, and luciferase reporter assay. Adenovirus-mediated CircOGDH knockdown ameliorated neuronal apoptosis induced by COL4A4 (Gallus collagen, type IV, alpha IV) overexpression. Transmission electron microscope, nanoparticle tracking analysis, and Western blot were performed to confirm exosomes. RESULTS: CircOGDH expression was dramatically and selectively upregulated in the penumbra tissue of middle cerebral artery occlusion mice and in the plasma of 45 patients with AIS showing a 54-fold enhancement versus noncerebrovascular disease controls. Partial regression analysis revealed that CircOGDH expression was positively correlated with the size of penumbra in patients with AIS. Sequestering of miR-5112 by CircOGDH enhanced COL4A4 expression to elevate neuron damage. Additionally, knockdown of CircOGDH significantly enhanced neuronal cell viability under ischemic conditions. Furthermore, the expression of CircOGDH in brain tissue was closely related to that in the serum of middle cerebral artery occlusion mice. Finally, we found that CircOGDH was highly expressed in plasma exosomes of patients with AIS compared with those in noncerebrovascular disease individuals. CONCLUSIONS: These results demonstrate that CircOGDH is a potential therapeutic target for regulating ischemia neuronal viability, and is enriched in neuron-derived exosomes in the peripheral blood, exhibiting a predictive biomarker of penumbra in patients with AIS.

Are 4f-Orbitals Engaged in Covalent Bonding Between Lanthanides and Triphenylphosphine Oxide? An Oxygen K-Edge X-ray Absorption Spectroscopy and Density Functional Theory Study.

The bonding covalency between trivalent lanthanides (Ln = La, Pr, Nd, Eu, Gd) and triphenylphosphine oxide (TPPO) is studied by X-ray absorption spectra (XAS) and density functional theory (DFT) calculations on the LnCl3(TPPO)3 complexes. The O, P, and Cl K-edge XAS for the single crystals of LnCl3(TPPO)3 were collected, and the spectra were interpreted based on DFT calculations. The O and P K-edge XAS spectra showed no significant change across the Ln series in the LnCl3(TPPO)3 complexes, unlike the Cl K-edge XAS spectra. The experimental O K-edge XAS spectra suggest no mixing between the Ln 4f- and the O 2p-orbitals in the LnCl3(TPPO)3 complexes. DFT calculations indicate that the amount of the O 2p character per Ln-O bond is less than 0.1% in the Ln 4f-based orbitals in all of the LnCl3(TPPO)3 complexes. The experimental spectra and theoretical calculations demonstrate that Ln 4f-orbitals are not engaged in the covalent bonding of lanthanides with TPPO, which contrasts the involvement of U 5f-orbitals in covalent bonding in the UO2Cl2(TPPO)2 complex. Results in this work reinforce our previous speculation that bonding covalency is potentially responsible for the extractability of monodentate organophosphorus ligands toward metal ions.

The Significant Role of New Particle Composition and Morphology on the HNO3-Driven Growth of Particles down to Sub-10 nm.

New particle formation and growth greatly influence air quality and the global climate. Recent CERN Cosmics Leaving OUtdoor Droplets (CLOUD) chamber experiments proposed that in cold urban atmospheres with highly supersaturated HNO3 and NH3, newly formed sub-10 nm nanoparticles can grow rapidly (up to 1000 nm h-1). Here, we present direct observational evidence that in winter Beijing with persistent highly supersaturated HNO3 and NH3, nitrate contributed less than ∼14% of the 8-40 nm nanoparticle composition, and overall growth rates were only ∼0.8-5 nm h-1. To explain the observed growth rates and particulate nitrate fraction, the effective mass accommodation coefficient of HNO3 (αHNO3) on the nanoparticles in urban Beijing needs to be 2-4 orders of magnitude lower than those in the CLOUD chamber. We propose that the inefficient uptake of HNO3 on nanoparticles is mainly due to the much higher particulate organic fraction and lower relative humidity in urban Beijing. To quantitatively reproduce the observed growth, we show that an inhomogeneous "inorganic core-organic shell" nanoparticle morphology might exist for nanoparticles in Beijing. This study emphasized that growth for nanoparticles down to sub-10 nm was largely influenced by their composition, which was previously ignored and should be considered in future studies on nanoparticle growth.

Potential prognostic value of CSF-targeted proteomics across the Alzheimer's disease continuum.

BACKGROUND: Core biomarkers for Alzheimer's disease (AD), such as Aß42 and tau, have demonstrated high prognostic accuracy but do not fully capture the complex pathophysiology of AD. In this study, our objective was to identify novel cerebrospinal fluid (CSF) biomarkers using proteomics across the entire AD continuum to predict conversion to AD and explore their involvement in AD pathogenesis. METHODS: A cohort of 186 cognitively normal (CN), 127 subjective memory complaint (SMC), 79 early mild cognitive impairment (EMCI), 249 late MCI (LMCI), and 132 AD individuals was analyzed, with a follow-up period of over 3 years for non-AD participants. CSF 65 peptides, as well as hippocampal and entorhinal volumes were analyzed, and cognitive function was evaluated using the 13-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog 13). Cox proportional hazards models and mediation analysis were performed to investigate associations and causal relationships. RESULTS: During the follow-up, approximately one-fourth (146/580) of the non-AD participants progressed to AD. After adjusting for baseline diagnosis (CN to LMCI) and other variables, multivariable Cox regression analysis identified three peptides (VAELEDEK, VSFELFADK, and VVSSIEQK) as significant predictors of conversion to AD. Incorporating these three peptides into the initial model significantly improved the C-statistic from 0.82 to 0.85 for predicting AD conversion, surpassing the predictive ability of Aß42 and P-tau. Moreover, hippocampal and entorhinal volumes mediated 30.3-53.8% of the association between the three peptides and ADAS-Cog 13 scores. CONCLUSIONS: These findings underscore the potential of these three peptides as robust prognostic biomarker candidates for AD conversion across the entire AD continuum, with a mechanism involving the mediation of hippocampal and entorhinal volumes.

Risk factors, prognostic factors, and nomograms for synchronous brain metastases of solid tumors: a population-based study.

In previous literatures, we found that similar studies on the short-term prognosis of synchronous brain metastases (S-BM) from other systems are rare. Our aim was to evaluate the early mortality rate of patients with S-BM from the Surveillance, Epidemiology, and End Result (SEER) database and explore the risk factors for early mortality (≤ 1 year). We used Kaplan-Meier (KM) curves to evaluate early mortality in patients with S-BM from the SEER database. Logistic regression analyses were used to identify significant independent prognostic factors in patients with a follow-up time > 12 months. And the meaningful factors were used to construct a nomogram of overall early death. The receiver operating characteristic (ROC) curve was used to test the predictive ability of the model, while the decision curve analysis (DCA) curve was used to validate the clinical application ability of the model. A total of 47,284 patients were used for univariate and multivariate logistic regression analysis to screen variables to constructing a nomogram. In the all-cause early mortality specific model, the area under the ROC (AUC) curve of the training set was 0.764 (95% confidence interval (CI): 0.758-0.769), and the AUC of the validation set was 0.761 (95% CI: 0.752-0.770). The DCA calibration curves of the training set and validation set indicate that the 1-year early mortality rate predicted by this model is consistent with the actual situation. We found that the 1-year early mortality rate was 76.4%. We constructed a validated nomogram using these covariates to effectively predict 1-year early mortality in patients with S-BM. This nomogram can help clinical workers screen high-risk patients to develop more reasonable treatment plans.

Hydrophilicity and Pore Structure Enhancement in Polyurethane/Silk Protein-Bismuth Halide Oxide Composite Films for Photocatalytic Degradation of Dye.

Polyurethane/silk protein-bismuth halide oxide composite films were fabricated using a blending-wet phase transformationin situsynthesis method. The crystal structure, micromorphology, and optical properties were conducted using XRD, SEM, and UV-Vis DRS characterize techniques. The results indicated that loaded silk protein enhanced the hydrophilicity and pore structure of the polyurethane composite films. The active species BiOX were observed to grow as nanosheets with high dispersion on the internal skeleton and silk protein surface of the polyurethane-silk protein film. The photocatalytic efficiency of BiOX/PU-SF composite films was assessed through the degradation of Rhodamine B under visible light irradiation. Among the tested films, the BiOBr/PU-SF composite exhibited the highest removal rate of RhB at 98.9%, surpassing the removal rates of 93.7% for the BiOCl/PU-SF composite and 85.6% for the BiOI/PU-SF composite. Furthermore, an active species capture test indicated that superoxide radical (•O2-) and hole (h+) species played a predominant role in the photodegradation process.

Synergistic Therapeutic Effects of D-Mannitol-Cerium-Quercetin (Rutin) Coordination Polymer Nanoparticles on Acute Lung Injury.

Acute lung injury (ALI) remains a significant global health issue, necessitating novel therapeutic interventions. In our latest study, we pioneered the use of D-mannitol-cerium-quercetin/rutin coordination polymer nanoparticles (MCQ/R NPs) as a potential treatment for ALI. The MCQ/R NPs, which integrate rutin and quercetin for their therapeutic potential and D-mannitol for its pulmonary targeting, displayed exceptional efficacy. By utilizing cerium ions for optimal nanoparticle assembly, the MCQ/R NPs demonstrated an average size of less than 160 nm. Impressively, these nanoparticles outperformed conventional treatments in both antioxidative capabilities and biocompatibility. Moreover, our in vivo studies on LPS-induced ALI mice showed a significant reduction in lung tissue inflammation. This groundbreaking research presents MCQ/R NPs as a promising new approach in ALI therapeutics.

Health risks and sources of trace elements and black carbon in PM2.5 from 2019 to 2021 in Beijing.

A comprehensive health risk assessment of PM2.5 is meaningful to understand the current status and directions regarding further improving air quality from the perspective of human health. In this study, we evaluated the health risks of PM2.5 as well as highly toxic inorganic components, including heavy metals (HMs) and black carbon (BC) based on long-term observations in Beijing from 2019 to 2021. Our results showed that the relative risks of chronic obstructive pulmonary disease, lung cancer, acute lower respiratory tract infection, ischemic heart disease, and stroke decreased by 4.07%-9.30% in 2020 and 2.12%-6.70% in 2021 compared with 2019. However, they were still at high levels ranging from 1.26 to 1.77, in particular, stroke showed the highest value in 2021. Mn had the highest hazard quotient (HQ, from 2.18 to 2.56) for adults from 2019 to 2021, while Ni, Cr, Pb, As, and BC showed high carcinogenic risks (CR > 1.0×10-6) for adults. The HQ values of Mn and As and the CR values of Pb and As showed constant or slight upwards trends during our observations, which is in contrast to the downward trends of other HMs and PM2.5. Mn, Cr, and BC are crucial toxicants in PM2.5. A significant shrink of southern region sourcesof HMs and BCshrank suggests the increased importance of local sources. Industry, dust, and biomass burning are the major contributors to the non-carcinogenic risks, while traffic emissions and industry are the dominant contributors to the carcinogenic risks in Beijing.

One-Pot Synthesis of Bi2 S3 /TiO2 /rGO Heterostructure with Red Light-Driven Photovoltaic Effect for Remote Electrotherapy-Assisted Wound Repair.

The past decades have witnessed the rational design of novel functional nanomaterials and the potential to revolutionize many applications. With the increasing focus on electronic biological processes, novel photovoltaic nanomaterials are highly expectable for empowering new therapeutic strategies such as establishing a link between endogenous electric field (EEF) and electrotherapy. Compared to traditional invasive stimulation, the light-initiating strategy has the advantages of non-invasion, non-power supply, and precise controllability. Whereas, common photoactivated materials require short-wavelength light excitation accompanied by poor tissue penetration and biohazard. Herein, by the construction of p-n heterostructured Bi2 S3 /TiO2 /rGO (BTG) nanoparticles, broadener light absorption and higher light conversion than regular UV excitation are realized. Simultaneously, the photoelectric performance of BTG heterostructure, as well as the synergistic effect of Bi2 S3 morphology, are revealed. Besides, the rationally designed biomimetic hydrogel matrix consisting of collagen and hyaluronic acid provides appropriate bioactivity, interface adhesion, mechanical matching, and electron transfer. Therefore, the photovoltaic BTG-loaded matrix provides a platform of light-driven electrical stimulation, coupling the EEF to modulate the electrophysiological and regeneration microenvironment. The implementation of photoelectric stimulation holds broad prospects for non-drug therapy and electrical-related biological process modulation including osseointegration, nerve regeneration, electronic skin, and wound healing.

Soliton interaction in a MXene-based mode-locked fiber laser.

MXenes are a class of two-dimensional layered structure ternary metal carbide or/and nitride materials. Recently, the MXene V2CTx has demonstrated excellent long-term stability, strong saturable absorption, and fast optical-switching capability, used to generate Q-switched and ultrashort pulsed lasers. However, bound-state fiber lasers based on V2CTx have not been reported yet. In this study, V2CTx is combined with a D-shaped fiber to form a saturable absorber device, whose modulation depth is measured to be 1.6%. By inserting the saturable absorber into an Er-doped fiber laser, bound states with different soliton separation and munbers are successfully obtained. Additionally, bound states with a compound soliton structure, such as the (2 + 2)- and (2 + 1)-type, are also realized. Our findings show that V2CTx can be developed as an efficient ultrafast photonics candidate to further understand the complex nonlinear dynamics of bound-state pulses in fiber lasers.

Temporal soliton dynamics of synchronised ultrafast fibre lasers.

Synchronised ultrafast soliton lasers have attracted great research interest in recent decades. However, there is a lack of comprehensive understanding regarding the buildup mechanism of synchronised pulses. Here, we report a dynamic analysis of independent and synchronised solitons buildup mechanisms in synchronised ultrafast soliton lasers. The laser comprises an erbium-doped fibre cavity and a thulium-doped fibre cavity bridged with a common arm. Pulses operating at two different wavelengths formed in the cavities are synchronised by cross-phase modulation-induced soliton correlation in the common fibre arm. We find that the whole buildup process of the thulium-doped fibre laser successively undergoes five different stages: continuous wave, relaxation oscillation, quasi-mode-locking, continuous wave mode-locking and synchronised mode-locking. It is found that the starting time of the synchronised solitons is mainly determined by the meeting time of dual-color solitons. Our results will further deepen the understanding of dual-color synchronised lasers and enrich the study of complex nonlinear system dynamics.

Dichromatic "Breather Molecules" in a Mode-Locked Fiber Laser.

Bound states of solitons ("molecules") occur in various settings, playing an important role in the operation of fiber lasers, optical emulation, encoding, and communications. Soliton interactions are generally related to breathing dynamics in nonlinear dissipative systems, and maintain potential applications in spectroscopy. In the present work, dichromatic breather molecules (DBMs) are created in a synchronized mode-locked fiber laser. Real-time delay-shifting interference spectra are measured to display the temporal evolution of the DBMs, that cannot be observed by means of the usual real-time spectroscopy. As a result, robust out-of-phase vibrations are found as a typical intrinsic mode of DBMs. The same bound states are produced numerically in the framework of a model combining equations for the population inversion in the mode-locked laser and cross-phase-modulation-coupled complex Ginzburg-Landau equations for amplitudes of the optical fields in the fiber segments of the laser cavity. The results demonstrate that the Q-switching instability induces the onset of breathing oscillations. The findings offer new possibilities for the design of various regimes of the operation of ultrafast lasers.

ROS-Responsive Prodrug Micelle Co-Delivery System for Synergistic Antiatherosclerotic Therapy.

Tanshinone IIA (TS-IIA) and salvianic acid A (SAA) are the main pharmacological active constituents of Danshen, which exhibit potent effects on atherosclerosis. A combination of TS-IIA and SAA might exert a synergistic antiatherosclerotic effect. However, the opposite solubility profiles of TS-IIA and SAA might lead to difficulty in achieving a synergistic combined effect of the two active components. Therefore, in this work, we fabricated a ROS-responsive prodrug micelle for the codelivery of TS-IIA and SAA (TS-IIA-PM) by self-assembling amphiphilic block copolymer PEG5000-SAA/PLA10000-APBA. The amphiphilic polymer was characterized by 1H NMR, FTIR, and alizarin red S competition tests. The ROS responsiveness of TS-IIA-PM was evidenced by time-course monitoring of particle size and morphology changes and drug release behavior in the presence of 1 mM H2O2. We found TS-IIA-PM was stable according to its critical micelle concentration and the unchanged particle sizes in 10% FBS for 7 days. The results of in vitro and in vivo tests revealed that TS-IIA-PM was safe and biocompatible. Furthermore, it was observed that TS-IIA and prodrug micelle could produce synergistic antiatherosclerotic effect based on the results of the antioxidant study, which was further confirmed by a series of pharmocodynamics studies, such as in vitro DiI-oxLDL uptake study, oil red O staining, cholesterol efflux study, inflammatory cytokine analysis, in vivo CD68 immunostaining, and lipid disposition staining studies. Collectively, TS-IIA-PM holds great potential for the safe and efficient codelivery of TS-IIA and SAA for synergistic antiatherosclerosis.

Reactive Chlorine Species Advancing the Atmospheric Oxidation Capacities of Inland Urban Environments.

Chlorine (Cl) radicals from photolabile chlorine species are highly reactive and can affect the fate of air pollutants in the atmosphere. Although several campaigns have been conducted, typically in coastal environments, long-term observations of reactive chlorine species and their impacts on atmospheric oxidation capacities (AOCs) are lacking. Here, we report nearly full-year observations of Cl2 and ClNO2 levels in Beijing and evaluate their impacts on the AOC with a box model coupled with Cl chemistry. Cl radicals promote the circulation of OH-HO2-RO2 by accelerating the OH chain lengths by up to 12.6% on average, hence boosting the AOC, especially in the winter or spring. This promotion effect is nonlinearly dependent on the VOC and NOx concentrations, thus leading to a slight shift in ozone formation from a VOC-sensitive regime to a transition regime with seasonal differences. Given the ubiquitous reactive chlorines in polluted inland urban regions, the AOCs and the formation of secondary pollutants will be underestimated if the reactive chlorine species are neglected.

Melatonin improves the ability of spermatozoa to bind with oocytes in the mouse.

CONTEXT AND AIMS: Melatonin is a powerful antioxidant regulating various biological functions, including alleviating male reproductive damage under pathological conditions. Here, we aim to analyse the effect of melatonin on normal male reproduction in mice. METHODS: Male mice received an intraperitoneal injection of melatonin (10mg/kg body weight) for 35 consecutive days. The testis and epididymis morphology, and epididymal sperm parameters were examined. PCNA, HSPA2, SYCP3, ZO-1 and CYP11A1 expressions in epididymis or testis were detected by immunohistochemistry or Western blotting. Male fertility was determined by in vivo and in vitro fertilisation (IVF) experiments. The differentially expressed sperm proteins were identified by proteomics. KEY RESULTS: No visible structural changes and oxidative damage in the testis and epididymis, and no significant side effects on testis weight, testosterone levels, sperm motility, and sperm morphology were observed in the melatonin-treatment group compared with the control group. Spermatogenesis-related molecules of PCNA, SYCP3, ZO-1, and CYP11A1 showed no significant differences in melatonin-treated testis. However, PCNA and HSPA2 increased their expressions in the epididymal initial segments in the melatonin-treatment group. Normal sperm fertilisation, two-cell and blastocyst development were observed in the melatonin-treated group, but melatonin significantly enhanced the sperm binding ability characterised as more sperm binding to one oocyte (control 7.2±1.3 versus melatonin 11.8±1.5). Sperm proteomics demonstrated that melatonin treatment enhanced the biological process of cell adhesion in sperm. CONCLUSIONS AND IMPLICATIONS: This study suggests that melatonin can promote sperm maturation and sperm function, providing important information for further research on the physiological function and protective effect of melatonin in male reproduction.

Human umbilical cord mesenchymal stem cells (hUC-MSCs) alleviate paclitaxel-induced spermatogenesis defects and maintain male fertility.

Chemotherapeutic drugs can cause reproductive damage by affecting sperm quality and other aspects of male fertility. Stem cells are thought to alleviate the damage caused by chemotherapy drugs and to play roles in reproductive protection and treatment. This study aimed to explore the effects of human umbilical cord mesenchymal stem cells (hUC-MSCs) on alleviating paclitaxel (PTX)-induced spermatogenesis and male fertility defects. An in vivo PTX-induced mice model was constructed to evaluate the reproductive toxicity and protective roles of hUC-MSCs in male fertility improvement. A 14 day PTX treatment regimen significantly attenuated mice spermatogenesis and sperm quality, including affecting spermatogenesis, reducing sperm counts, and decreasing sperm motility. hUC-MSCs treatment could significantly improve sperm functional indicators. Mating experiments with normal female mice and examination of embryo development at 7.5 days post-coitum (dpc) showed that hUC-MSCs restored male mouse fertility that was reduced by PTX. In IVF experiments, PTX impaired sperm fertility and blastocyst development, but hUC-MSCs treatment rescued these indicators. hUC-MSCs' protective role was also displayed through the increased expression of the fertility-related proteins HSPA2 and HSPA4L in testes with decreased expression in the PTX-treated group. These changes might be related to the PTX-induced decreases in expression of the germ cell proliferation protein PCNA and the meiosis proteins SYCP3, MLH1, and STRA8, which were restored after hUC-MSCs treatment. In the PTX-treated group, the expression of testicular antioxidant proteins SIRT1, NRF2, CAT, SOD1, and PRDX6 was significantly decreased, but hUC-MSCs could maintain these expressions and reverse PTX-related increases in BAX/BCL2 ratios. hUC-MSCs may be a promising agent with antioxidant and anti-apoptosis characteristics that can maintain sperm quality following chemotherapy treatment.