Multimorbidity, lifestyle, and cognitive function: A cross-cultural study on the role of diabetes, cardiovascular disease, cancer, and chronic respiratory diseases.

BACKGROUND: The effect of lifestyle factors on cognitive function related to four major noncommunicable diseases (NCDs) including diabetes, cardiovascular disease, cancer, and chronic respiratory diseases, and the relationship between these NCDs and cognitive function have not been fully studied. We aimed to investigate the longitudinal associations between these NCDs and cognitive function in middle-aged and older people, and the combined effects of lifestyle factors. METHODS: By employing the data from three large-scale cohort studies from the U.S. Health and Retirement Study (2010-2019), English Longitudinal Study of Aging (2014-2019), and China Health and Retirement Longitudinal Study (2011-2019), this study carried out a multi-cohort analysis to 77, 210 participants. Fixed-effects regression models were used to examine associations between NCD status and cognitive function. Margin plots were used to illustrate the effect of lifestyle factors. RESULTS: Our findings revealed the dose-dependent association between mounting these NCDs and declining cognitive performance, ranging from one NCD (ß = -0.05, 95 % CI: -0.08 to -0.02) to four NCDs (ß = -0.51, 95 % CI: -0.75 to -0.28). Decline in cognitive function associated with NCDs was exacerbated with physical inactivity, current smoking status, and an increase in unhealthy lifestyle behaviors. LIMITATIONS: The observational study design precludes causal interrogation of lifestyles and four NCDs on cognitive function. CONCLUSIONS: An increasing number of these NCDs were dose-dependently associated with the decline in cognitive function score. Unhealthy lifestyle factors expedite decline in cognitive function linked to these NCDs.

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.

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.

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.

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.

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.

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.

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.

Metabolomic Profiling of Brain Protective Effect of Edaravone on Cerebral Ischemia-Reperfusion Injury in Mice.

Edaravone (EDA) injection has been extensively applied in clinics for treating stroke. Nevertheless, the metabolite signatures and underlying mechanisms associated with EDA remain unclear, which deserve further elucidation for improving the accurate usage of EDA. Ischemia stroke was simulated by intraluminal occlusion of the right middle cerebral artery for 1 h, followed by reperfusion for 24 h in mice. Brain infarct size, neurological deficits, and lactate dehydrogenase (LDH) levels were improved by EDA. Significantly differential metabolites were screened with untargeted metabolomics by cross-comparisons with pre- and posttreatment of EDA under cerebral ischemia/reperfusion (I/R) injury. The possibly involved pathways, such as valine, leucine, and isoleucine biosynthesis, and phenylalanine, taurine, and hypotaurine metabolisms, were enriched with differential metabolites and relevant regulatory enzymes, respectively. The network of differential metabolites was constructed for the integral exhibition of metabolic characteristics. Targeted analysis of taurine, an important metabolic marker, was performed for further validation. The level of taurine decreased in the MCAO/R group and increased in the EDA group. The inhibition of EDA on cerebral endothelial cell apoptosis was confirmed by TdT-mediated dUTP nick-end labeling (TUNEL) stain. Cysteine sulfinic acid decarboxylase (CSAD), the rate-limiting enzyme of taurine generation, significantly increased along with inhibiting endothelial cell apoptosis after treatment of EDA. Thus, CSAD, as the possible new therapeutic target of EDA, was selected and validated by Western blot and immunofluorescence. Together, this study provided the metabolite signatures and identified CSAD as an unrecognized therapeutic intervention for EDA in the treatment of ischemic stroke via inhibiting brain endothelial cell apoptosis.

YiQiFuMai lyophilized injection attenuates cerebral ischemic injury with inhibition of neuronal autophagy through intervention in the NMMHC IIA-actin-ATG9A interaction.

BACKGROUND: YiQiFuMai lyophilized injection (YQFM) is derived from a traditional Chinese medicine prescription termed Shengmai San.YQFM is clinically applied to the treatment of cardiovascular and cerebrovascular diseases. It has been found that critical components of YQFM affect non-muscle myosin heavy chain IIA (NMMHC IIA), but its regulation in the excessive autophagy and the underlying mechanism has yet to be clarified. PURPOSE: To evaluate whether YQFM has neuroprotective effects on cerebral ischemia/reperfusion-induced injury by inhibiting NMMHC IIA-actin-ATG9A interaction for autophagosome formation. METHODS: The neuroprotective effects of YQFM were investigated in vivo in mice with middle cerebral artery occlusion/reperfusion (MCAO/R) (n = 6) by detecting neurological deficits, infarct volume, and histopathological changes. The NMMHC IIA-actin-ATG9A interaction was determined using immunofluorescence co-localization, co-immunoprecipitation, and proximity ligation assay. Rat pheochromocytoma (PC12) cells subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) were used to mimic neurons in in vitro experiments. RESULTS: In MCAO/R model mice, YQFM (1.342 g/kg) attenuated brain ischemia/reperfusion-induced injury by regulating NMMHC IIA-actin-mediated ATG9A trafficking. YQFM (400 µg/ml) also exerted similar effects on OGD/R-induced PC12 cells. Furthermore, RNAi of NMMHC IIA weakened the NMMHC IIA-F-actin-dependent ATG9A trafficking and, therefore, attenuated the neuroprotective activities of YQFM in vitro. CONCLUSION: These findings demonstrated that YQFM exerted neuroprotective effects by regulating the NMMHC IIA-actin-ATG9A interaction for autophagosome formation. This evidence sheds new light on the potential mechanism of YQFM in the treatment of cerebral ischemia/reperfusion.

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.

A review of the ethnopharmacology, phytochemistry and pharmacology of Notopterygium incisum.

ETHNOPHARMACOLOGICAL RELEVANCE: Notopterygium incisum Ting ex H.T. Chang, known in Chinese as 'Qianghuo' is a traditional Chinese medicinal herb with the rhizome and roots associated with meridians of the kidney and urinary bladder. It is pungent, bitter and warm in nature. It has been used over the years to disperse cold, prevent painful obstructions from wind, damp and warm pain. It has also been used with other herbs to treat wind-cold exterior syndrome and wind-cold-damp bi-syndromes and has been known to grow well in regions of high altitude such as Gansu, Tibet etc. THE AIM OF THE REVIEW: This systematic review focuses on the ethnopharmacological uses of this herb, including recent advances on the phytochemical and pharmacological study of N. incisum. Recent analytical methods developed for the quantitative and qualitative determination of constituents in this herb have also been reviewed. Additionally, future trends and prospects in the study of this herb have been proposed. MATERIALS AND METHOD: Various literature and electronic databases such as Pubmed, Science Direct, Springer, Wiley etc were searched and data obtained. Other online academic libraries such as Google Scholar and ethnopharmacological literature were searched systematically for more information on the herb. RESULTS: This review focuses on the ethnopharmacological uses of N. incisum and also the various chemical constituents present in the herb and their various therapeutic effects such as analgesic, anti-inflammatory, anti-cancer and antioxidants effects. Analytical methods developed for the quantitative and qualitative determination of various compounds in this herb were further reviewed. CONCLUSION: In this paper, we have reviewed various researches conducted on N. incisum especially in areas of its ethnopharmacological use, phytochemicals, pharmacology and developed analytical methods. This herb has been used over the years in treating headache, rheumatoid arthritis, cold, diaphoretic etc, prompting many types of research into identifying which compounds are responsible for these activities and their mechanism of action. More research is needed in the area of pharmacokinetics and toxicology to give further information on the clinical use and control the quality of the herb.