Machine learning-derived identification of prognostic signature for improving prognosis and drug response in patients with ovarian cancer.

Clinical assessments relying on pathology classification demonstrate limited effectiveness in predicting clinical outcomes and providing optimal treatment for patients with ovarian cancer (OV). Consequently, there is an urgent requirement for an ideal biomarker to facilitate precision medicine. To address this issue, we selected 15 multicentre cohorts, comprising 12 OV cohorts and 3 immunotherapy cohorts. Initially, we identified a set of robust prognostic risk genes using data from the 12 OV cohorts. Subsequently, we employed a consensus cluster analysis to identify distinct clusters based on the expression profiles of the risk genes. Finally, a machine learning-derived prognostic signature (MLDPS) was developed based on differentially expressed genes and univariate Cox regression genes between the clusters by using 10 machine-learning algorithms (101 combinations). Patients with high MLDPS had unfavourable survival rates and have good prediction performance in all cohorts and in-house cohorts. The MLDPS exhibited robust and dramatically superior capability than 21 published signatures. Of note, low MLDIS have a positive prognostic impact on patients treated with anti-PD-1 immunotherapy by driving changes in the level of infiltration of immune cells. Additionally, patients suffering from OV with low MLDIS were more sensitive to immunotherapy. Meanwhile, patients with low MLDIS might benefit from chemotherapy, and 19 compounds that may be potential agents for patients with low MLDIS were identified. MLDIS presents an appealing instrument for the identification of patients at high/low risk. This could enhance the precision treatment, ultimately guiding the clinical management of OV.

Comparative Analysis of the Chloroplast Genomes of Eight Species of the Genus Lirianthe Spach with Its Generic Delimitation Implications.

Based on Sima and Lu's system of the family Magnoliaceae, the genus Lirianthe Spach s. l. includes approximately 25 species, each with exceptional landscaping and horticultural or medical worth. Many of these plants are considered rare and are protected due to their endangered status. The limited knowledge of species within this genus and the absence of research on its chloroplast genome have greatly impeded studies on the relationship between its evolution and systematics. In this study, the chloroplast genomes of eight species from the genus Lirianthe were sequenced and analyzed, and their phylogenetic relationships with other genera of the family Magnoliaceae were also elucidated. The results showed that the chloroplast genome sizes of the eight Lirianthe species ranged from 159,548 to 159,833 bp. The genomes consisted of a large single-copy region, a small single-copy region, and a pair of inverted repeat sequences. The GC content was very similar across species. Gene annotation revealed that the chloroplast genomes contained 85 protein-coding genes, 37 tRNA genes, and 8 rRNA genes, totaling 130 genes. Codon usage analysis indicated that codon usage was highly conserved among the eight Lirianthe species. Repeat sequence analysis identified 42-49 microsatellite sequences, 16-18 tandem repeats, and 50 dispersed repeats, with microsatellite sequences being predominantly single-nucleotide repeats. DNA polymorphism analysis revealed 10 highly variable regions located in the large single-copy and small single-copy regions, among which rpl32-trnL, petA-psbJ, and trnH-psbA were the recommended candidate DNA barcodes for the genus Lirianthe species. The inverted repeat boundary regions show little variation between species and are generally conserved. The result of phylogenetic analysis confirmed that the genus Lirianthe s. l. is a monophyletic taxon and the most affinal to the genera, Talauma and Dugandiodendron, in Sima and Lu's system and revealed that the genus Lirianthe s. s. is paraphyletic and the genus Talauma s. l. polyphyletic in Xia's system, while Magnolia subsection Gwillimia is paraphyletic and subsection Blumiana polyphyletic in Figlar and Nooteboom's system. Morphological studies found noticeable differences between Lirianthe species in aspects including leaf indumentum, stipule scars, floral orientation, tepal number, tepal texture, and fruit dehiscence. In summary, this study elucidated the chloroplast genome evolution within Lirianthe and laid a foundation for further systematic and taxonomic research on this genus.

Endothelial Conditional Knockdown of NMMHC IIA (Nonmuscle Myosin Heavy Chain IIA) Attenuates Blood-Brain Barrier Damage During Ischemia-Reperfusion Injury.

BACKGROUND AND PURPOSE: In ischemic stroke, breakdown of the blood-brain barrier (BBB) aggravates brain damage. Endothelial detachment contributes to BBB disruption and neurovascular dysfunction, but its regulation in stroke has yet to be clarified. We investigated the function of NMMHC IIA (nonmuscle myosin heavy chain IIA) in the endothelium on BBB breakdown and its potential mechanisms. METHODS: Endothelial conditional knockdown NMMHC IIA (Myh9ECKD) was constructed in vivo and in vitro, and its role was explored in middle cerebral artery occlusion/reperfusion-injured mice and oxygen-glucose deprivation/reoxygenation-injured brain microvascular endothelial cells. The degree of brain injury was analyzed using staining (2,3,5-triphenyltetrazolium chloride, hematoxylin, and eosin) and electron microscopy. BBB breakdown was investigated with leakage of Evans Blue dye and expression of TJs (tight junctions) and MMP (matrix metallopeptidase)-2/9. Transcriptomics for enrichment analysis was adopted to explore the potential downstream signaling pathways of NMMHC IIA involved in middle cerebral artery occlusion/reperfusion-induced BBB dysfunction. RESULTS: NMMHC IIA expression was upregulated in endothelial cells after cerebral ischemia/reperfusion injury. Myh9ECKD mice exhibited improvement in endothelial barrier hyperpermeability and TJs integrity stimulated by cerebral ischemia/reperfusion. Blebbistatin (NMMHC II inhibitor) treatment exerted the same effect. Transcriptomics showed that NMMHC IIA was involved in regulating various BBB-related genomic changes in the middle cerebral artery occlusion/reperfusion model, and NMMHC IIA was confirmed to significantly modulate Hippo and peroxisome proliferator-activated receptor gamma/nuclear factor-kappa B signaling pathways, which are closely related to BBB damage. CONCLUSIONS: Our findings provide some new insights into how NMMHC IIA contributes to maintaining the integrity of the cerebral endothelial barrier. NMMHC IIA could be a potential therapeutic target for ischemic stroke.

LncRNA AFAP1-AS1 regulates proliferation and apoptosis of endometriosis through activating STAT3/TGF-ß/Smad signaling via miR-424-5p.

AIM: Endometriosis is a common gynecological disorder characterized by chronic pelvic pain and infertility, which negatively affects women's health worldwide. AFAP1-AS1 has been implicated in endometriosis lesions recently, but its mechanism of endometriosis progression remains unclear. METHODS: Endometrial stromal cells (ESCs) were used to identify the role of AFAP1-AS1 in endometriosis. The migratory capability was determined by transwell. Gene and protein expressions were identified by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. Cell viability and apoptosis were detected by MTT assays and flow cytometry, respectively. Luciferase report assays were used to identify the interaction of AFAP1-AS1, miR-424-5p and signal transducer and activator of transcription 3 (STAT3). RESULTS: AFAP1-AS1 knockdown or miR-424-5p overexpression inhibited proliferation and migration, and promoted apoptosis in ESCs. In addition, knockdown of AFAP1-AS1 repressed the expression of ki-67 and Bcl-2, and promoted the levels of cleaved caspase-3 and Bax. Furthermore, knockdown of AFAP1-AS1 inhibited the conversion of E-cadherin to N-cadherin and the expression of Snail. Moreover, AFAP1-AS1 activated the STAT3/transforming growth factor-ß1 (TGF-ß1)/Smad2 axis via directly targeting miR-424-5p. The regulatory effect of AFAP1-AS1 silencing in ESC migration, proliferation, and apoptosis was reversed by miR-424-5p inhibition or STAT3 overexpression. CONCLUSIONS: AFAP1-AS1 silencing could inhibit cell proliferation and promote apoptosis by regulating STAT3/TGF-ß/Smad signaling pathway via targeting miR-424-5p in ESCs. AFAP1-AS1 may be a potential therapeutic target of controlling the progression of endometriosis.

Microwave-Assisted Extraction Combined with In-Capillary [Fe(ferrozine)3]2+-CE-DAD to Screen Active Components with the Ability to Chelate Ferrous Ions from Flos Sophorae Immaturus (Flos Sophorae).

An efficient microwave-assisted extraction (MAE) combined with in-capillary [Fe(ferrozine)3]2+-capillary electrophoresis-Diode Array Detector (in-capillary [Fe(ferrozine)3]2+-CE-DAD) was developed to screen active components with the ability to chelate ferrous ions and determine the total antioxidant activity. The MAE conditions, including methanol concentration, extraction power, extraction time, and the ratio of material to liquid, were optimized by an L9(34) orthogonal experiment. Background buffer, voltage, and cartridge temperature that affect the separation of six compounds were optimized. It was found that rutin and quercetin were the main components chelating ferrous ions in Flos Sophorae Immaturus (Flos Sophorae) by the in-capillary [Fe(ferrozine)3]2+-CE-DAD. The recoveries were ranged from 95.2% to 104%. It was concluded that the MAE combined with in-capillary [Fe(ferrozine)3]2+-CE-DAD method was a simple, reliable, and efficient tool for screening active components from the complex traditional Chinese medicine samples and evaluating their ability to chelate ferrous ions.

Screening bioactive compounds from natural product and its preparations using capillary electrophoresis.

Bioactive ingredients of natural products can protect human body from harm, as well as prevent and treat disease. Screening bioactive compounds from natural products is attracting particular attention. It is a great challenge to separate and detect the active compounds from complex matrix natural products. CE plays a vital role in screening active compounds because of its unique features such as high-efficiency separation, short-analysis time, minimal sample consumption, and ease to realize automatization etc. Additionally, CE has been developed various modes owing to its abundant advantages in analysis and separation of compounds. The purpose of this work is to review previous developments and applications of CE in screening bioactive compounds derived from natural products from 2007 to 2017. This review does not only summarize the traditional methods of detecting active ingredients but also briefly introduces some novel assays. The trends in the application of CE in active compounds screening are addressed in the article.

The microemulsion electrokinetic capillary chromatography combined with reversed-electrode polarity stacking mode for enriching and quantifying lignanoids and ginsenosides in TCMs preparation Shengmai injection.

An on-line large volume sample stacking with polarity switching (LVSS) method was proposed for simultaneously determining lignanoids and ginsenosides in MEEKC. The parameters including the pH value and concentration of buffer solution, SDS, organic modifier, oil phase, running voltage, and temperature as well as injection time, sample matrix, stacking voltage, and time influencing separation and stacking were systematically optimized. The method was verified by performing precision, accuracy, stability, and recovery. Its reliability was proved by separating and quantifying two lignanoids and three ginsenosides in Shengmai injectionSMI. The sensitivity of these compounds was improved by MEEKC-LVSS method for 6-11 times than conventional MEEKC. Thus, this developed on-line MEEKC-LVSS method was sensitive, practical, and reliable.

Coordination of care in the Chinese health care systems: a gap analysis of service delivery from a provider perspective.

BACKGROUND: Increases in health care utilization and costs, resulting from the rising prevalence of chronic conditions related to the aging population, is exacerbated by a high level of fragmentation that characterizes health care systems in China. There have been several pilot studies in China, aimed at system-level care coordination and its impact on the full integration of health care system, but little is known about their practical effects. Huangzhong County is one of the pilot study sites that introduced organizational integration (a dimension of integrated care) among health care institutions as a means to improve system-level care coordination. The purposes of this study are to examine the effect of organizational integration on system-level care coordination and to identify factors influencing care coordination and hence full integration of county health care systems in rural China. METHODS: We chose Huangzhong and Hualong counties in Qinghai province as study sites, with only Huangzhong having implemented organizational integration. A mixed methods approach was used based on (1) document analysis and expert consultation to develop Best Practice intervention packages; (2) doctor questionnaires, identifying care coordination from the perspective of service provision. We measured service provision with gap index, overlap index and over-provision index, by comparing observed performance with Best Practice; (3) semi-structured interviews with Chiefs of Medicine in each institution to identify barriers to system-level care coordination. RESULTS: Twenty-nine institutions (11 at county-level, 6 at township-level and 12 at village-level) were selected producing surveys with a total of 19 schizophrenia doctors, 23 diabetes doctors and 29 Chiefs of Medicine. There were more care discontinuities for both diabetes and schizophrenia in Huangzhong than in Hualong. Overall, all three index scores (measuring service gaps, overlaps and over-provision) showed similar tendencies for the two conditions. The gap indices of schizophrenia (> 5.10) were bigger for diabetes (< 2.60) in both counties. The over-provision indices of schizophrenia (> 3.25) were bigger than diabetes (< 1.80) in both counties. Overlap indices for the two conditions exceeded justified overlaps, especially for diabetes. Gap index scores for schizophrenia interventions at the township-level and over-provision index scores for diabetes interventions at both village- and township-level showed big differences between the two counties. Insufficient medical staff with appropriate competencies, lack of motivation for care coordination and related supportive policies as well as unconnected information system were identified as barriers to system-level care coordination in both counties. CONCLUSION: Findings demonstrate that organizational integration in Huangzhong has not achieved a higher level of care coordination at this stage. System-level care coordination is most problematic at village-level institutions in Hualong, but at county-level institutions in Huangzhong. These findings suggest that attention be given to other aspects of integration (e.g., clinical and service integration) to promote system-level care coordination and contribute to the full integration of health care system in the pilot county.

The effect of health literacy on health investment intention: a cross-sectional study among petrochemical employees in China.

Backgrounds: In the petrochemical industry, employees are exposed to various health hazards, which pose serious challenges to their health and hinder the sustainable development of the petrochemical industry. Investing in health has proved a potential strategy to enhance general health. However, global health investment is notably insufficient, mainly due to the public's limited intention to invest in their health. While past research has identified various determinants of health investment intentions, the relationship between health literacy and health investment intention remains somewhat controversial and needs more empirical validation. Objectives: This study aims to assess the level of health literacy and health investment intention among employees in one of China's largest petrochemical companies and to explore the effect of health literacy on health investment intention. Methods: A cross-sectional study was conducted in a petrochemical company. The valid sample size for this study was 39,911 respondents. Data were collected using a designed questionnaire, including socio-demographic information, questions about health investment intention, and the "2020 National Health Literacy Monitoring Questionnaire." Several statistical analysis methods were employed, including descriptive analysis, Chi-square test, logistic regression, and multiple linear regression. Results: The study disclosed an average health literacy score of 56.11 (SD = 10.34) among employees, with 52.1% surpassing the qualification threshold. The "Chronic Disease" dimension exhibited the lowest qualification rate at 33.0%. Furthermore, 71.5% of the employees expressed an intention to invest in health, yet a significant portion (34.5%) opted for the minimal investment choice, less than 2,000 RMB. Logistic regression analysis indicated a positive correlation between health literacy and health investment intention (OR = 1.474; p < 0.001). This association's robustness was further indicated by multiple linear regression analyses (ß = 0.086, p<0.001). Conclusion: The employees' health literacy significantly exceeds the national average for Chinese citizens, yet the qualified rate in the "Chronic Disease" dimension remains notably low. A majority of employees have the intention to invest in health, albeit modestly. Furthermore, while health literacy does positively influence health investment intention, this effect is somewhat limited. Accordingly, personalized Health education should be prioritized, with a focus on improving chronic disease knowledge and facilitating the internalization of health knowledge into health beliefs.

Selective extraction and analysis of phenolic acids in herbal plants using Fe3O4@MXene@PEI aerogel.

A magnetic MXene aerogel (Fe3O4@MXene@PEI) was prepared by crosslinking amino modified MXene with polyethyleneimine using epichlorohydrin as a cross-linker. Adsorption properties of Fe3O4@MXene@PEI aerogel for phenolic acids were evaluated by adsorption kinetics and isotherms experiments, showing that the high adsorption affinity was governed by multilayer chemisorption process. An efficient MSPE/HPLC method was developed for the determination of phenolic acids with excellent selectivity, good linearity (0.025-5.0 µg mL-1), low LODs (0.007-0.017 µg mL-1), and satisfactory recoveries (80.0-120.0 %). Moreover, the antioxidant activity of the Fe3O4@MXene@PEI purified compounds was superior to that of the conventional method as demonstrated by the results of scavenging experiments on 2,2 -diphenyl-1-picrylhydrazyl radical scavenging assay. Finally, 65 organic acids were identified in the Fe3O4@MXene@PEI treated honeysuckle extracts by UHPLC-Q-Exactive Orbitrap MS/MS analysis. The proposed sorbent exhibits remarkable promise for the selective separation and purification of organic acids from herbal products.

Aloe-emodin alleviates cerebral ischemia-reperfusion injury by regulating microglial polarization and pyroptosis through inhibition of NLRP3 inflammasome activation.

BACKGROUND: Microglial activation plays a crucial role in injury and repair after cerebral ischemia, and microglial pyroptosis exacerbates ischemic injury. NOD-like receptor protein 3 (NLRP3) inflammasome activation has an important role in microglial polarization and pyroptosis. Aloe-emodin (AE) is a natural anthraquinone compound originated from rhubarb and aloe. It exerts antioxidative and anti-apoptotic effects during cerebral ischemia/reperfusion (I/R) injury. However, whether AE affects microglial polarization, pyroptosis, and NLRP3 inflammasome activation remains unknown. PURPOSE: This study aimed to explore the effects of AE on microglial polarization, pyroptosis, and NLRP3 inflammasome activation in the cerebral infarction area after I/R. METHODS: The transient middle cerebral artery occlusion (tMCAO) and oxygen-glucose deprivation/re-oxygenation (OGD/R) methods were used to create cerebral I/R models in vivo and in vitro, respectively. Neurological scores and triphenyl tetrazolium chloride and Nissl staining were used to assess the neuroprotective effects of AE. Immunofluorescence staining, quantitative polymerase chain reaction and western blot were applied to detect NLRP3 inflammasome activation and microglial polarization and pyroptosis levels after tMCAO or OGD/R. Cell viability and levels of interleukin (IL)-18 and IL-1ß were measured. Finally, MCC950 (an NLRP3-specific inhibitor) was used to evaluate whether AE affected microglial polarization and pyroptosis by regulating the activation of the NLRP3 inflammasome. RESULTS: AE improved neurological function scores and reduced the infarct area, brain edema rate, and Nissl-positive cell rate following I/R injury. It also showed a protective effect on BV-2 cells after OGD/R. AE inhibited microglial pyroptosis and induced M1 to M2 phenotype transformation and suppressed microglial NLRP3 inflammasome activation after tMCAO or OGD/R. The combined administration of AE and MCC950 had a synergistic effect on the inhibition of tMCAO- or OGD/R-induced NLRP3 inflammasome activation, which subsequently suppressed microglial pyroptosis and induced microglial phenotype transformation. CONCLUSION: AE exerts neuroprotective effects by regulating microglial polarization and pyroptosis through the inhibition of NLRP3 inflammasome activation after tMCAO or OGD/R. These findings provide new evidence of the molecular mechanisms underlying the neuroprotective effects of AE and may support the exploration of novel therapeutic strategies for cerebral ischemia.

Different effects of selenium speciation on selenium absorption, selenium transformation and cadmium antagonism in garlic.

Currently, planting selenium-rich crops using inorganic selenium such as selenate and selenite is used to address human selenium deficiency problems. In this paper, besides the above two traditional inorganic selenium speciation, we chose a new organic selenium speciation of potassium selenocyanoacetate to investigate the different effects of selenium speciation on selenium absorption, selenium transformation and cadmium antagonism via foliar application. Plantingexperiments showed that the selenium content of garlic bulbs treated with organic selenium was 1.8-3.9 times higher than that of inorganic selenium. Additionally, the absorption and transformation efficiency of organic selenium in garlic was also the highest, reaching over 95 %. Importantly, it was noteworthy that the cadmium content in bulbs treated with organic selenium was significantly lower than the Chinese food safety standard (0.2 mg/kg). Hence, this study provides an efficient organic selenium speciation which is beneficial to meet human selenium requirements and ensure safe utilization of cadmium-contaminated soils.

Alisol B regulates AMPK/mTOR/SREBPs via directly targeting VDAC1 to alleviate hyperlipidemia.

BACKGROUND: The occurrence of hyperlipidemia is significantly influenced by lipid synthesis, which is regulated by sterol regulatory element binding proteins (SREBPs), thus the development of drugs that inhibit lipid synthesis has become a popular treatment strategy for hyperlipidemia. Alisol B (ALB), a triterpenoid compound extracted from Alisma, has been reported to ameliorate no-nalcoholic steatohepatitis (NASH) and slow obesity. However, the effect of ALB on hyperlipidemia and mechanism are unclear. PURPOSE: To examine the therapeutic impact of ALB on hyperlipidemia whether it inhibits SREBPs to reduce lipid synthesis. STUDY DESIGN: HepG2, HL7702 cells, and C57BL/6J mice were used to explore the effect of ALB on hyperlipidemia and the molecular mechanism in vivo and in vitro. METHODS: Hyperlipidemia models were established using western diet (WD)-fed mice in vivo and oleic acid (OA)-induced hepatocytes in vitro. Western blot, real-time PCR and other biological methods verified that ALB regulated AMPK/mTOR/SREBPs to inhibit lipid synthesis. Cellular thermal shift assay (CETSA), molecular dynamics (MD), and ultrafiltration-LC/MS analysis were used to evaluate the binding of ALB to voltage-dependent anion channel protein-1 (VDAC1). RESULTS: ALB decreased TC, TG, LDL-c, and increased HDL-c in blood, thereby ameliorating liver damage. Gene set enrichment analysis (GSEA) indicated that ALB inhibited the biosynthesis of cholesterol and fatty acids. Consistently, ALB inhibited the protein expression of n-SREBPs and downstream genes. Mechanistically, the impact of ALB on SREBPs was dependent on the regulation of AMPK/mTOR, thereby impeding the transportation of SREBPs from endoplasmic reticulum (ER) to golgi apparatus (GA). Further investigations indicated that the activation of AMPK by ALB was independent on classical upstream CAMKK2 and LKB1. Instead, ALB resulted in a decrease in ATP levels and an increase in the ratios of ADP/ATP and AMP/ATP. CETSA, MD, and ultrafiltration-LC/MS analysis indicated that ALB interacted with VDAC1. Molecular docking revealed that ALB directly bound to VDAC1 by forming hydrogen bonds at the amino acid sites S196 and H184 in the ATP-binding region. Importantly, the thermal stabilization of ALB on VDAC1 was compromised when VDAC1 was mutated at S196 and H184, suggesting that these amino acids played a crucial role in the interaction. CONCLUSION: Our findings reveal that VDAC1 serves as the target of ALB, leading to the inhibition of lipid synthesis, presents potential target and candidate drugs for hyperlipidemia.

Exploring the anti-ferroptosis mechanism of Kai-Xin-San against Alzheimer's disease through integrating network pharmacology, bioinformatics, and experimental validation strategy in vivo and in vitro.

ETHNOPHARMACOLOGICAL RELEVANCE: Kai Xin San (KXS), first proposed by Sun Simiao during the Tang Dynasty, has been utilized to treat dementia by tonifying qi and dispersing phlegm. AIM OF THE STUDY: This study aimed to elucidate the mechanism by which KXS exerts its therapeutic effects on Alzheimer's disease (AD) by targeting ferroptosis, using a combination of network pharmacology, bioinformatics, and experimental validation strategies. MATERIALS AND METHODS: The active target sites and the further potential mechanisms of KXS in protecting against AD were investigated through molecular docking, molecular dynamics simulation, and network pharmacology, and combined with the validation of animal experiments. RESULTS: Computational and experimental findings provide the first indication that KXS significantly improves learning and memory defects and inhibits neuronal ferroptosis by repairing mitochondria damage and upregulating the protein expression of ferroptosis suppressor protein 1 (FSP1) in vivo APP/PS1 mice AD model. According to bioinformatics analysis, the mechanism by which KXS inhibits ferroptosis may involve SIRT1. KXS notably upregulated the mRNA and protein expression of SIRT1 in both vivo APP/PS1 mice and in vitro APP-overexpressed HT22 cells. Additionally, KXS inhibited ferroptosis induced by APP-overexpression in HT22 cells through activating the SIRT1-FSP1 signal pathway. CONCLUSIONS: Collectively, our findings suggest that KXS may inhibit neuronal ferroptosis through activating the SIRT1/FSP1 signaling pathway. This study reveals the scientific basis and underlying modern theory of replenishing qi and eliminating phlegm, which involves the inhibition of ferroptosis. Moreover, it highlights the potential application of SIRT1 or FSP1 activators in the treatment of AD and other ferroptosis-related diseases.

Efficacy of Cellular Therapy for Azoospermia in Animal Models: A Systematic Review and Meta-Analysis.

This study investigated the efficacy of stem cell transplantation for azoospermia, a major cause of male infertility. We conducted a systematic meta- analysis to assess the therapeutic effectiveness of stem cell transplant, using different transplant methods, injection sites, and stem cell types, and the reliability of this approach in different animal species. PubMed, the Cochrane Library, and Embase were searched for studies published from January 2006 to February 2022 that evaluated the use of stem cell transplant to treat azoospermia. We included 18 studies and conducted the analyses using Review Manager 5.2 software. Expression of the meiosis-related genes Vasa, Scp3, and Dazl and the average hematoxylin and eosin- positive staining area were improved after stem cell transplant. Subgroup analyses by mode of transplant showed higher expression of Scp3 and Dazl in the xenotransplant group. Although subgroup analyses by injection site showed that the seminiferous tubule group showed the most significant effect on Scp3 expression, spermatogenesis and repair of damaged testis were induced in the tunica albuginea group. The testicular torsion group also induced high levels of Scp3. Another subgroup analysis by stem cell type showed that umbilical cord mesenchymal stem cells promoted the highest expression of meiosis-related genes and successfully induced spermatogenesis and the repair of damaged testis. Urine-derived stem cells, spermatogonial stem cells, and amniotic fluid-derived stem cells showed significantly therapeutic effects; however, more studies are needed for definitive conclusions. Subgroup analyses by type of azoospermia animal model indicated that the use of stem cell transplant in rat or mouse models had an obvious therapeutic effect, but no significant therapeutic effect was seen in azoospermia hamsters. The meta-analysis confirmed that stem cell transplant can effectively treat azoospermia in animal models. Xenotransplant is shown to enhance the therapeutic effects of stem cell transplant on azoospermia.

Radix Rehmanniae Praeparata (Shu Dihuang) exerts neuroprotective effects on ICV-STZ-induced Alzheimer's disease mice through modulation of INSR/IRS-1/AKT/GSK-3ß signaling pathway and intestinal microbiota.

Radix Rehmanniae Praeparata (RRP, Shu Dihuang in Cinese) is widely used as primal medicine in Chinese herbal formula for the treatment of Alzheimer's disease (AD). However, the underlying mechanism of RRP for AD remains unclear. The aim of this study was to investigate the therapeutic effect of RRP on intracerebroventricular injection of streptozotocin (ICV-STZ)-induced AD model mice and its potential mechanism. ICV-STZ mice were continuously gavaged with RRP for 21 days. The pharmacological effects of RRP were evaluated by behavioral tests, brain tissue H&E staining and hippocampal tau protein phosphorylation levels. The expression levels of insulin receptor (INSR), IRS-1, pSer473-AKT/AKT and pSer9-GSK-3ß/GSK-3ß proteins in hippocampal and cortical tissues were detected by Western-blot method. The 16S rRNA gene sequencing was used to analyze the changes of intestinal microbiota in mice. The compounds in RRP were analyzed by mass spectrometry and their binding ability to INSR proteins was detected by molecular docking. The results showed that RRP ameliorated cognitive dysfunction and neuronal pathological changes of brain tissue in ICV-STZ mice, reduced tau protein hyperphosphorylation, INSR, IRS-1, pSer473-AKT/AKT, and pSer9-GSK-3ß/GSK-3ß levels in hippocampal and cortical tissues. Meanwhile, RRP reversed ICV-STZ-induced dysregulation of intestinal microbiota in AD mice. Mass spectrometry analysis showed that the RRP consisted mainly of seven compounds, namely Acteoside (Verbascoside), 5-Hydroxymethyl-2-furaldehyde (5-HMF), Apigenin7-O-glucuronide, Icariin, Gallic acid, Quercetin-3ß-D-glucoside, and Geniposide. Molecular docking results further indicated that the compounds in RRP have binding ability to INSR protein and potential multiple synergistic effects. RRP ameliorates cognitive dysfunction and brain histopathological changes in AD mice. The mechanism of RRP ameliorating AD may be related to the regulation of INSR/IRS-1/AKT/GSK-3ß signaling pathway and intestinal microbiota. This study supports the potential anti-AD efficacy of RRP and initially reveals the pharmacological mechanism of RRP, providing a theoretical basis for further clinical application of RRP.

Hederagenin improves Alzheimer's disease through PPARα/TFEB-mediated autophagy.

BACKGROUND: Autophagic flux is coordinated by a network of master regulatory genes, which centered on transcription factor EB (TFEB). The disorders of autophagic flux are closely associated with Alzheimer's disease (AD), and thus restoring autophagic flux to degrade pathogenic proteins has become a hot therapeutic strategy. Hederagenin (HD), a triterpene compound, isolated from a variety food such as Matoa (Pometia pinnata) Fruit, Medicago sativa, Medicago polymorpha L. Previous studies have shown that HD has the neuroprotective effect. However, the effect of HD on AD and underlying mechanisms are unclear. PURPOSE: To determine the effect of HD on AD and whether it promotes autophagy to reduce AD symptoms. STUDY DESIGN: BV2 cells, C. elegans and APP/PS1 transgenic mice were used to explore the alleviative effect of HD on AD and the molecular mechanism in vivo and in vitro. METHODS: The APP/PS1 transgenic mice at 10 months were randomized into 5 groups (n = 10 in each group) and orally administrated with either vehicle (0.5% CMCNa), WY14643 (10 mg/kg/d), low-dose of HD (25 mg/kg/d), high-dose of HD (50 mg/kg/d) or MK-886 (10 mg/kg/d) + HD (50 mg/kg/d) for consecutive 2 months. The behavioral experiments including morris water maze test, object recognition test and Y maze test were performed. The effects of HD on Aß deposition and alleviates Aß pathology in transgenic C. elegans were operated using paralysis assay and fluorescence staining assay. The roles of HD in promoting PPARα/TFEB-dependent autophagy were investigated using the BV2 cells via western blot analysis, real-time quantitative PCR (RT-qPCR), molecular docking, molecular dynamic (MD) simulation, electron microscope assay and immunofluorescence. RESULTS: In this study, we found that HD upregulated mRNA and protein level of TFEB and increased the distribution of TFEB in the nucleus, and the expressions of its target genes. HD also promoted the expressions of LC3BII/LC3BI, LAMP2, etc., and promoted autophagy and the degradation of Aß. HD reduced Aß deposition in the head area of C. elegans and Aß-induced paralysis. HD improved cognitive impairment and pathological changes in APP/PS1 mice by promoting autophagy and activating TFEB. And our results also showed that HD could strongly target PPARα. More importantly, these effects were reversed by treatment of MK-886, a selective PPARα antagonist. CONCLUSION: Our present findings demonstrated that HD attenuated the pathology of AD through inducing autophagy and the underlying mechanism associated with PPARα/TFEB pathway.

Design, synthesis and in vitro/in vivo anticancer activity of tranylcypromine-based triazolopyrimidine analogs as novel LSD1 inhibitors.

Histone lysine specific demethylase 1 (LSD1) is responsible for the demethylation of mono-/dimethylated lysine residue on histone proteins. LSD1 plays an extensive and essential role in the pathogenesis and progression of many human diseases such as cancers, and thus is becoming an attractive therapeutic target for cancer treatment. Tranylcypromine (TCP) is an important chemical template for developing irreversible LSD1 inhibitors, representing a major chemotype of clinical candidates. Here we report a novel pool of TCP derivatives with triazolopyrimidine as a privileged heterocylic motif. Starting from ticagrelor, a clinically available antiplatelet agent, as a hit compound, our medicinal efforts have led to the identification of compound 9j with nanomolar inhibitory potency against LSD1 as well as broad-spectrum antiproliferative activities against tumor cells. Enzyme studies show that compound 9j is selective over MAO-A/B enzymes, and also cellular active to elevate the expression of H3K4me2 by inhibiting LSD1 in cells. Furthermore, in a H1650 xenograft mouse model, oral administration of compound 9j at low 10 and 20 mg/kg dosages could enable a significant reduction in tumor size and a remarkable extension of survival. The current work is expected to provide an additional strategy to achieve new TCP-based LSD1 inhibitors.

Inhibition of ferroptosis through regulating neuronal calcium homeostasis: An emerging therapeutic target for Alzheimer's disease.

Alzheimer's disease (AD), a chronic and progressive neurodegenerative disease, generates a serious threat to the health of the elderly. The AD brain is microscopically characterized by amyloid plaques and neurofibrillary tangles. There are still no effective therapeutic drugs to restrain the progression of AD though much attention has been paid to exploit AD treatments. Ferroptosis, a type of programmed cell death, has been reported to promote the pathological occurrence and development of AD, and inhibition of neuronal ferroptosis can effectively improve the cognitive impairment of AD. Studies have shown that calcium (Ca2+) dyshomeostasis is closely related to the pathology of AD, and can drive the occurrence of ferroptosis through several pathways, such as interacting with iron, and regulating the crosstalk between endoplasmic reticulum (ER) and mitochondria. This paper mainly reviews the roles of ferroptosis and Ca2+ in the pathology of AD, and highlights that restraining ferroptosis through maintaining the homeostasis of Ca2+ may be an innovative target for the treatment of AD.

Exploration of the main active components and pharmacological mechanism of Yerba Mate based on network pharmacology.

INTRODUCTION: Yerba mate is widely consumed in South American countries and is gaining popularity around the world. Long-term consumption of yerba mate has been proven to have health-care functions and therapeutic effects on many diseases; however, its underlying mechanism has not been clearly elucidated. In this research, we explored the pharmacological mechanism of yerba mate through a network pharmacological approach. MATERIAL AND METHODS: The bioactive components of yerba mate were screened from published literature and the Traditional Chinese Medicine System Pharmacology Database (TCMSP), and the targets and related diseases were retrieved by TCMSP. Furthermore, the component-target-disease network an protein-protein interaction (PPI) network were constructed, and combined with gene ontology (GO) functional analysis and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analysis to explore the pharmacological mechanism of yerba mate. RESULTS: As a result, 16 bioactive components of yerba mate were identified, which acted on 229 targets in total. Yerba mate can be used to treat 305 diseases, such as breast cancer, asthma, Alzheimer's disease, osteoarthritis, diabetes mellitus, atherosclerosis, and obesity. Protein kinase B (AKT1), signal transducer and activator of transcription 3 (STAT3), mitogen-activated protein kinase 1 (MAPK1), transcription factor AP-1 (JUN), cellular tumour antigen (p53) TP53, tumour necrosis factor (TNF), transcription factor p65 (RELA), interleukin-6 (IL6), amyloid-beta precursor protein (APP), and vascular endothelial growth factor A (VEGFA) were identified as the key targets of yerba mate playing pharmacological roles. The signalling pathways identified by KEGG pathway enrichment analysis that were most closely related to the effects of yerba mate included pathways in cancer, fluid shear stress and atherosclerosis, and human cytomegalovirus infection. CONCLUSION: the results of our study preliminarily verify the basic pharmacological action and possible mechanism of yerba mate and provide a reference for the further development of its medicinal value.