Role of miRNAs in macrophage-mediated kidney injury.

Macrophages, crucial components of the human immune system, can be polarized into M1/M2 phenotypes, each with distinct functions and roles. Macrophage polarization has been reported to be significantly involved in the inflammation and fibrosis observed in kidney injury. MicroRNA (miRNA), a type of short RNA lacking protein-coding function, can inhibit specific mRNA by partially binding to its target mRNA. The intricate association between miRNAs and macrophages has been attracting increasing interest in recent years. This review discusses the role of miRNAs in regulating macrophage-mediated kidney injury. It shows how miRNAs can influence macrophage polarization, thereby altering the biological function of macrophages in the kidney. Furthermore, this review highlights the significance of miRNAs derived from exosomes and extracellular vesicles as a crucial mediator in the crosstalk between macrophages and kidney cells. The potential of miRNAs as treatment applications and biomarkers for macrophage-mediated kidney injury is also discussed.

DDX5 inhibits hyaline cartilage fibrosis and degradation in osteoarthritis via alternative splicing and G-quadruplex unwinding.

Hyaline cartilage fibrosis is typically considered an end-stage pathology of osteoarthritis (OA), which results in changes to the extracellular matrix. However, the mechanism behind this is largely unclear. Here, we found that the RNA helicase DDX5 was dramatically downregulated during the progression of OA. DDX5 deficiency increased fibrosis phenotype by upregulating COL1 expression and downregulating COL2 expression. In addition, loss of DDX5 aggravated cartilage degradation by inducing the production of cartilage-degrading enzymes. Chondrocyte-specific deletion of Ddx5 led to more severe cartilage lesions in the mouse OA model. Mechanistically, weakened DDX5 resulted in abundance of the Fn1-AS-WT and Plod2-AS-WT transcripts, which promoted expression of fibrosis-related genes (Col1, Acta2) and extracellular matrix degradation genes (Mmp13, Nos2 and so on), respectively. Additionally, loss of DDX5 prevented the unfolding Col2 promoter G-quadruplex, thereby reducing COL2 production. Together, our data suggest that strategies aimed at the upregulation of DDX5 hold significant potential for the treatment of cartilage fibrosis and degradation in OA.

Correlation between daily exercise load and physical fitness among primary school students / 中国学校卫生

Objective@#To understand the relationship between daily exercise load and physical fitness of primary school students, so as to provide relevant theoretical basis for the development of on campus physical education plans and the improvement of procedural physical health management for elementary school students.@*Methods@#A total of 223 students from 6 classes in a primary school in Beijing were selected by a stratified random cluster sampling method from May to June 2023. The daily exercise load of the students was monitored by Polar Verity Sense heart rate armband. The duration of moderate to vigorous physical activity (MVPA) and daily Training Impulse (TRIMP) value were calculated, and the related indexes of daily exercise load were analyzed. Chi square test and univariate Logistic regression analysis were used to analyze the correlation between daily exercise load and physical fitness assessment levels, and multi factor ordinal Logistic regression analysis was used to explore the influencing factors of physical fitness assessment levels.@*Results@#The average time spent in MVPA was (21.65±17.48) min. The TRIMP value was (361.47±124.81). The time spent in MVPA of primary school students in outdoor class, zero point sports, recess and after class PE were ( 8.86 ±8.56, 9.41±10.47, 1.97±3.12, 2.46±2.57) min, respectively. TRIMP values were (68.89±20.84, 72.83±30.27, 51.68±18.23, 19.99±5.78) in outdoor class, zero point sports, recess and after class PE, respectively. The results of univariate analysis showed that there were statistically significant differences in physical fitness levels among students with different genders, grades, and BMI ( χ 2=7.13, 19.04, 32.98, P <0.05). The duration of daily MVPA, along with TRIMP value during outdoor class, zero point sports, recess, and after PE class were all statistically significant with physical fitness levels ( OR =1.07, 1.05, 1.02, 1.03, 1.11, P <0.05). The results of multi factor ordinal Logistic regression analysis showed that the primary school grade (lower grade: OR =9.24, middle grade: OR =7.81), BMI (abnormal: OR =0.21), duration of daily MVPA in school ( OR =1.06), and TRIMP value during outdoor class ( OR =1.05) were statistically significant with physical fitness levels ( P <0.05).@*Conclusions@#There is a positive correlation between physical fitness and different grades, BMI, daily exercise load, and outdoor exercise load. Increasing daily exercise load can improve students physical health. It is suggested to tailor the school sports program to suit primary school students, increase both the intensity and duration of school daily sports, and promote procedural physical health management for elementary school students.

Role of miR­181a­5p in cancer (Review).

MicroRNAs (miRNAs) are non­coding RNAs (ncRNAs) that can post­transcriptionally suppress targeted genes. Dysregulated miRNAs are associated with a variety of diseases. MiR­181a­5p is a conserved miRNA with the ability to regulate pathological processes, such as angiogenesis, inflammatory response and obesity. Numerous studies have demonstrated that miR­181a­5p exerts regulatory influence on cancer development and progression, acting as an oncomiR or tumor inhibitor in various cancer types by impacting multiple hallmarks of tumor. Generally, miR­181a­5p binds to target RNA sequences with partial complementarity, resulting in suppression of the targeted genes of miR­181a­5p. However, the precise role of miR­181a­5p in cancer remains incompletely understood. The present review aims to provide a comprehensive summary of recent research on miR­181a­5p, focusing on its involvement in different types of cancer and its potential as a diagnostic and prognostic biomarker, as well as its function in chemoresistance.

Pharmacological properties and underlying mechanisms of aurantio­obtusin (Review).

Herbal medicine has been widely applied for a range of diseases in China since antiquity. Cassia obtusifolia L. and Cassia tora L. are plants whose seeds have high reported medicinal values and have been documented to function as a laxative, to lower lipid level and to lower blood pressure. The main active ingredient in Cassia seeds is aurantio-obtusin (AO), which is an anthraquinone monomer compound. Currently, AO is listed in China as a quality control index component of Cassia seeds. In clinical practice in China, AO is typically used to treat obesity, diabetes and its complications, non-alcoholic fatty liver disease and allergic reactions. In addition, AO has been reported to confer insecticidal activities and antimalarial effects. Previous studies have even suggested that AO is a potential therapeutic candidate for a variety of diseases with research value. Therefore, the present review summarizes and discuss the existing literature on AO to provide a review of its pharmacological activity and mechanism of action, with the aim of providing a basis for its development and utilization in a clinical setting.

Secular trend analysis of antibiotic utilisation in some hospitals in Southern Sichuan from 2010 to 2020.

In order to assess the effectiveness of the Special Antimicrobial Stewardship Campaign launched by Ministry of Health of China in 2011, this study focused on the effectiveness and trends in the clinical use of antimicrobial drugs in selected hospitals in Southern Sichuan, China. This study collected and analyzed antibiotic data from 9 hospitals in Southern Sichuanin 2010, 2015, and 2020, including the rate of antibiotic use, expense, the intensity of antibiotic use and antibiotic use during the type I incisions of perioperative period. After 10 years of continuous improvement, the utilization rate of antibiotics in outpatients of the 9 hospitals continued to decline and was controlled below 20% by 2020, while the utilization rate in inpatients also significantly decreased, most were controlled within 60%. The use intensity of antibiotics (DDD (defined daily doses) per 100 bed-days) decreased from an average of 79.95 in 2010 to 37.96 in 2020. The prophylactic use of antibiotics decreased significantly in type I incision. The proportion of use within 30 min-1 h before operation was significantly increased. After the special rectification and sustained development of the clinical application of antibiotics, the relevant indicators of antibiotics tend to be stable, indicating that this Administration of antimicrobial drugs is conducive to improving the level of rational clinical application of antibiotics.

The characteristics of daily exercise load of students of different grades in a primary school in Beijing / 中国学校卫生

Objective@#To analyze the characteristics of the daily exercise load and the One Hour of Moderate to Vigorous Physical Activity (MVPA) per day among primary school students, so as to provide a reference for improving the quality of the physical activity of primary school students in school.@*Methods@#A total of 223 students from an elementary school in Beijing from May to June of 2023, were selected by stratified random cluster sampling method. The Polar Verity Sense heart rate arm band was used to monitor and evaluate the daily exercise load heart rate according to different grades, gender and physical quality.@*Results@#The average heart rate of primary school students in outdoor class, zero point sports, recess and indoor class was (130.01±13.11, 119.89± 16.02,109.96±8.11,96.81±7.89) times/min, respectively, and only 4.04% students met the standard of 1 hour MVPA daily. From the perspective of different grades, the MVPA time ratio of lower grade students in outdoor class, zero point sports and big break was 28.41%, 42.47% and 8.24%, that of middle grade students was 18.33%, 6.41% and 5.90%, and that of senior students was 45.91%, 3.88% and 11.43%. The number of students who achieved 1 hour daily MVPA was 5.41%, 0 and 6.67%. Time ratio of MVPA in outdoor classes, zero hour sports and big breaks accounted for 30.09%, 16.34% and 9.23% for boys, 31.70%, 16.24 % and 6.13% for girls, and the interval distribution of boys and girls who achieved MVPA for one hour per day was 5.88% and 2.86%.Time ratio of MVPA for students with excellent physical fitness were 33.19%, 21.76% and 8.25% in outdoor class, zero point sports and big break, while those with good physical fitness were 29.76%, 12.93% and 8.19%.A total of 21.78%, 5.99% and 4.80% of the students passed the physical fitness test, and the number of students with excellent, good and passed the physical fitness test who achieved the daily 1 hour MVPA was 5.88%, 3.77% and 0.@*Conclusion@#In the present study, elementary and middle school students time for in school physical activity was adequate, but there are problems of low loading intensity and insufficient time for MVPA. It is necessary to arrange targeted physical activity programs for students of different grades, genders and physical fitness levels to increase the daily exercise load of students in school.

Analysis of exercise density and exercise load in different physical classes for second year junior high school students from Beijing City / 中国学校卫生

Objective@#To explore the exercise intensity and effective exercise load of different physical fitness classes for second year junior high school students in Beijing, so as to provide a reference for optimizing the teaching content of physical fitness classes, reasonably regulating exercise load and the scientific development of physical fitness.@*Methods@#From October to November 2022, 30 second year junior high school students from a middle school in Xicheng District, Beijing were selected to have their heart rate monitored during physical fitness classes using Polar heart rate monitors. Heart rate intervals and training impulse (TRIMP) were used to quantify exercise intensity and load. Independent sample t-test was used to statistically analyze differences in heart rate across different dimensions.@*Results@#The average heart rate of students in physical fitness classes was (140.62±9.41) counts/min, with effective exercise load (heart rates ≥120 counts/min) time accounting for 77.2%, and heart rate load of moderate to vigorous physical activity (MVPA) time accounting for 51.9%. The average heart rates for speed, speed endurance, and endurance physical fitness classes were (137.89±8.82) (137.67±11.27) and (145.35±8.98) counts/min, respectively. The average heart rates of male and female students in physical education class were (144.22±24.95) and (136.31±28.78) counts/min, and the difference was not statistically significant ( t=4.04, P >0.05). The cumulative durations of effective exercise load among male and female students were (34.08± 7.52 ) and ( 28.43 ±5.39) min, respectively. The average TRIMP value for physical fitness classes were (100.46±16.56), with a exercise density of 72.06%.@*Conclusions@#The exercise intensity of physical fitness classes for secondyear junior high school students in Beijing is appropriate, mainly with moderate to vigorous intensity, and the accumulated time of MVPA is sufficient. The average heart rate and exercise density of students meet the requirements. Scientific setting of physical fitness class exercise load should be based on individual differences in students physical fitness, in order to improve the physical health level of middle school students.

Comprehensive analysis of chemokines family and related regulatory ceRNA network in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is one of the world's commonest malignancies with a high fatality rate. Chemokines not only regulate immune response but also participate in tumor development and metastasis and yet the mechanism of chemokines in LUAD remains unclear. In this study, transcriptional expression profiles, mutation data, and copy number variation data were downloaded from The Cancer Genome Atlas (TCGA). Risk gene protein expression was assessed by the Clinical Proteomic Tumor Analysis Consortium (CPTAC) and the Human Protein Atlas (HPA). Gene Expression Omnibus (GEO) data was used to validate the prognostic model. We summarized the genetic mutation variation landscape of chemokines. The risk prognosis model was developed based on differentially expressed chemokines, and patients in the high-risk score (RS) group had lower survival rates. Gene Set Enrichment Analysis (GSEA) revealed that high-RS patients were associated with metabolic transformation pathways, while low-RS patients were associated with immune-related pathways. Compared with the high-RS group, the low-RS group had higher immune/stromal/estimate scores calculated by the ESTIMATE package. The proportion of immune cells obtained using the CIBERSORT package was significantly different between the two groups. Most of the immune checkpoints were highly expressed in low-RS samples. Finally, we discovered that the lncRNA MIR17HG/AC009299.3/miR-21-5p/CCL20 regulatory network might be crucial in the pathogenesis of LUAD. In conclusion, we developed a risk signature and chemokine-related competing endogenous RNA (ceRNA) network.

PROTACs in gastrointestinal cancers.

Proteolysis targeting chimera (PROTAC) presents a powerful strategy for targeted protein degradation (TPD). The heterobifunctional PROTAC molecule consists of an E3 ligase ligand covalently linked to a protein of interest (POI) via a linker. PROTAC can induce ubiquitinated proteasomal degradation of proteins by hijacking the ubiquitin-proteasome degradation system (UPS). This technique has the advantages of broad targeting profile, good cell permeability, tissue specificity, high selectivity, oral bioavailability, and controllability. To date, a growing number of PROTACs targeting gastrointestinal cancers have been successfully developed, and, in many cases, their POIs have been validated as clinical drug targets. To the best of our knowledge, 15 PROTACs against various targets are currently tested in clinical trials, and many more are likely to be added in the near future. Therefore, this paper details the mechanism, research progress, and application in clinical trials of PROTACs, and summarizes the research achievements related to PROTACs in gastrointestinal cancers. Finally, we discuss the advantages and potential challenges of PROTAC for cancer treatment.

Salvianolic acid B inhibits RAW264.7 cell polarization towards the M1 phenotype by inhibiting NF-κB and Akt/mTOR pathway activation.

M1 macrophages secrete a large number of proinflammatory factors and promote the expansion of atherosclerotic plaques and processes. Salvianolic acid B (Sal B) exerts anti-inflammatory, antitumor and other effects, but no study has addressed whether Sal B can regulate the polarization of macrophages to exert these anti-atherosclerotic effects. Therefore, we investigated the inhibition of Sal B in M1 macrophage polarization and the underlying mechanism. The effects of different treatments on cell viability, gene expression and secretion of related proteins, phenotypic markers and cytokines were detected by MTT and western blot assays, RT‒qPCR and ELISAs. Cell viability was not significantly changed when the concentration of Sal B was less than 200 µM, and Lipopolysaccharide (LPS) (100 ng/mL) + interferon-γ (IFN-γ) (2.5 ng/mL) successfully induced M1 polarization. RT‒qPCR and ELISAs indicated that Sal B can downregulate M1 marker (Inducible Nitric Oxide Synthase (iNOS), Tumor Necrosis Factor-α (TNF-α), and Interleukin-6 (IL-6)) and upregulate M2 marker (Arginase-1 (Arg-1) and Interleukin-10 (IL-10)) expression. Western blotting was performed to measure the expression of Nuclear Factor-κB (NF-κB), p-Akt, p-mTOR, LC3-II, Beclin-1, and p62, and the results suggested that Sal B inhibits the M1 polarization of RAW264.7 macrophages by promoting autophagy via the NF-κB signalling pathway. The study indicated that Sal B inhibits M1 macrophage polarization by inhibiting NF-κB signalling pathway activation and downregulating Akt/mTOR activation to promote autophagy.

ChIP-Hub provides an integrative platform for exploring plant regulome.

Plant genomes encode a complex and evolutionary diverse regulatory grammar that forms the basis for most life on earth. A wealth of regulome and epigenome data have been generated in various plant species, but no common, standardized resource is available so far for biologists. Here, we present ChIP-Hub, an integrative web-based platform in the ENCODE standards that bundles >10,000 publicly available datasets reanalyzed from >40 plant species, allowing visualization and meta-analysis. We manually curate the datasets through assessing ~540 original publications and comprehensively evaluate their data quality. As a proof of concept, we extensively survey the co-association of different regulators and construct a hierarchical regulatory network under a broad developmental context. Furthermore, we show how our annotation allows to investigate the dynamic activity of tissue-specific regulatory elements (promoters and enhancers) and their underlying sequence grammar. Finally, we analyze the function and conservation of tissue-specific promoters, enhancers and chromatin states using comparative genomics approaches. Taken together, the ChIP-Hub platform and the analysis results provide rich resources for deep exploration of plant ENCODE. ChIP-Hub is available at https://biobigdata.nju.edu.cn/ChIPHub/ .

Therapeutic effect and mechanism of polysaccharides from Anoectochilus Roxburghii (Wall.) Lindl. in diet-induced obesity.

BACKGROUND: Recent studies have shown that polysaccharides from Anoectochilus roxburghii (Wall.) Lindl. (ARPs) can reduce blood glucose levels, ameliorate oxidative stress and inflammation. However, whether ARPs have a beneficial effect on diet-induced obesity remain to be determined. PURPOSE: This study aims to investigate the effect and mechanism of ARPs in improving obesity and metabolic disorders induced by high-fat diet (HFD). METHODS: In this study, 6-week-old male mice were fed with HFD or chow diet for 13 weeks, and a dietary supplementation with ARPs was carried out. Glucose tolerance test and insulin tolerance test were performed to measure the glucose tolerance and insulin sensitivity. Adipose tissue and liver were isolated for analysis by qRT-PCR, Western blotting, hematoxylin-eosin staining and immunostaining. RESULTS: At week 13, body weight and fat mass were significantly increased by HFD, but ARPs supplementation abolished these phenotypes. Compared with HFD group, thermogenic genes including Ucp-1, Pgc-1α, Prdm16 and Dio2 in adipose tissue were up-regulated in ARPs-treated mice. In addition, ARPs decreased liver lipid accumulation by reducing lipid synthesis and increasing oxidation. Meanwhile, dyslipidemia and insulin resistance induced by HFD were improved by ARPs. Mechanistically, ARPs can promote fat thermogenesis via AMPK/SIRT1/PGC-1α signaling pathway. CONCLUSION: Dietary supplementation of ARPs can protect mice against diet-induced obesity, fatty liver and insulin resistance. Our study reveals a potential therapeutic effect for ARPs in regulating energy homeostasis.

Impact of proton pump inhibitor management committee's multifaceted interventions on acid suppressant prescribing patterns in outpatient and emergency departments.

BACKGROUND: A nationwide campaign for rational proton pump inhibitor (PPI) use launched in 2015 had a positive impact for hospitalized patients PPI use. But there were few studies focusing on the rational use of PPIs in outpatients. In 2018, the PPI management committee conducted a year-long intervention on the appropriate use of PPIs in outpatient and emergency departments, including clinical pharmacist interventions and stewardship interventions. The purpose of this study was to examine the impact of the PPI management committee's multifaceted interventions by comparing the real-world acid suppressant prescribing patterns for outpatients before (2017) and after intervention (2019) at a Chinese tertiary teaching hospital. METHODS: Prescriptions containing any acid suppressant in outpatient and emergency departments in baseline (2017) and postintervention (2019) periods were extracted from the hospital information system and the prescription automatic screening system. Acid suppressant prescribing patterns were evaluated based on primary diagnoses and patient demographics. The prescribed acid suppressants stratified using age groups (< 7, 7-17, 18-45, 46-65, 66-85 and > 85 years) were also examined. RESULT: The utilization rate of acid suppressant in 2017 and 2019 was 2.5% (41,165/1,619,366) and 2.2% (49,550/2,236,471), respectively (P < 0.0001). 60,135 acid suppressant prescriptions were obtained in 2017 and 73,275 in 2019. The rate of acid suppressant prescriptions for the approved indications significantly increased from 62.6% (2017) to 65.4% (2019) (P < 0.0001). Prescriptions diagnosed as abnormal symptoms, signs and clinical manifestations, decreased in 2019 (13.0% vs. 16.5%, P < 0.0001). The most frequently prescribed PPIs differed between 2017 and 2019 (rabeprazole 2017 vs. esomeprazole 2019). Omeprazole was the most common PPI and cimetidine was the most common H2RA prescribed to patients aged < 18 years in 2017 and 2019. A total of CNY11.83 million was spent on acid suppressants in 2019, accounting for about 48.7% of total medication cost, increased by 11.3% from 2017 (37.4%). CONCLUSION: The proportion of acid suppressant prescriptions for approved indications was enhanced after the PPI management committee's multifaceted interventions, but there were still some problems in the selection of acid suppressants.

Allosteric inhibition reveals SHP2-mediated tumor immunosuppression in colon cancer by single-cell transcriptomics.

Colorectal cancer (CRC), a malignant tumor worldwide consists of microsatellite instability (MSI) and stable (MSS) phenotypes. Although SHP2 is a hopeful target for cancer therapy, its relationship with innate immunosuppression remains elusive. To address that, single-cell RNA sequencing was performed to explore the role of SHP2 in all cell types of tumor microenvironment (TME) from murine MC38 xenografts. Intratumoral cells were found to be functionally heterogeneous and responded significantly to SHP099, a SHP2 allosteric inhibitor. The malignant evolution of tumor cells was remarkably arrested by SHP099. Mechanistically, STING-TBK1-IRF3-mediated type I interferon signaling was highly activated by SHP099 in infiltrated myeloid cells. Notably, CRC patients with MSS phenotype exhibited greater macrophage infiltration and more potent SHP2 phosphorylation in CD68+ macrophages than MSI-high phenotypes, suggesting the potential role of macrophagic SHP2 in TME. Collectively, our data reveals a mechanism of innate immunosuppression mediated by SHP2, suggesting that SHP2 is a promising target for colon cancer immunotherapy.

Changes of BKCA current and vascular reactivity in vascular smooth muscle of thoracic aorta and mesenteric artery in type 2 diabetic rats.

The relationship between large conductance calcium activated potassium channel (BKCa) and vascular lesions in type 2 diabetes mellitus (T2DM) was investigated by observing vascular reactivity of thoracic aorta and mesenteric artery and the current changes of BKCa in vascular smooth muscle cells (VSMCs). The thoracic aorta and mesenteric artery of T2DM rats were isolated, the whole cell perforated patch clamp experiment and single channel patch clamp experiment of acute enzyme separation of thoracic aorta and mesenteric artery smooth muscle cells were performed to measure the membrane capacitance and the amplitude of macro current. And the vascular ring experiment was performed to observe the change of relaxation percentage. The results showed that the amplitude of BKCa current in vascular smooth muscle cells of diabetic rats was higher than that of the control group. The channel current had outward rectifying characteristics. BKCa is related to vascular reactivity and smooth muscle relaxation in T2DM rats. The opening probability of BKCa in VSMCs of diabetic rats was significantly increased. This study suggests that BKCa may be a new target for diabetic vascular disease.

Alpha-solanine Anti-tumor Effects in Non-small Cell Lung Cancer Through Regulating the Energy Metabolism Pathway.

BACKGROUND: Lung cancer is a malignant tumor with a high incidence in China, especially non-small cell lung cancer (NSCLC), which is the main threat to human life, with terrible morbidity and mortality. The research on the treatment and mechanism of NSCLC has been the forefront and hotspot of research. Recent patents show that alpha-solanine (α-solanine) exhibits the best anti-cancer activity, although its target and related mechanism remain to be elucidated. OBJECTIVES: This study aims to explore the possible targets and mechanisms of α-solanine in the treatment of NSCLC through network pharmacology and experimental verification. METHODS: Network pharmacology was applied to screen the possible targets of α-solanine on NSCLC, construct core networks, and perform GO enrichment and KEGG pathway analysis to predict the mechanism of α-solanine against NSCLC. Experiments were implemented to verify the results of network pharmacology in vitro. The A549 and PC-9 cells were exposed to α-solanine to assess the anti-tumor effect. Cell apoptosis was determined by the Annexin-V/PI assay. Targeted energy metabolomics was used to validate the network pharmacology results, and energy metabolism pathway- related proteins were detected by immunofluorescence and western blot. RESULTS: Network pharmacology showed that there were 130 potential targets of α-solanine and NSCLC. GO, and KEGG analysis showed that the energy metabolism pathway is the main pathway for α-solanine to exert anti-tumor effects on NSCLC. Experimental results showed that α-solanine inhibited cell proliferation, migration, invasion and promoted cell apoptosis. At the same time, after α-solanine treatment, the energy metabolism pathway-related proteins, including GPI, ALDOA, TPI1, PKLR, LDHA, and ALDH3, were expressed reduced. In addition, α-solanine also affects the amino acid metabolism of A549 and PC-9 cells. CONCLUSION: Based on a combination of network pharmacological prediction and experimental verification, α-solanine may exert anti-NSCLC effects by regulating the energy metabolism pathway.

Pharmacotranscriptomic profiling of resistant triple-negative breast cancer cells treated with lapatinib and berberine shows upregulation of PI3K/Akt signaling under cytotoxic stress.

Triple-negative breast cancer (TNBC) is the most incurable type of breast cancer, accounting for 15-20% of breast cancer cases. Lapatinib is a dual tyrosine kinase inhibitor targeting EGFR and Her2, and berberine (BBR) is a plant-based alkaloid suggested to inhibit several cancer signaling pathways. We previously reported that lapatinib activates the Akt oncoprotein in MDA-MB231 TNBC cells. The present study determined the mechanism(s) of Akt activation in response to lapatinib, BBR, and capivasertib (Akt inhibitor) as well as the role of Akt signaling in chemoresistance in TNBC cells. Genetic profiles of 10 TNBC cell lines and patients were analyzed using datasets obtained from Gene Expression Omnibus and The Cancer Genome Atlas Database. Then, the effects of lapatinib, BBR, and capivasertib on treated MDA-MB231 and MCF-7 cell lines were studied using cytotoxicity, immunoblot, and RNA-sequencing analyses. For further confirmation, we also performed real-time PCR for genes associated with PI3K signaling. MDA-MB231 and MCF-7 cell lines were both strongly resistant to capivasertib largely due to significant Akt activation in both breast cancer cell lines, while lapatinib and BBR only enhanced Akt signaling in MDA-MB231 cells. Next-generation sequencing, functional enrichment analysis, and immunoblot revealed downregulation of CDK6 and DNMT1 in response to lapatinib and BBR lead to a decrease in cell proliferation. Expression of placental, fibroblast growth factor, and angiogenic biomarker genes, which are significantly associated with Akt activation and/or dormancy in breast cancer cells, was significantly upregulated in TNBC cells treated with lapatinib and BBR. Lapatinib and BBR activate Akt through upregulation of alternative signaling, which lead to chemoresistance in TNBC cell. In addition, lapatinib overexpresses genes related to PI3K signaling in resistant TNBC cell model.

Allosteric inhibition of SHP2 uncovers aberrant TLR7 trafficking in aggravating psoriasis.

Psoriasis is a complex chronic inflammatory skin disease with unclear molecular mechanisms. We found that the Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) was highly expressed in both psoriatic patients and imiquimod (IMQ)-induced psoriasis-like mice. Also, the SHP2 allosteric inhibitor SHP099 reduced pro-inflammatory cytokine expression in PBMCs taken from psoriatic patients. Consistently, SHP099 significantly ameliorated IMQ-triggered skin inflammation in mice. Single-cell RNA sequencing of murine skin demonstrated that SHP2 inhibition impaired skin inflammation in myeloid cells, especially macrophages. Furthermore, IMQ-induced psoriasis-like skin inflammation was significantly alleviated in myeloid cells (monocytes, mature macrophages, and granulocytes)-but not dendritic cells conditional SHP2 knockout mice. Mechanistically, SHP2 promoted the trafficking of toll-like receptor 7 (TLR7) from the Golgi to the endosome in macrophages by dephosphorylating TLR7 at Tyr1024, boosting the ubiquitination of TLR7 and NF-κB-mediated skin inflammation. Importantly, Tlr7 point-mutant knock-in mice showed an attenuated psoriasis-like phenotype compared to wild-type littermates following IMQ treatment. Collectively, our findings identify SHP2 as a novel regulator of psoriasis and suggest that SHP2 inhibition may be a promising therapeutic approach for psoriatic patients.

Gardenia jasminoides Ellis Fruit Extracts Attenuated Colitis in 2,4,6-Trinitrobenzenesulfonic Acid-Induced Rats.

Ulcerative colitis (UC) is a relapsing inflammatory disease with an unknown precise etiology. The purpose of this study is to investigate the protective effects of Gardenia jasminoides Ellis fruit extracts (GFE) on 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis in rats. GFE (50 mg/kg, 100 mg/kg) were administered orally for 7 days after induction. Meanwhile, the chemical components of GFE were performed by UPLC-QTOF-MS/MS. GFE significantly decreased DAI scores and ameliorated macroscopic and histologic damage. It also reduced the levels of MPO, NO, MDA, IL-1ß, TNF-α, and IL-6, while increasing the level of SOD. Moreover, 56 components were identified in GFE using a UPLC-QTOF-MS/MS method, which can be categorized into six structural groups. Our results indicated that GFE has an ameliorative effect on TNBS-induced colitis in rats, which may further verify its anti-inflammatory and antioxidative properties. Therefore, GFE can be a promising protective agent of colitis that deserves further investigation.