Systematic druggable genome-wide Mendelian randomization identifies therapeutic targets for sarcopenia.

BACKGROUND: There are no effective pharmacological treatments for sarcopenia. We aim to identify potential therapeutic targets for sarcopenia by integrating various publicly available datasets. METHODS: We integrated druggable genome data, cis-eQTL/cis-pQTL from human blood and skeletal muscle tissue, and GWAS summary data of sarcopenia-related traits to analyse the potential causal relationships between drug target genes and sarcopenia using the Mendelian Randomization (MR) method. Sensitivity analyses and Bayesian colocalization were employed to validate the causal relationships. We also assessed the side effects or additional indications of the identified drug targets using a phenome-wide MR (Phe-MR) approach and investigated actionable drugs for target genes using available databases. RESULTS: MR analysis identified 17 druggable genes with potential causation to sarcopenia in human blood or skeletal muscle tissue. Six of them (HP, HLA-DRA, MAP 3K3, MFGE8, COL15A1, and AURKA) were further confirmed by Bayesian colocalization (PPH4 > 90%). The up-regulation of HP [higher ALM (beta: 0.012, 95% CI: 0.007-0.018, P = 1.2*10-5) and higher grip strength (OR: 0.96, 95% CI: 0.94-0.98, P = 4.2*10-5)], MAP 3K3 [higher ALM (beta: 0.24, 95% CI: 0.21-0.26, P = 1.8*10-94), higher grip strength (OR: 0.82, 95% CI: 0.75-0.90, P = 2.1*10-5), and faster walking pace (beta: 0.03, 95% CI: 0.02-0.05, P = 8.5*10-6)], and MFGE8 [higher ALM (muscle eQTL, beta: 0.09, 95% CI: 0.06-0.11, P = 6.1*10-13; blood pQTL, beta: 0.05, 95% CI: 0.03-0.07, P = 3.8*10-09)], as well as the down-regulation of HLA-DRA [lower ALM (beta: -0.09, 95% CI: -0.11 to -0.08, P = 5.4*10-36) and lower grip strength (OR: 1.13, 95% CI: 1.07-1.20, P = 1.8*10-5)] and COL15A1 [higher ALM (muscle eQTL, beta: -0.07, 95% CI: -0.10 to -0.04, P = 3.4*10-07; blood pQTL, beta: -0.05, 95% CI: -0.06 to -0.03, P = 1.6*10-07)], decreased the risk of sarcopenia. AURKA in blood (beta: -0.16, 95% CI: -0.22 to -0.09, P = 2.1*10-06) and skeletal muscle (beta: 0.03, 95% CI: 0.02 to 0.05, P = 5.3*10-05) tissues showed an inverse relationship with sarcopenia risk. The Phe-MR indicated that the six potential therapeutic targets for sarcopenia had no significant adverse effects. Drug repurposing analysis supported zinc supplementation and collagenase clostridium histolyticum might be potential therapeutics for sarcopenia by activating HP and inhibiting COL15A1, respectively. CONCLUSIONS: Our research indicated MAP 3K3, MFGE8, COL15A1, HP, and HLA-DRA may serve as promising targets for sarcopenia, while the effectiveness of zinc supplementation and collagenase clostridium histolyticum for sarcopenia requires further validation.

The Effects of Optimal Dietary Vitamin D3 on Growth and Carcass Performance, Tibia Traits, Meat Quality, and Intestinal Morphology of Chinese Yellow-Feathered Broiler Chickens.

This study aimed to assess the effects of different dietary vitamin D3 (VD3) levels on growth and carcass performance, tibia traits, meat quality, and intestinal morphology of yellow-feathered broilers. One-day-old broilers (n = 1440) were assigned into four treatment groups with six replicates per group, and each replicate contained 60 chicks. Dietary VD3 significantly improved the growth performance and carcass traits of broilers, and only low-dose VD3 supplementation decreased the abdominal fat percentage. High-dose VD3 supplementation improved intestinal morphology in the finisher stage, while the b* value of breast muscle meat color decreased markedly under VD3 supplementation (p < 0.05). Serum Ca and P levels and the tibia composition correlated positively with dietary VD3 supplementation at the early growth stage. The weight, length, and ash contents of the tibia increased linearly with increasing dietary VD3, with maximum values achieved in the high-dose group at all three stages. Intestinal 16S rRNA sequencing and liver transcriptome analysis showed that dietary VD3 might represent an effective treatment in poultry production by regulating lipid and immune-related metabolism in the gut-liver axis, which promotes the metabolism through the absorption of calcium and phosphorus in the intestine and improves their protective humoral immunity and reduces infection mortality. Dietary VD3 positively affected the growth-immunity and bone development of broilers during the early stage, suggesting strategies to optimize poultry feeding.

Biomarkers and coptis chinensis activity for rituximab-resistant diffuse large B-cell lymphoma: Combination of bioinformatics analysis, network pharmacology and molecular docking.

BACKGROUND: Rituximab resistance is one of the great challenges in the treatment of diffuse large B-cell lymphoma (DLBCL), but relevant biomarkers and signalling pathways remain to be identified. Coptis chinensis and its active ingredients have antitumour effects; thus, the potential bioactive compounds and mechanisms through which Coptis chinensis acts against rituximab-resistant DLBCL are worth exploring. OBJECTIVE: To elucidate the core genes involved in rituximab-resistant DLBCL and the potential therapeutic targets of candidate monomers of Coptis chinensis. METHODS: Using the Traditional Chinese Medicine System Pharmacology Database and Analysis Platform (TCMSP), the Similarity Ensemble Approach and Swiss Target Prediction, the main ingredients and pharmacological targets of Coptis chinensis were identified through database searches. Through the overlap between the pharmacological targets of Coptis chinensis and the core targets of rituximab-resistant DLBCL, we identified the targets of Coptis chinensis against rituximab-resistant DLBCL and constructed an active compound-target interaction network. The targets and their corresponding active ingredients of Coptis chinensis against rituximab-resistant DLBCL were molecularly docked. RESULTS: Berberine, quercetin, epiberberine and palmatine, the active components of Coptis chinensis, have great potential for improving rituximab-resistant DLBCL via PIK3CG. CONCLUSION: This study revealed biomarkers and Coptis chinensis-associated molecular functions for rituximab-resistant DLBCL.

Insights and future prospects of traditional Chinese medicine in the treatment of functional dyspepsia.

BACKGROUND: Functional dyspepsia (FD) is a prevalent and challenging gastrointestinal disorder. Conventional medicine often faces limitations in providing effective treatment for FD, thus indicating the need to explore alternative approaches. Traditional Chinese medicine (TCM), which is rooted in ancient Chinese traditions and has evolved over thousands of years, offers a holistic approach to well-being. TCM incorporates herbal remedies, acupuncture, and other therapies while shaping the future of complementary and alternative medicine. PURPOSE: To review the existing literature on the current status and future prospects of using TCM to treat FD. METHODS: We extensively searched the PubMed, Google Scholar, Embase, an China National Knowledge Internet databases from inception to May 31, 2023 to identify relevant literature. We also searched the reference lists of the included articles. RESULTS: Clinical evidence-based research has explored the efficacy of TCM in treating FD. Recent research has illuminated the multifaceted mechanisms through which TCM interventions affect FD. TCM is a promising alternative, as it emphasizes a holistic approach and holds potential advantages in addressing the complex nature of FD. CONCLUSIONS: The integration of TCM and Western medicine offers a comprehensive approach to understanding and managing FD by bridging traditional wisdom with modern scientific understanding. This paper highlights the practical implications of this integration, the challenges to be addressed, and the potential for international collaboration to further elucidate the efficacy of TCM. However, continued research and dialog are needed to advance the modern development of TCM and to improve the quality of life of FD patients.

Gastrodin alleviates mitochondrial dysfunction by regulating SIRT3-mediated TFAM acetylation in vascular dementia.

BACKGROUND: Mitochondrial dysfunction is key to the pathogenesis of vascular dementia (VaD). Sirtuin-3 (SIRT3), an essential member of the sirtuins family, has been proven to be a critical sirtuin in regulating mitochondrial function. The phenolic glucoside gastrodin (GAS), a bioactive ingredient from Gastrodiae Rhizome (known in Chinese as Tian ma) demonstrates significant neuroprotective properties against central nervous system disorders; however, the precise mechanisms through which GAS modulates VaD remain elusive. PURPOSE: This study aims to investigate whether GAS confers a protective role against VaD, and to figure out the underlying molecular mechanisms. METHODS: A bilateral common carotid artery occlusion (BCCAO)-mediated chronic cerebral hypoperfusion (CCH) VaD rat model and a hypoxia model using HT22 cells were employed to investigate pharmacological properties of GAS in mitigating mitochondrial dysfunction. A SIRT3 agonist resveratrol (RES), a SIRT3 inhibitor 3-TYP and SIRT3-knockdown in vitro were used to explore the mechanism of GAS in association with SIRT3. The ability of SIRT3 to bind and deacetylate mitochondrial transcription factor A (TFAM) was detected by immunoprecipitation assay, and TFAM acetylation sites were further validated using mass spectrometry. RESULTS: GAS increased SIRT3 expression and ameliorated mitochondrial structure, mitochondrial respiration, mitochondrial dynamics along with upregulated TFAM, mitigating oxidative stress and senescence. Comparable results were noted with the SIRT3 agonist RES, indicating an impactful neuroprotection played by SIRT3. Specifically, the attenuation of SIRT3 expression through knockdown techniques or exposure to the SIRT3 inhibitor 3-TYP in HT22 cells markedly abrogated GAS-mediated mitochondrial rescuing function. Furthermore, our findings elucidate a novel facet: SIRT3 interacted with and deacetylated TFAM at the K5, K7, and K8 sites. Decreased SIRT3 is accompanied by hyper-acetylated TFAM. CONCLUSION: The present results were the first to demonstrate that the SIRT3/TFAM pathway is a protective target for reversing mitochondrial dysfunction in VaD. The findings suggest that GAS-mediated modulation of the SIRT3/TFAM pathway, a novel mechanism, could ameliorate CCH-induced VaD, offering a potentially beneficial therapeutic strategy for VaD.

Ecological risk assessment under the PSR framework and its application to shallow urban lakes.

Shallow urban lakes are naturally vulnerable to ecosystem degradation. Rapid urbanization in recent decades has led to a variety of aquatic problems such as eutrophication, algal blooms, and biodiversity loss, increasing the risk to lake-wide ecological sustainability. Instead of a simple binary assessment of ecological risk, holistic evaluation frameworks that consider multiple stressors and receptors can provide a more comprehensive assessment of overall ecological risk. In this study, we analyzed a combined dataset of government statistics, remote sensing images, and 1 year of field measurements to develop an index system for urban lake ecological risk assessment based on the pressure-state-response (PSR) framework. We used the developed ecological safety index (ESI) system to evaluate the ecological risk for three urban lakes in Jiangsu Province, China: Lake Yangcheng-LYC, Lake Changdang-LCD, and Lake Tashan-LTS. LYC and LTS were classified as "mostly safe" and "generally recognized as safe," respectively, while LCD was assessed as having "potential ecological risk." Our data suggest that socioeconomic pressure and aquatic health are the two main factors affecting the ecological risk in both LYC and LCD. The ecological risk of LTS could be improved more effectively if regional management plans are well implemented. Our study highlights the pressure of external wastewater loading, low forest-grassland coverage, and lake shoreline damage on the three selected urban lakes. The findings of this study can inform watershed management for lake ecosystem restoration and environmental sustainability.

Synergism of fermented feed and ginseng polysaccharide on growth performance, intestinal development, and immunity of Xuefeng black-bone chickens.

Microbial fermented feed (MF) is considered a valuable strategy to bring advantages to livestock and is widely practiced. Oral supplementation of Ginseng polysaccharide (Gps) eliminated weight loss in chickens following vaccination. This study investigated the effects of the combined use of Gps and MF on growth performance and immune indices in Xuefeng black-bone chickens. A total of 400 Xuefeng black-bone chickens at the age of 1 day were randomly assigned to four groups. Normal feed group (Control group), ginseng polysaccharide (200 mg/kg) group (Gps group), microbially fermented feed (completely replace the normal feed) group (MF group), and microbially fermented feed and add ginseng polysaccharide just before use (MF + Gps group). Each group contained 5 pens per treatment and 20 birds per pen. The body weight and average daily gain in the Gps, MF, and MF + Gps groups increased significantly (P < 0.01), while the feed conversion ratio decreased significantly (P < 0.01). The combined use of MF and Gps showed a synergistic effect. There was no significant difference in villus height (cecal) between the experimental group and the Con group. The crypt depth of the three experimental groups exhibited a significantly lower value compared to the Control group (P < 0.05). The V/C ratio of the Gps group and MF + Gps was significantly increased (P < 0.05), but there was no significant difference in the MF group. Moreover, the diarrhea rate of the Gps and the MF + Gps groups was lower than that of the Con group, while that of the MF + Gps group decreased the mortality rate (P < 0.05). The serum tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6) levels in the MF, Gps, and MF + Gps groups decreased significantly (P < 0.01), the serum immunoglobulin G (IgG) levels increased significantly (P < 0.01), while the combination of MF and Gps had a synergistic effect. The combined use of Gps and MF not only further improved growth performance and immune parameters, but also reduced the diarrhea rate and mortality.

Ultrashort channel MoSe2transistors with selenium atoms replaced at the interface: first-principles quantum-transport study.

Realizing n- and p-type transition metal dichalcogenide (TMD)-based field-effect transistors for nanoscale complementary metal oxide semiconductor (CMOS) applications remains challenging owing to undesirable contact resistance. Quantumtransport calculations were performed by replacing single-sided Se atoms of TMD near the interface with As or Br atoms to further improve the contact resistance. Here, partial selenium replacement produced a novel interface with a segment of metamaterial MoSeX (Pt/MoSeX/MoSe2; X = As, Br). Such stable metamaterials exhibit semi-metallicity, and the contact resistance can be thus lowered. Our findings provide insights into the potential of MoSe2-based nano-CMOS logic devices.

Effect of Electroacupuncture Stimulation on Proliferation and Differentiation of Endogenous Neural Stem Cells in Rats with Spinal Cord Injury.

The aim of this work was to investigate the effects of electroacupuncture (EA) stimulation on the proliferation and differentiation of endogenous neural stem cells (NSCs) in rats with spinal cord injury (SCI). One hundred rats were included and randomly divided into the sham-operation (SO) group, model (MO) group, EA group, and preacupuncture stimulation (PAS) group, with 25 rats in each group. All the rats in the SO group had their spinal cord of thoracic segment T10 exposed but without SCI. In the remaining three groups, the modified Allen's weight dropping method was adopted to make SCI models. Those in the SO group and the MO group did not receive any treatment. Those in the EA group were treated with EA after the modelling was completed, which stopped when the samples were collected at each time point. The spinal cord tissue of rats was subjected to immunohistochemical staining and real-time quantitative polymerase chain reaction (PCR) to detect the expressions of neurofilament nestin and glial fibrillary acidic protein (GFAP). The Basso-Beattie-Bresnahan (BBB) score of the MO group was much lower than that of the SO group on the 3rd, 7th, and 14th days after surgery (P < 0.05). The BBB scores of the EA group and PAS group were notably higher than that of the MO group (P < 0.05). The number of nestin-, GFAP-, and MAP-2-positive cells was significantly increased in rat tissues after spinal cord injury. On the 3rd, 7th, and 14th days postoperatively, the numbers of nestin-positive cells in the EA and PAS groups were considerably higher than those in the MO group (P < 0.01). However, the numbers of GFAP-positive cells in the EA and PAS groups were considerably decreased compared with those in the MO group (P < 0.01). The positive rate of MAP-2 in the model group was significantly increased compared to that in the sham-operation group (P < 0.001). The positive rates of MAP-2 in the EA group and PAS group were significantly higher than those in the MO group (P < 0.01). After spinal cord injury, EA could activate the proliferation of endogenous NSCs and promote their differentiation into neuronal cells. Consequently, injuries were repaired, and functions were rehabilitated.

Anthocyanins-natural pigment of colored rice bran: Composition and biological activities.

Rice by-products are a potential source of various bioactive substances with great processing potential, which are receiving increasing attention. Among them, rice bran is a by-product of rice milling, with high nutritional value and health benefits. Colored rice bran contains a large amount of anthocyanins responsible for color and bioactivities. And anthocyanins are often added to foods as a natural pigment, serving to enhance both the visual appeal and nutritional value. Recent advances in the composition and bioactivities of four common colored rice bran anthocyanins (black, purple, red, and purple red rice) are reviewed in this paper. Rice bran anthocyanins have been confirmed to exhibit biological potential for human health, with their main biological activities being antioxidant, anti-atherosclerosis, anti-cancer, neuroprotective, retinoprotective, immunomodulatory, anti-aging and anti-obesity effects. The structure of anthocyanins determines their biological activities. The anthocyanins composition of rice bran with different colors varied greatly, while that of rice bran with the same color is also slightly different, which is attributed to the rice varieties, growing environment and cropping conditions. However, it remains necessary to conduct further clinical studies to support the health activities of anthocyanins. The present review provides information value for the further development and comprehensive utilization of rice bran anthocyanins.

Review of research progress on the role of the effective components of traditional Chinese medicine in sepsis with multiple organ dysfunction.

The concept of sepsis has recently evolved from one of a 'systemic inflammatory response syndrome caused by infection' to a 'severe, potentially fatal organic dysfunction caused by an inadequate or imbalanced host response to infection'. Organ dysfunction is closely related to sepsis. Multiple organ dysfunction syndrome (MODS) is the most serious outcome of sepsis, often leading to a poor prognosis. However, specific drugs for sepsis and MODS caused by sepsis remain undetermined, and the fatality rate is relatively high. Under the guidance of modern medicine, traditional Chinese medicine (TCM) has gained a wealth of experience in the prevention and treatment of sepsis and plays a key role via the effects of its numerous components, pathways and targets. This study used 'Sepsis', 'Organ dysfunction' and 'Traditional Chinese medicine' as strategies for searching the databases of Chinese National Knowledge Infrastructure, Wanfang, PubMed and The Web of Science. This paper presents an overview of the current status of TCM component formulations for preventing and treating sepsis with MODS to provide a theoretical basis for clinical treatment and drug development.

[Metabarcoding Profiling of Phytoplankton Communities Associated with Algal Blooms and Determining Related Drivers in Baiyangdian Lake].

Phytoplankton are the main cause of algal blooms. To identify bloom algae and assess the risks of the algal blooms in Baiyangdian Lake, a survey on 373 sites was conducted in August 2020. The phytoplankton were studied via both morphological-based density counting and metabarcoding profiling. Then, the bloom degree was classed according to algae density, and the relationship between the community of bloom algae and environmental variables were modeled to determine key factors constraining spatial variation in bloom algae communities. The results showed that more than 95% of the sampling sites were free from the risk of algal blooms(phytoplankton density<2×106 cells·L-1), and only five sites had a slight risk of algal blooms. A total of 90 species with potential of algal blooming were detected, including 20 dominant species, which were mainly affiliated with Chlorophyta, Cyanophyta, and Euglenophyta. Communities of bloom algae significantly varied among different regions(P<0.05). Total phosphorus(TP), total nitrogen(TN), and ammonia nitrogen(NH4+-N) were the key factors significantly affecting the spatial variation in algal bloom communities. At the phylum level, these key factors were significantly positively correlated with Chlorophyta, whereas at the species level, species in Bacillariophyta and Chlorophyta responded significantly to these key factors. Thus, our findings suggested that nutrient levels were significantly related to bloom algae communities, and we proposed that controlling the input of nutrients such as nitrogen and phosphorus and regulating the hydrological process of the lake would be effective management techniques to prevent algal blooms in Baiyangdian Lake.

NIR-dye bridged human serum albumin reassemblies for effective photothermal therapy of tumor.

Human serum albumin (HSA) based drug delivery platforms that feature desirable biocompatibility and pharmacokinetic property are rapidly developed for tumor-targeted drug delivery. Even though various HSA-based platforms have been established, it is still of great significance to develop more efficient preparation technology to broaden the therapeutic applications of HSA-based nano-carriers. Here we report a bridging strategy that unfastens HSA to polypeptide chains and subsequently crosslinks these chains by a bridge-like molecule (BPY-Mal2) to afford the HSA reassemblies formulation (BPY@HSA) with enhanced loading capacity, endowing the BPY@HSA with uniformed size, high photothermal efficacy, and favorable therapeutic features. Both in vitro and in vivo studies demonstrate that the BPY@HSA presents higher delivery efficacy and more prominent photothermal therapeutic performance than that of the conventionally prepared formulation. The feasibility in preparation, stability, high photothermal conversion efficacy, and biocompatibility of BPY@HSA may facilitate it as an efficient photothermal agents (PTAs) for tumor photothermal therapy (PTT). This work provides a facile strategy to enhance the loading capacity of HSA-based crosslinking platforms in order to improve delivery efficacy and therapeutic effect.

High-throughput screening and quantification of pesticides in Lilii Bulbus using ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry.

Lilii Bulbus is a notable flower in Chinese cuisine, and has also been used as a Chinese herbal medicine for over 2000 years. This work presents an analytical method for rapidly screening multiple pesticide residues in Lilii Bulbus using ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS). For sample pre-treatment, the QuEChERS method is employed, and targeted MS/MS is adopted for data acquisition. Moreover, a database containing 515 pesticides with accurate mass database and a high-resolution fragment ion spectrum library is established in this work. In addition, the qualitative and quantitative results of the screening method are validated. The results show that within the linear concentration range of 2 to 200 µg L-1, for each pesticide, 89.3% of the pesticides exhibit linear correlation coefficients R2 equal to or exceeding 0.990. The limit of quantification for all pesticides is below 50 µg kg-1. With a recovery of 70% to 120% and RSD ≤ 20% as the satisfactory standards, 387 (75.0%), 411 (79.7%) and 420 (81.4%) pesticides meet the standards at the three addition levels of 10 µg kg-1, 20 µg kg-1, and 100 µg kg-1, respectively. By utilizing the proposed method, pesticide residues in 100 samples are investigated, providing scientific data to ensure the safety of pesticide residues and demonstrating the general applicability of the method for routine monitoring of pesticide residues in Lilii Bulbus.

Assessing anti-doping knowledge among Taiwanese pharmacists.

BACKGROUND: Taiwan's unique health behaviour, such as extensive exposure to Chinese Herbal Medicine (CHM), has introduced a risk of inadvertent doping among competing athletes. Pharmacy professionals have an imperative role in advising athletes on the safe use of medicines. This study provides an overview of anti-doping knowledge and educational needs among pharmacists in Taiwan and examines influencing factors. METHODS: A cross-sectional online questionnaire survey consisting of five domains, namely demographic characteristics, source of prohibited substances, identification of prohibited substances, understanding of doping control, and education needs on anti-doping, was distributed to the registered pharmacists in Taiwan. In total, 491 responses were included in the analyses. RESULTS: Respondents (65% female, aged 41.9 ± 11.4 years, with 68% having a Bachelor's degree) reported a moderate anti-doping knowledge score of 37.2 ± 4.9, ranging from 21 to 48 (out of 51). Fifteen per cent of them had the experience of being counselled about drug use in sports. Higher knowledge scores were observed in younger respondents, showing an age-dependent effect (p < 0.001). Individuals practising in southern Taiwan (compared to northern Taiwan) and those working at clinics (compared to hospitals) exhibited lower knowledge. Most of the respondents (90%) knew that stimulant ephedrine is prohibited in sports, but few had recognised diuretic furosemide (38%) and CHM (7%) containing ß2-agonist higenamine. Approximately 90% of respondents agreed with the need for anti-doping education. CONCLUSIONS: This study highlights the heterogeneity of anti-doping knowledge among pharmacy professionals and provides practical relevance in organising future educational topics and research-based activities.

Ethyl ferulate suppresses post-myocardial infarction myocardial fibrosis by inhibiting transforming growth factor receptor 1.

BACKGROUND: With an increasing number of myocardial infarction (MI) patients, myocardial fibrosis is becoming a widespread health concern. It's becoming more and more urgent to conduct additional research and investigations into efficient treatments. Ethyl ferulate (EF) is a naturally occurring substance with cardioprotective properties. However, the extent of its impact and the underlying mechanism of its treatment for myocardial fibrosis after MI remain unknown. PURPOSE: The goal of this study was to look into how EF affected the signaling of the TGF-receptor 1 (TGFBR1) in myocardial fibrosis after MI. METHODS: Echocardiography, hematoxylin-eosin (HE) and Masson trichrome staining were employed to assess the impact of EF on heart structure and function in MI-affected mice in vivo. Cell proliferation assay (MTS), 5-Ethynyl-2'-deoxyuridine (EdU), and western blot techniques were employed to examine the influence of EF on native cardiac fibroblast (CFs) proliferation and collagen deposition. Molecular simulation and surface plasmon resonance imaging (SPRi) were utilized to explore TGFBR1 and EF interaction. Cardiac-specific Tgfbr1 knockout mice (Tgfbr1ΔMCK) were utilized to testify to the impact of EF. RESULTS: In vivo experiments revealed that EF alleviated myocardial fibrosis, improved cardiac dysfunction after MI and downregulated the TGFBR1 signaling in a dose-dependent manner. Moreover, in vitro experiments revealed that EF significantly inhibited CFs proliferation, collagen deposition and TGFBR1 signaling followed by TGF-ß1 stimulation. More specifically, molecular simulation, molecular dynamics, and SPRi collectively showed that EF directly targeted TGFBR1. Lastly, knocking down of Tgfbr1 partially reversed the inhibitory activity of EF on myocardial fibrosis in MI mice. CONCLUSION: EF attenuated myocardial fibrosis post-MI by directly suppressing TGFBR1 and its downstream signaling pathway.

Multi-omics analysis reveals the mechanism of action of ophiopogonin D against pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease with limited therapeutic strategies. Therefore, there is an urgent need to search for safe and effective drugs to treat this condition. Ophiopogonin D (OP-D), a steroidal saponin compound extracted from ophiopogon, possesses various pharmacological properties, including anti-inflammatory, antioxidant, and antitumor effects. However, the potential pharmacological effect of OP-D on pulmonary fibrosis remains unknown. PURPOSE: The aim of this study was to investigate whether OP-D can improve pulmonary fibrosis and to explore its mechanism of action. METHODS: The effect of OP-D on pulmonary fibrosis was investigated in vitro and in vivo using a mouse model of IPF induced by bleomycin and an in vitro model of human embryonic lung fibroblasts induced by transforming growth factor-ß1 (TGF-ß1). The mechanism of action of OP-D was determined using multi-omics techniques and bioinformatics. RESULTS: OP-D attenuated epithelial-mesenchymal transition and excessive deposition of extracellular matrix in the lungs, promoted the apoptosis of lung fibroblasts, and blocked the differentiation of lung fibroblasts into myofibroblasts. The multi-omics techniques and bioinformatics analysis revealed that OP-D blocked the AKT/GSK3ß pathway, and the combination of a PI3K/AKT inhibitor and OP-D was effective in alleviating pulmonary fibrosis. CONCLUSION: This study demonstrated for the first time that OP-D can reduce lung inflammation and fibrosis. OP-D is thus a potential new drug for the prevention and treatment of pulmonary fibrosis.

Xiaojianzhong decoction attenuates aspirin-induced gastric mucosal injury via the PI3K/AKT/mTOR/ULK1 and AMPK/ULK1 pathways.

CONTEXT: Xiaojianzhong decoction (XJZD), classically prescribed in Chinese medicine, has protective and healing effects on gastric mucosal injury. However, the exact mechanism behind this effect remains unclear. OBJECTIVE: To investigate the effect of XJZD on gastric mucosal injury and explore its underlying mechanisms. MATERIALS AND METHODS: C57BL/6 mice were randomized into six groups (n = 10): the control group receiving sterile water, the model (aspirin 300 mg/kg), the XJZD high-dose (12 g/kg), XJZD medium-dose (6 g/kg), XJZD low-dose (3 g/kg) and omeprazole (20 mg/kg) groups, by gavage daily for 14 days. The area of gastric mucosal injury, mucosal injury index and degree of histopathological damage were analysed. Gastric mucosal epithelial cell apoptosis was detected. Epithelial cell autophagy was observed. The expression levels of tight junction proteins and proteins related to apoptosis, autophagy and the pentose phosphate pathway were analysed. RESULTS: The results showed that after treatment with XJZD (12, 6 and 3 g/kg), the mucosal injury area was reduced (83.4%, 22.6% and 11.3%), the expression level of ZO-1 and occludin was up-regulated, the apoptosis rate of epithelial cells was reduced (40.8%, 25.4% and 8.7%), the expression of autophagy-related proteins LC3 and Beclin1 was decreased and the expression of p62 was increased, the PI3K/AKT/mTOR/ULK1(ser757) signalling pathway was activated, and the AMPK/ULK1(ser317) signalling pathway was inhibited. In addition, XJZD can antagonize the imbalance of redox homeostasis caused by aspirin and protect the gastric mucosa. DISCUSSION AND CONCLUSIONS: XJZD protects against aspirin-induced gastric mucosal injury, implying it to be a potential therapeutic agent.

Jian-Pi-Yin decoction attenuates lactose-induced chronic diarrhea in rats by regulating GLP-1 and reducing NHE3 ubiquitination and phosphorylation.

Objectives: Jian-Pi-Yin decoction (JPY), a prescription derived from the traditional Chinese medicine Shen-Ling-Bai-Zhu-San, has shown good clinical efficacy in the treatment of diarrhea caused by lactose intolerance. However, the mechanism of action of JPY in the treatment of diarrhea is not fully understood. Design: In this study, a rat diarrhea model was induced by high lactose feeding combined with standing on a small platform to investigate the ameliorating effect of JPY on hyper lactose-induced diarrhea in rats and its possible mechanism. Methods: The rat model of hyper lactose diarrhea was given high, medium, and low doses of JPY and the positive control drug Smida by gavage for 1 week. At the same time, NA+-H+ exchanger 3 (NHE3) inhibitor Tenapanor was administered orally for 3 weeks. Body weight, food intake, water intake, grip strength, and severity of diarrhea symptoms were measured in rats throughout the study. The serum, colon, and jejunum tissues of the model and drug-treated rats were collected for histopathological examination and analysis of relevant indicators. Results: JPY significantly alleviated the symptoms of fatigue, diet reduction and diarrhea in the model group. Glucagon-like peptide-1 (GLP-1) and cyclic adenosine monophosphate (cAMP) expression were also down-regulated after JPY treatment. JPY can significantly promote NHE3 in intestinal tissues of rats with diarrhea, and the mechanism is related to the decrease of GLP-1, inhibition of cAMP/PKA pathway activation, an increase of ubiquitin-specific protease 7 (USP7) and USP10 expression, and decrease of NHE3 ubiquitination and phosphorylation. Conclusion: JPY can reduce the expression of GLP-1, reduce the ubiquitination and phosphorylation of NHE3, regulate the expression of NHE3, at least partly improve ion transport in the intestinal epithelium, and improve the imbalance of electrolyte absorption, thus significantly reducing the diarrhea symptoms of rats with high lactose combined with small platform standing. Innovation: In this study, we explored the mechanism of intestinal GLP-1 activation of cAMP/PKA signaling pathway from multiple dimensions, and increased its expression by reducing phosphorylation and ubiquitination of NHE3, thereby treating chronic diarrhea associated with lactose intolerance.

Recent advance in phytonanomedicine and mineral nanomedicine delivery system of the treatment for acute myeloid leukemia.

Acute myeloid leukemia (AML) is an invasive hematopoietic malignancy caused by excessive proliferation of myeloblasts. Classical chemotherapies and cell transplantation therapies have remarkable efficacy in AML treatment; however, 30-40% of patients relapsed or had refractory disease. The resistance of AML is closely related to its inherent cytogenetics or various gene mutations. Recently, phytonanomedicine are found to be effective against resistant AML cells and have become a research focus for nanotechnology development to improve their properties, such as increasing solubility, improving absorption, enhancing bioavailability, and maintaining sustained release and targeting. These novel phytonanomedicine and mineral nanomedicine, including nanocrystals, nanoemulsion, nanoparticles, nanoliposome, and nanomicelles, offer many advantages, such as flexible dosages or forms, multiple routes of administration, and curative effects. Therefore, we reviewed the application and progress of phytomedicine in AML treatment and discussed the limitations and future prospects. This review may provide a solid reference to guide future research on AML treatment.