Investigation on the mechanisms of scorpion venom in hepatocellular carcinoma model mice via untargeted metabolomics profiling.

Metabolic reprogramming is frequently accompanied by hepatocellular carcinoma (HCC) progression. Disrupted metabolites act as potential biomarkers and drug therapeutic targets for HCC. Peptide extract of scorpion venom (PESV) induces cytotoxic anti-proliferative effects and apoptosis in tumors. However, the action mechanisms of PESV remain unknown. This study aimed to explore the serum metabolic profiles of tumor-bearing mouse model. We generated an orthotopic HCC xenograft mouse model by implanting H22 cells into the left hepatic lobe of male C57BL/6 mice. After surgery, the mice were assigned to two groups randomly: PESV (PESV-treated 40 mg/kg daily, i.g.; n = 6) and control (treated with the solvent equally for 14 d, n = 6) groups. Based on an untargeted metabolomics approach using ultra-high-performance liquid chromatography/quadrupole time-of-flight mass spectrometry, differential metabolites were screened via univariate and multivariate data analyses. A total of 48 differential metabolites in negative ion mode and 63 in positive ion mode were identified in the serum samples. Furthermore, metabolic pathway analysis revealed that aminoacyl-tRNA biosynthesis, amino acid pathway, glutathione metabolism, protein transports, protein digestion and absorption, and cAMP signaling pathways play vital roles in PESV-induced inhibition of tumors. These findings highlight the distinct changes in the metabolic profiles of HCC-bearing mice after PESV treatment, suggesting the potential of the identified metabolic molecules as therapeutic targets for HCC.

Integrative analysis of transcriptome and metabolome reveal the differential tolerance mechanisms to low and high salinity in the roots of facultative halophyte Avicennia marina.

Mangroves perform a crucial ecological role along the tropical and subtropical coastal intertidal zone where salinity fluctuation is frequently happened. However, the differential responses of mangrove plant at transcriptome combined metabolome level to variable salinity are not well documented. In this study, we used Avicennia marina, a pioneer species of mangrove wetlands and one of the most salt-tolerant mangroves, to investigate the differential salt tolerance mechanisms under low and high salinity using ICP-MS, transcriptomic and metabolomic analysis. The results showed that HAK8 was up-regulated and transported K+ into the roots under low salinity. However, under high salinity, AKT1 and NHX2 were strongly induced, which indicated the transport of K+ and Na+ compartmentalization to maintain ion homeostasis. In addition, A. marina tolerates low salinity by up-regulating ABA signaling pathway and accumulating more mannitol, unsaturated fatty acids, amino acids, and L-ascorbic acid in the roots. Under high salinity, A. marina undergoes a more drastic metabolic network rearrangement in the roots, such as more L-ascorbic acid and oxiglutatione were up-regulated, while carbohydrates, lipids and amino acids were down-regulated in the roots, finally glycolysis and TCA cycle were promoted to provide more energy to improve salt tolerance. Our findings suggest that the major salt tolerance traits in A. marina can be attributed to complex regulatory and signaling mechanisms, and show significant differences between low and high salinity.

Construction and evaluation of AuNPs enhanced electrochemical immunosensors with [Fe(CN)6]3-/4- and PPy probe for highly sensitive detection of human chorionic gonadotropin.

Human chorionic gonadotropin (HCG), a vital protein for pregnancy determination and a marker for trophoblastic diseases, finds application in monitoring early pregnancy and ectopic pregnancy. This study presents an innovative approach employing electrochemical immunosensors for enhanced HCG detection, utilizing Anti-HCG antibodies and gold nanoparticles (AuNPs) in the sensor platform. Two sensor configurations were optimized: BSA/Anti-HCG/c-AuNPs/MEL/e-AuNPs/SPCE with [Fe(CN)6]3-/4- as a redox probe (1) and BSA/Anti-HCG/PPy/e-AuNPs/SPCE using polypyrrole (PPy) as a redox probe (2). The first sensor offers linear correlation in the 0.10-500.00 pg∙mL-1 HCG range, with a limit of detection (LOD) of 0.06 pg∙mL-1, sensitivity of 32.25 µA∙pg-1∙mL∙cm-2, RSD <2.47 %, and a recovery rate of 101.03-104.81 %. The second sensor widens the HCG detection range (40.00 fg∙mL-1-5.00 pg∙mL-1) with a LOD of 16.53 fg∙mL-1, ensuring precision (RSD <1.04 %) and a recovery range of 94.61-106.07 % in serum samples. These electrochemical immunosensors have transformative potential in biomarker detection, offering enhanced sensitivity, selectivity, and stability for advanced healthcare diagnostics.

Follicular CD8+ T cells promote immunoglobulin production and demyelination in multiple sclerosis and a murine model.

Emerging evidence underscores the importance of CD8+ T cells in the pathogenesis of multiple sclerosis (MS), but the precise mechanisms remain ambiguous. This study intends to elucidate the involvement of a novel subset of follicular CD8+ T cells (CD8+CXCR5+ T) in MS and an experimental autoimmune encephalomyelitis (EAE) murine model. The expansion of CD8+CXCR5+ T cells was observed in both MS patients and EAE mice during the acute phase. In relapsing MS patients, higher frequencies of circulating CD8+CXCR5+ T cells were positively correlated with new gadolinium-enhancement lesions in the central nervous system (CNS). In EAE mice, frequencies of CD8+CXCR5+ T cells were also positively correlated with clinical scores. These cells were found to infiltrate into ectopic lymphoid-like structures in the spinal cords during the peak of the disease. Furthermore, CD8+CXCR5+ T cells, exhibiting high expression levels of ICOS, CD40L, IL-21, and IL-6, were shown to facilitate B cell activation and differentiation through a synergistic interaction between CD40L and IL-21. Transferring CD8+CXCR5+ T cells into naïve mice confirmed their ability to enhance the production of anti-MOG35-55 antibodies and contribute to the disease progression. Consequently, CD8+CXCR5+ T cells may play a role in CNS demyelination through heightening humoral immune responses.

Common dietary emulsifiers promote metabolic disorders and intestinal microbiota dysbiosis in mice.

Dietary emulsifiers are linked to various diseases. The recent discovery of the role of gut microbiota-host interactions on health and disease warrants the safety reassessment of dietary emulsifiers through the lens of gut microbiota. Lecithin, sucrose fatty acid esters, carboxymethylcellulose (CMC), and mono- and diglycerides (MDG) emulsifiers are common dietary emulsifiers with high exposure levels in the population. This study demonstrates that sucrose fatty acid esters and carboxymethylcellulose induce hyperglycemia and hyperinsulinemia in a mouse model. Lecithin, sucrose fatty acid esters, and CMC disrupt glucose homeostasis in the in vitro insulin-resistance model. MDG impairs circulating lipid and glucose metabolism. All emulsifiers change the intestinal microbiota diversity and induce gut microbiota dysbiosis. Lecithin, sucrose fatty acid esters, and CMC do not impact mucus-bacterial interactions, whereas MDG tends to cause bacterial encroachment into the inner mucus layer and enhance inflammation potential by raising circulating lipopolysaccharide. Our findings demonstrate the safety concerns associated with using dietary emulsifiers, suggesting that they could lead to metabolic syndromes.

Effect of Different Yeasts on the Higher Alcohol Content of Mulberry Wine.

Healthy, nutritious, and delicious mulberry wine is loved by everyone, but there is no specific yeast for mulberry wine. To screen for yeasts with low-yield higher alcohols for the fermentation of mulberry wine, we tested five commonly used commercial yeasts available on the market to ferment mulberry wine. All five yeasts were able to meet the requirements in terms of yeast fermentation capacity, speed, and physical and chemical markers of mulberry wine. The national standards were met by the fermentation requirements and the fermented mulberry wine. We identified yeast DV10 as a yeast with low-yield higher alcohols suitable for mulberry wine fermentation. The total higher alcohol content in fermented mulberry wine was 298 mg/L, which was 41.9% lower than that of fermented mulberry wine with yeast EC118. The contents of 17 free amino acids and five sugars in mulberry juice and five yeast-fermented mulberry wines were tested. The results showed that the higher the amino acid and sugar content in yeast-fermented mulberry wine, the higher the content of higher alcohols produced by fermentation. A correlation analysis performed on each higher alcohol produced when yeast DV10 fermented the mulberry wine indicated decreased sugar and related amino acids. The findings demonstrated a substantial negative correlation among the levels of increased alcohol, decreased sugar, and matching amino acid content. Considering the correlation values among increased alcohol, decreased sugar, and related amino acids, the very slight difference suggests that both sugar anabolism and amino acid catabolism pathways have an equivalent impact on the synthesis of higher alcohols during the fermentation of mulberry wine. These results provide a theoretical basis for reducing the content of higher alcohols in mulberry wines, given the history and foundation for producing mulberry wine.

Dysfunction of STING Autophagy Degradation in Senescent Nucleus Pulposus Cells Accelerates Intervertebral Disc Degeneration.

The pathogenesis of Intervertebral Disc Degeneration (IDD) is complex and multifactorial, with cellular senescence of nucleus pulposus (NP) cells and inflammation playing major roles in the progression of IDD. The stimulator of interferon genes (STING) axis is a key mediator of inflammation during infection, cellular stress, and tissue damage. Here, we present a progressive increase in STING in senescent NP cells with the degradation disorder. The STING degradation function in normal NP cells can prevent IDD. However, the dysfunction of STING degradation through autophagy causes the accumulation and high expression of STING in senescent NP cells as well as inflammation continuous activation together significantly promotes IDD. In senescent NP cells and intervertebral discs (IVDs), we found that STING autophagy degradation was significantly lower than that of normal NP cells and IVDs when STING was activated by 2'3'-cGAMP. Also, the above phenomenon was found in STINGgt/gt, cGAS-/- mice with models of age-induced, lumbar instability-induced IDD as well as found in the rat caudal IVD puncture models. Taken together, we suggested that the promotion of STING autophagy degradation in senescent NP Cells demonstrated a potential therapeutic modality for the treatment of IDD.

Multifunctional fluorescence/photoacoustic bimodal imaging of γ-glutamyltranspeptidase in liver disorders under different triggering conditions.

Hepatocellular carcinoma (HCC) seriously threatens the human health. Previous investigations revealed that γ-glutamyltranspeptidase (GGT) was tightly associated with the chronic injury, hepatic fibrosis, and the development of HCC, therefore might act as a potential indicator for monitoring the HCC-related processes. Herein, with the contribution of a structurally optimized probe ETYZE-GGT, the bimodal imaging in both far red fluorescence (FL) and photoacoustic (PA) modes has been achieved in multiple HCC-related models. To our knowledge, this work covered the most comprehensive models including the fibrosis and developed HCC processes as well as the premonitory induction stages (autoimmune hepatitis, drug-induced liver injury, non-alcoholic fatty liver disease). ETYZE-GGT exhibited steady and practical monitoring performances on reporting the HCC stages via visualizing the GGT dynamics. The two modes exhibited working consistency and complementarity with high spatial resolution, precise apparatus and desirable biocompatibility. In cooperation with the existing techniques including testing serum indexes and conducting pathological staining, ETYZE-GGT basically realized the universal application for the accurate pre-clinical diagnosis of as many HCC stages as possible. By deeply exploring the mechanically correlation between GGT and the HCC process, especially during the premonitory induction stages, we may further raise the efficacy for the early diagnosis and treatment of HCC.

Acupuncture in Multiple Myeloma Peripheral Neuropathy: A Systematic Review.

Background: Peripheral neuropathy (PN) is a prevalent complication of multiple myeloma (MM), due to the disease itself or its treatment. Despite extensive research, the optimal treatment for multiple myeloma peripheral neuropathy (MMPN) remains unclear. Clinical practice has shown the potential efficacy of acupuncture in managing MMPN. This study aimed to conduct a comprehensive analysis of the literature to assess the effectiveness and safety of acupuncture as a treatment for MMPN. Methods: The PubMed, Web of Science, MEDLINE, Cochrane Library, and Embase databases were comprehensively searched from inception to November 1, 2023 to identify relevant studies pertaining to the use of acupuncture to treat MMPN. Results: A total of five studies, encompassing 97 patients diagnosed with drug-related PN, were ultimately included in this analysis. The literature lacks any reports pertaining to the utilization of acupuncture for disease-related PN. ST36, LI4, SP6, and EX-LE-10 were found to be the most frequently chosen acupoints. Following acupuncture treatment, there was a consistent reduction in scores on the Visual Analogue Scale (VAS), Neuropathic Pain Scale (NPS), Brief Pain Inventory-Short Form (BPI-SF), and Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) among MMPN patients. The results of Nerve Conduction Velocity (NCV) tests yielded conflicting results. No severe adverse effects were reported. Conclusion: The use of acupuncture for disease-related PN has not been studied to date. Acupuncture is safe for drug-related PN and is helpful for relieving pain. But uncertainty exists regarding the efficacy of this approach because there is substantial heterogeneity with respect to acupuncture treatment regimens, and more high-quality studies on this topic are warranted.

Hydrogel-exosome system in tissue engineering: A promising therapeutic strategy.

Characterized by their pivotal roles in cell-to-cell communication, cell proliferation, and immune regulation during tissue repair, exosomes have emerged as a promising avenue for "cell-free therapy" in clinical applications. Hydrogels, possessing commendable biocompatibility, degradability, adjustability, and physical properties akin to biological tissues, have also found extensive utility in tissue engineering and regenerative repair. The synergistic combination of exosomes and hydrogels holds the potential not only to enhance the efficiency of exosomes but also to collaboratively advance the tissue repair process. This review has summarized the advancements made over the past decade in the research of hydrogel-exosome systems for regenerating various tissues including skin, bone, cartilage, nerves and tendons, with a focus on the methods for encapsulating and releasing exosomes within the hydrogels. It has also critically examined the gaps and limitations in current research, whilst proposed future directions and potential applications of this innovative approach.

Investigation of the causal association between Parkinson's disease and autoimmune disorders: a bidirectional Mendelian randomization study.

Background: To date, an increasing number of epidemiological evidence has pointed to potential relationships between Parkinson's disease (PD) and various autoimmune diseases (AIDs), however, no definitive conclusions has been drawn about whether PD is causally related to AIDs risk. Methods: By employing summary statistics from the latest and most extensive genome-wide association studies (GWAS), we performed a bidirectional two-sample Mendelian randomization (MR) analysis to investigate the causal associations between PD and a variety of 17 AIDs, encompassing multiple sclerosis, neuromyelitis optica spectrum disorder, myasthenia gravis, asthma, inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome, celiac disease, primary biliary cirrhosis, primary sclerosing cholangitis, type 1 diabetes, ankylosing spondylitis, rheumatoid arthritis, systemic lupus erythematosus, psoriasis and vitiligo. Inverse-variance weighted (IVW) was adopted as the main statistical approach to obtain the causal estimates of PD on different AIDs, supplemented by a series of complementary analyses (weighted median, MR Egger regression, and MR-PRESSO) for further strengthening the robustness of results. Results: Our MR findings suggested that genetically predicted higher liability to PD was causally associated with a decreased risk of irritable bowel syndrome (OR = 0.98; 95% CI: 0.96-0.99; P = 0.032). On the contrary, IVW analysis showed a potential positive correlation between genetically determined PD and the incidence of type 1 diabetes (OR = 1.10; 95%CI: 1.02-1.19; P = 0.010). Subsequent MR tests ended up in similar results, confirming our findings were reliable. Additionally, in the reverse MR analyses, we did not identify any evidence to support the causal relationship of genetic predisposition to AIDs with PD susceptibility. Conclusion: In general, a bifunctional role that PD exerted on the risk of developing AIDs was detected in our studies, both protecting against irritable bowel syndrome occurrence and raising the incidence of type 1 diabetes. Future studies, including population-based observational studies and molecular experiments in vitro and in vivo, are warranted to validate the results of our MR analyses and refine the underlying pathological mechanisms involved in PD-AIDs associations.

Chromosome-level genome assembly and annotation of the cold-water species Ophiura sarsii.

The cold-water species Ophiura sarsii, a brittle star, is a key echinoderm in the Arctic continental shelf region, highly sensitive to climate change. However, the absence of a high-quality genome has hindered a thorough understanding of its adaptive evolution. In this study, we reported the first chromosome-level genome assembly of O. sarsii. The genome assembly totalled 1.57 Gb, encompassing 19 chromosomes with a GC content of 37.11% and a scaffold N50 length of 78.03 Mb. The Benchmarking Universal Single-Copy Orthologs (BUSCO) assessment yielded a completeness estimate of 93.5% for this assembly. We predicted a total of 27,099 protein-coding genes, with 25,079 functionally annotated. The genome was comprised of 58.09% transposable elements. This chromosome-level genome of O. sarsii contributes to our understanding of the origin and evolution of marine organisms.

Correlation between thyroid hormone sensitivity and the risk of polycystic ovary syndrome.

OBJECTIVE: There has been some confusion in earlier research on the connection between thyroid function and polycystic ovary syndrome (PCOS). This research is aimed to probe into the correlation between thyroid condition and the risk of PCOS from a new standpoint of thyroid hormone sensitivity. METHODS: This research comprised 415 females with PCOS from Drum Tower Hospital Affiliated with the Medical School of Nanjing University, and 137 non-PCOS individuals were selected as the normal control. Based on free thyroxine (FT4), free triiodothyronine (FT3), and thyroid-stimulating hormone (TSH), we calculated the thyroid hormone sensitivity indices, which consist of Thyroid Feedback Quantile-based Index (TFQI), Thyroid-stimulating Hormone Index (TSHI), Thyrotroph Thyroxine Resistance Index (TT4RI) and Free Triiodothyronine /Free thyroxine (FT3/FT4). The binary logistic regression model was adopted to investigate the correlation between thyroid hormone sensitivity indices with the risk of PCOS. Pearson or Spearman correlation analysis was employed to explore the association among thyroid-related measures with metabolic parameters in PCOS. RESULTS: Results of this research showed that females with PCOS had rising TFQI, TSHI, TT4RI, and FT3/FT4 levels compared with the control group. After adjustment for the impact of various covariates, there was no significant correlation between FT3/FT4 and the risk of PCOS; However, the odds ratio of the third and fourth vs. the first quartile of TFQI were 3.57(95% confidence interval [CI]:1.08,11.87) and 4.90(95% CI:1.38,17.38) respectively; The odds ratio of the fourth vs. the first quartile of TSHI was 5.35(95% CI:1.48,19.37); The odds ratio of the second vs. the first quartile of TT4RI was 0.27(95%CI 0.09,0.82). In addition, no significant correlation was observed between thyroid-related measures and metabolic measures in females with PCOS. CONCLUSIONS: A reduction in the sensitivity of central thyroid hormone is closely correlated with a higher risk of PCOS. Further research is necessary to corroborate our findings and the supporting mechanisms.

Mechanisms of myeloid-derived suppressor cell-mediated immunosuppression in colorectal cancer and related therapies.

Severe immunosuppression is a hallmark of colorectal cancer (CRC). Myeloid-derived suppressor cells (MDSCs), one of the most abundant components of the tumor stroma, play an important role in the invasion, metastasis, and immune escape of CRC. MDSCs create an immunosuppressive microenvironment by inhibiting the proliferation and activation of immunoreactive cells, including T and natural killer cells, as well as by inducing the proliferation of immunosuppressive cells, such as regulatory T cells and tumor-associated macrophages, which, in turn, promote the growth of cancer cells. Thus, MDSCs are key contributors to the emergence of an immunosuppressive microenvironment in CRC and play an important role in the breakdown of antitumor immunity. In this narrative review, we explore the mechanisms through which MDSCs contribute to the immunosuppressive microenvironment, the current therapeutic approaches and technologies targeting MDSCs, and the therapeutic potential of modulating MDSCs in CRC treatment. This study provides ideas and methods to enhance survival rates in patients with CRC.

The Evaluation of Teleost-Derived Antimicrobial Peptides Against Neisseria gonorrhoeae.

Introduction Gonorrhea has become an emerging sexually transmitted infection worldwide. The multi-antibiotic resistance facilitates the transmission; thus, new antibiotics or alternatives are needed. Antimicrobial peptides (AMP) are antimicrobials naturally secreted by the host as a defense material. Teleost-derived AMP have gained attention over the past two decades due to their potent efficacy toward microorganisms. This study examines teleost-derived AMP against Neisseria gonorrhoeae (GC), the responsible bacteria for gonorrhea, to evaluate the antibiotic potential as a future alternative for preventing gonorrhea. Methods Minimal inhibitory concentration (MIC) and time-killed assay were conducted to evaluate the inhibition concentration of each AMP. Transmission electron microscopy was used to confirm the potential mode of action. The inhibition of microcolony formation and adherence to epithelial cells were examined to assess the infection inhibition. Results Pardaxin-based (flatfish pardaxin {PB2}) and piscidin-based (striped bass piscidin 1 {PIS} and tilapia piscidin {TP} 4) AMP were effective toward GC under or equal to 7.5 µg/mL as of minimal inhibitory concentration. Transmission electron microscopy images revealed that these AMP attack bacterial membranes as membrane blebbing and breakage were observed. These AMP also effectively reduced the GC biofilm formation, as well as their adherence to human endocervical epithelial cells. Conclusion Pardaxin-based (PB2) and piscidin-based (PIS and TP4) teleost-derived AMP can inhibit GC and potentially serve as the new antibiotic alternative for preventing GC colonization and infection. This study will shed some light on the future development of teleost-derived AMP in treating gonorrhea and maintaining reproductive health.

The "depict" strategy for discovering new compounds in complex matrices: Lycibarbarspermidines as a case.

The comprehensive detection and identification of active ingredients in complex matrices is a crucial challenge. Liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS) is the most prominent analytical platform for the exploration of novel active compounds from complex matrices. However, the LC-HRMS-based analysis workflow suffers from several bottleneck issues, such as trace content of target compounds, limited acquisition for fragment information, and uncertainty in interpreting relevant MS2 spectra. Lycibarbarspermidines are vital antioxidant active ingredients in Lycii Fructus, while the reported structures are merely focused on dicaffeoylspermidines due to their low content. To comprehensively detect the new structures of lycibarbarspermidine derivatives, a "depict" strategy was developed in this study. First, potential new lycibarbarspermidine derivatives were designed according to the biosynthetic pathway, and a comprehensive database was established, which enlarged the coverage of lycibarbarspermidine derivatives. Second, the polarity-oriented sample preparation of potential new compounds increased the concentration of the target compounds. Third, the construction of the molecular network based on the fragmentation pathway of lycibarbarspermidine derivatives broadened the comprehensiveness of identification. Finally, the weak response signals were captured by data-dependent scanning (DDA) followed by parallel reaction monitoring (PRM), and the efficiency of acquiring MS2 fragment ions of target compounds was significantly improved. Based on the integrated strategy above, 210 lycibarbarspermidine derivatives were detected and identified from Lycii Fructus, and in particular, 170 potential new compounds were structurally characterized. The integrated strategy improved the sensitivity of detection and the coverage of low-response components, and it is expected to be a promising pipeline for discovering new compounds.

Impact of job embeddedness on miners' safety performance: the role of perceived insider status and safety climate.

The present study aims to explore the mechanism for the impact of job embeddedness on safety performance, the mediating role of perceived insider status and the cross-level moderating role of safety climate among miners. The questionnaire data used for analysis in this study were collected from 310 miners in 38 coal mine production teams in China. Bootstrap analysis was performed to explore the mediating role of perceived insider status, and multilevel linear analysis was performed to explore the cross-level moderating role of safety climate. The results showed that job embeddedness was positively related to miners' safety performance; perceived insider status mediating the relationship between job embeddedness and miners' safety performance; and safety climate moderating the relationship between perceived insider status and miners' safety performance across levels.

Succession of microbiota and its influence on the dynamics of volatile compounds in the semi-artificial inoculation fermentation of mulberry wine.

To improve the delightful flavor of mulberry wine through semi-artificial inoculation fermentation with Saccharomyces cerevisiae, we studied the dynamics change of microbiota, along with the physicochemical properties and metabolite profiles and their interaction relationship during the fermentation process. The abundance of lactic acid bacteria (Weissella, Lactobacillus, Fructobacillus, and Pediococcus) increased significantly during fermentation, while yeasts gradually established dominance. The inter-kingdom network of the dominant genera analysis further identified the following as core microbiota: Alternaria, Botrytis, Kazachstania, Acremonium, Mycosphaerella, Pediococcus, Gardnerella, and Schizothecium. Additionally, pH, alcohol, and total acid were significantly affected by microbiota variation. Fourteen of all identified volatile compounds with key different aromas were screened using PCA, OPLS-DA, and rOAV. The network of interconnected core microbiota with key different aromas revealed that Kazachstania and Pediococcus had stronger correlations with 1-butanol, 3-methyl-, propanoic acid, and 2-methyl-ethyl ester.

Systematic review of melatonin in cerebral ischemia-reperfusion injury: critical role and therapeutic opportunities.

Cerebral ischemia-reperfusion (I/R) injury is the predominant causes for the poor prognosis of ischemic stroke patients after reperfusion therapy. Currently, potent therapeutic interventions for cerebral I/R injury are still very limited. Melatonin, an endogenous hormone, was found to be valid in preventing I/R injury in a variety of organs. However, a systematic review covering all neuroprotective effects of melatonin in cerebral I/R injury has not been reported yet. Thus, we perform a comprehensive overview of the influence of melatonin on cerebral I/R injury by collecting all available literature exploring the latent effect of melatonin on cerebral I/R injury as well as ischemic stroke. In this systematic review, we outline the extensive scientific studies and summarize the beneficial functions of melatonin, including reducing infarct volume, decreasing brain edema, improving neurological functions and attenuating blood-brain barrier breakdown, as well as its key protective mechanisms on almost every aspect of cerebral I/R injury, including inhibiting oxidative stress, neuroinflammation, apoptosis, excessive autophagy, glutamate excitotoxicity and mitochondrial dysfunction. Subsequently, we also review the predictive and therapeutic implications of melatonin on ischemic stroke reported in clinical studies. We hope that our systematic review can provide the most comprehensive introduction of current advancements on melatonin in cerebral I/R injury and new insights into personalized diagnosis and treatment of ischemic stroke.

A POLR3B-variant reveals a Pol III transcriptome response dependent on La protein/SSB.

RNA polymerase III (Pol III, POLR3) synthesizes tRNAs and other small non-coding RNAs. Human POLR3 pathogenic variants cause a range of developmental disorders, recapitulated in part by mouse models, yet some aspects of POLR3 deficiency have not been explored. We characterized a human POLR3B:c.1625A>G;p.(Asn542Ser) disease variant that was found to cause mis-splicing of POLR3B. Genome-edited POLR3B1625A>G HEK293 cells acquired the mis-splicing with decreases in multiple POLR3 subunits and TFIIIB, although display auto-upregulation of the Pol III termination-reinitiation subunit POLR3E. La protein was increased relative to its abundant pre-tRNA ligands which bind via their U(n)U-3'-termini. Assays for cellular transcription revealed greater deficiencies for tRNA genes bearing terminators comprised of 4Ts than of ≥5Ts. La-knockdown decreased Pol III ncRNA expression unlinked to RNA stability. Consistent with these effects, small-RNAseq showed that POLR3B1625A>G and patient fibroblasts express more tRNA fragments (tRFs) derived from pre-tRNA 3'-trailers (tRF-1) than from mature-tRFs, and higher levels of multiple miRNAs, relative to control cells. The data indicate that decreased levels of Pol III transcripts can lead to functional excess of La protein which reshapes small ncRNA profiles revealing new depth in the Pol III system. Finally, patient cell RNA analysis uncovered a strategy for tRF-1/tRF-3 as POLR3-deficiency biomarkers.