A chemically adjustable BMP6-IL6 axis in mesenchymal stem cells drives acute myeloid leukemia cell differentiation.

Chemotherapy alone or in combination with allogeneic stem cell transplantation has been the standard of care for acute myeloid leukemia (AML) for decades. Leukemia relapse with limited treatment options remains the main cause of treatment failure. Therefore, an effective and safe approach to improve treatment outcomes is urgently needed for most AML patients. Mesenchymal stem cells (MSCs) have been reported to efficiently induce apoptosis and shape the fate of acute myeloid leukemia cells. Here, we identified LG190155 as a potent compound that enhances the antileukemia efficiency of MSCs. Pretreatment of MSCs with LG190155 significantly provoked differentiation in both AML patient-derived primary leukemia cells and AML cell lines and reduced the tumor burden in the AML mouse model. Using the quantitative proteomic technique, we discovered a pivotal mechanism that mediates AML cell differentiation, in which autocrine bone morphogenetic protein 6 (BMP6) in MSCs boosted IL-6 secretion and further acted on leukemic cells to trigger differentiation. Furthermore, the activity of the BMP6-IL6 axis was dramatically enhanced by activating vitamin D receptor (VDR) in MSCs. Our data illustrated an effective preactivated approach to reinforcing the antileukemia effect of MSCs, which could serve as an effective therapeutic strategy for AML.

A patent review on HMGB1 inhibitors for the treatment of liver diseases.

INTRODUCTION: HMGB1 is a non-histone chromatin protein released or secreted in response to tissue damage or infection. Extracellular HMGB1, as a crucial immunomodulatory factor, binds with several different receptors to innate inflammatory responses that aggravate acute and chronic liver diseases. The increased levels of HMGB1 have been reported in various liver diseases, highlighting that it represents a potential biomarker and druggable target for therapeutic development. AREAS COVERED: This review summarizes the current knowledge on the structure, function, and interacting receptors of HMGB1 and its significance in multiple liver diseases. The latest patented and preclinical studies of HMGB1 inhibitors (antibodies, peptides, and small molecules) for liver diseases are summarized by using the keywords 'HMGB1,' 'HMGB1 antagonist, HMGB1-inhibitor,' 'liver disease' in Web of Science, Google Scholar, Google Patents, and PubMed databases in the year from 2017 to 2023. EXPERT OPINIONS: In recent years, extensive research on HMGB1-dependent inflammatory signaling has discovered potent inhibitors of HMGB1 to reduce the severity of liver injury. Despite significant progress in the development of HMGB1 antagonists, few of them are approved for clinical treatment of liver-related diseases. Developing safe and effective specific inhibitors for different HMGB1 isoforms and their interaction with receptors is the focus of future research.

Isolation and microbial transformation of tea sapogenin from seed pomace of Camellia oleifera with anti-inflammatory effects.

In the current study, tea saponin, identified as the primary bioactive constituent in seed pomace of Camellia oleifera Abel., was meticulously extracted and hydrolyzed to yield five known sapogenins: 16-O-tiglogycamelliagnin B (a), camelliagnin A (b), 16-O-angeloybarringtogenol C (c), theasapogenol E (d), theasapogenol F (e). Subsequent biotransformation of compound a facilitated the isolation of six novel metabolites (a1-a6). The anti-inflammatory potential of these compounds was assessed using pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns molecules (DAMPs)-mediated cellular inflammation models. Notably, compounds b and a2 demonstrated significant inhibitory effects on both lipopolysaccharide (LPS) and high-mobility group box 1 (HMGB1)-induced inflammation, surpassing the efficacy of the standard anti-inflammatory agent, carbenoxolone. Conversely, compounds d, a3, and a6 selectivity targeted endogenous HMGB1-induced inflammation, showcasing a pronounced specificity. These results underscore the therapeutic promise of C. oleifera seed pomace-derived compounds as potent agents for the management of inflammatory diseases triggered by infections and tissue damage.

Novel insights into the rhizosphere and seawater microbiome of Zostera marina in diverse mariculture zones.

BACKGROUND: Seagrasses offer various ecosystem services and possess high levels of primary productivity. However, the development of mariculture has affected the homeostasis of seagrass meadow ecosystems. Plant-microbiome associations are essential for seagrasses health, but little is known about the role of environmental microbiomes and how they affect seagrass in a mariculture environment. In this study, we investigated the influence of mariculture on the rhizosphere and seawater microbiome surrounding Zostera marina and focused on the bacterial, eukaryotic, and fungal components in the composition, diversity, metabolism, and responses to mariculture-related environmental factors. RESULTS: Significant differences in the composition, richness, diversity, and internal relations of the bacterial community between the seawater and rhizosphere sediment surrounding Z. marina were observed, while differences in the eukaryotic and fungal communities were less significant. More complex bacterial and fungal co-occurrence networks were found in the seawater and rhizosphere sediment of the Saccharina japonica (SJ) and sea cucumber (SC) culture zones. The seawater in the SJ zone had higher levels of dissimilatory and assimilatory nitrate reduction, denitrification, and nitrogen fixation processes than the other three zones. The assimilatory sulfate reduction enzymes were higher in the rhizosphere sediments of the SJ zone than in the other three zones. Tetracycline, sulfonamide, and diaminopyrimidine resistance genes were enriched in the mariculture SJ and SC zones. CONCLUSIONS: Our findings might contribute to a better understanding of the effects of mariculture on the seagrass and the meadow ecosystems and thus revealing their potential operating mechanisms. These insights may serve to raise awareness of the effects of human activities on natural ecosystems, regulation of antibiotic usage, and environmental restoration. Video Abstract.

The role of neridronate in the management of osteoporosis: A meta-analysis.

BACKGROUND: It is estimated that 1 in 3 women and 1 in 5 men over the age of 50 worldwide will experience an osteoporosis fracture during their lives. Neridronate is a third-generation bisphosphonate with established efficacy in metabolic bone disease. It can be used in the treatment of osteoporosis. OBJECTIVES: We aimed to conduct a meta-analysis of the effect of neridronate on the treatment of osteoporosis. MATERIAL AND METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations were used to guide the present study. We searched PubMed and the Cochrane Central Register of Controlled Trials (CENTRAL) for reports published until August 31, 2021, related to neridronate and osteoporosis. The modification of the bone mineral density (BMD, g/cm2) of the patient is the core indicator for neridronate treatment. RESULTS: Significant increases in the BMD of the lumbar spine (mean difference (MD) = 5.99, 95% confidence interval (95% CI): 3.96-8.02), femoral neck (MD = 4.51, 95% CI: 2.01-7.01) and total hip (MD = 2.55, 95% CI: 2.10-3.00) were found. Greater improvement in the BMD of the lumbar spine and femoral neck could also be detected in patients with postmenopausal osteoporosis than with other causes of osteoporosis. Moreover, significant decreases in serum C-telopeptide of collagen type I (sCTX, standardized mean difference (SMD) = -0.84, 95% CI: -1.32--0.37) and bone alkaline phosphatase (ALP, MD = -5.29, 95% CI: -7.31--3.26) levels were observed. CONCLUSION: The pool analysis of the selected clinical trials indicates the great benefit of neridronate in improving the condition of patients with osteoporosis of all causes, particularly patients with postmenopausal osteoporosis, which causes an increase in BMD as well as in sCTX and bone ALP levels.

A meta-analysis of the risk factors for lateral epicondylitis.

BACKGROUND: Very few meta-analyses discussed risk factors for lateral epicondylitis (LE), and previous meta-analyses reached conflicting conclusions with each other on some specific risk factors. PURPOSE: To investigate the risk factors for LE through meta-analysis. STUDY DESIGN: Meta-analysis. METHODS: PubMed, Embase, and Web of Science databases were searched for relevant studies in January 2022. Raw data were extracted into a predefined worksheet, and quality analysis was conducted by the Quality in Prognosis Studies (QUIPS) tool. Pooled effect sizes and 95% confidence intervals were calculated. R package "meta" was used for statistical analysis. RESULTS: 22 studies were included in the meta-analysis. Female sex (odds ratio [OR]=1.33 and p-value<0.05), smoking history (OR=1.46 and p-value<0.001), manual labor (OR=2.39 and p-value<0.001), and hypercholesterolemia (OR=1.67 and p-value<0.05) were significant risk factors for LE. CONCLUSIONS: Female gender, smoking history, manual labor, and hypercholesterolemia could increase the risk of LE. According to an additional literature review, statin treatment for hypercholesterolemia is described as potentially related to the development of LE.

Long-term effectiveness of conservative management for lateral epicondylitis: a meta-analysis.

OBJECTIVE: To investigate the long-term (>12 months) effectiveness of conservative management for lateral epicondylitis. DATA SOURCES: PubMed and Embase databases were searched for relevant studies from inception to March 2023. STUDY SELECTION AND DATA EXTRACTION: Only English-written randomized controlled trial (RCT) with data download as well as follow up ≥12 months were acceptable. Raw data were extracted into a predefined worksheet, and quality analysis was conducted based on the Cochrane risk-of-bias tool version 2 (RoB2). DATA SYNTHESIS: The standardized mean difference (SMD) with 95% confidence interval (CI) were calculated. RESULTS: Extracorporeal shock wave therapy (ESWT) could significantly relive pain for lateral epicondylitis patients in the long term (SMD: -0.19, 95% CI [-0.36, -0.02]); however, there was no significant difference between ESWT and control groups in long-term function outcome (SMD: 0.24, 95% CI [-0.02, -0.49]). No significant difference could be observed between (1) exercise and control groups in pain (SMD: -0.21, 95% CI [-0.60, 0.18]) or function (SMD: 0.06, 95% CI [-0.11, 0.23]), (2) corticosteroids and placebo groups in pain (SMD: 0.70, 95% CI [-0.43, 1.82]) or function (SMD: -0.02, 95% CI [-0.36, 0.31]), and (3) platelet-rich plasma (PRP) in pain (SMD: -0.30, 95% CI [-0.85, 0.25]) and function (SMD: -0.08, 95% CI [-0.78, 0.62]). CONCLUSION: The present conventional conservative management for lateral epicondylitis, with the exception of ESWT, a lack adequate evidence supporting their long-term effectiveness.

Research on the interaction of astragaloside IV and calycosin in Astragalus membranaceus with HMGB1.

BACKGROUND: High mobility group box 1 protein (HMGB1), a lethal late inflammatory mediator, contributes to the pathogenesis of diverse inflammatory and infectious diseases. Astragaloside IV and calycosin as active ingredients in Astragalus membranaceus, possess potent regulatory ability on HMGB1-induced inflammation, however, the interaction between these two phytochemicals and HMGB1 has not been elucidated yet. METHODS: To further investigate the interaction of astragaloside IV, calycosin with HMGB1 protein, surface plasma resonance (SPR) and a series of spectroscopic methods, including UV spectra, fluorescence spectroscopy, circular dichroism (CD), were used. Molecular docking was also carried out to predict the atomic level's binding modes between two components and HMGB1. RESULTS: Astragaloside IV and calycosin were found to be able to bind HMGB1 directly and affect the secondary structure and environment of the chromogenic amino acids of HMGB1 to different extents. In silico, astragaloside IV and calycosin showed a synergistic effect by binding to the two independent domains B-box and A-box in HMGB1, respectively, where hydrogen and hydrophobicity bonds were regarded as the crucial forces. CONCLUSION: These findings showed that the interaction of astragaloside IV and calycosin with HMGB1 impaired its proinflammatory cytokines function, providing a new perspective for understanding the mechanism of A. membranaceus in treating aseptic and infectious diseases.

A novel mesenchymal stem cell-based regimen for acute myeloid leukemia differentiation therapy.

Currently the main treatment of acute myeloid leukemia (AML) is chemotherapy combining hematopoietic stem cell transplantation. However, the unbearable side effect of chemotherapy and the high risk of life-threatening infections and disease relapse following hematopoietic stem cell transplantation restrict its application in clinical practice. Thus, there is an urgent need to develop alternative therapeutic tactics with significant efficacy and attenuated adverse effects. Here, we revealed that umbilical cord-derived mesenchymal stem cells (UC-MSC) efficiently induced AML cell differentiation by shuttling the neutrophil elastase (NE)-packaged extracellular vesicles (EVs) into AML cells. Interestingly, the generation and release of NE-packaged EVs could be dramatically increased by vitamin D receptor (VDR) activation in UC-MSC. Chemical activation of VDR by using its agonist 1α,25-dihydroxyvitamin D3 efficiently enhanced the pro-differentiation capacity of UC-MSC and then alleviated malignant burden in AML mouse model. Based on these discoveries, to evade the risk of hypercalcemia, we synthetized and identified sw-22, a novel non-steroidal VDR agonist, which exerted a synergistic pro-differentiation function with UC-MSC on mitigating the progress of AML. Collectively, our findings provided a non-gene editing MSC-based therapeutic regimen to overcome the differentiation blockade in AML.

Novel MeON-glycosides of ursolic acid: Synthesis, antitumor evaluation, and mechanism studies.

Ursolic acid (UA) is a pentacyclic triterpenoid widely found in in medicinal plants, edible plants, fruits, and flowers. The great interest in this bioactive compound is related to the positive effects in human health. However, its limited solubility, moderate biological activity and poor bioavailability limit the potential and further applications of UA. Here, we explored the efficacy of MeON-Glycosides of UA in inhibiting tumor cell proliferation. A number of compounds showed significant antitumor activity against tested five cancer cell lines. Among them, compound 2a exhibited the most potent activity against HepG2 cells with IC50 values of 3.1 ± 0.5 µM. Especially, compound 2a could induce HepG2 cells apoptosis and reduce mitochondrial membrane potential. Western blot analysis showed that compound 2a up-regulated Bax, cleaved caspase-3/9, cleaved PARP levels and down-regulated Bcl-2 level of HepG2 cells. These results indicated that compound 2a could obviously induce the apoptosis of HepG2 cells. At the same time, compound 2a significantly decreased the expression of p-AKT and p-mTOR, which indicated that compound 2a might exert its cytotoxic effect by targeting PI3K/AKT/mTOR signaling pathway. Moreover, the in silico ADME predictions showed that compound 2a has improved water solubility and other properties. Thus, compound 2a may be a promising antitumor candidate, which may be potentially used to prevent or treat cancers.

Culture-Independent Single-Cell PacBio Sequencing Reveals Epibiotic Variovorax and Nucleus Associated Mycoplasma in the Microbiome of the Marine Benthic Protist Geleia sp. YT (Ciliophora, Karyorelictea).

Microbes in marine sediments constitute up to five-sixths of the planet's total biomass, but their diversity is little explored, especially for those forming associations with unicellular protists. Heterotrophic ciliates are among the most dominant and diversified marine benthic protists and comprise hotspot niches of bacterial colonization. To date, studies using culture-independent single-cell approaches to explore microbiomes of marine benthic ciliates in nature are almost absent, even for the most ubiquitous species. Here, we characterize the major bacterial groups associated with a representative marine benthic ciliate, Geleia sp. YT, collected directly from the coastal zone of Yantai, China. PacBio sequencing of the nearly full-length 16Sr RNA genes was performed on single cells of Geleia. Fluorescence in situ hybridization (FISH) analysis with genus-specific probes was further applied to locate the dominant bacterial groups. We identified a Variovorax-like bacterium as the major epibiotic symbiont residing in the kineties of the ciliate host. We provide evidence of a nucleus-associated bacterium related to the human pathogen Mycoplasma, which appeared prevalently in the local populations of Geleia sp. YT for 4 months. The most abundant bacterial taxa associated with Geleia sp. YT likely represent its core microbiome, hinting at the important roles of the ciliate-bacteria consortium in the marine benthos. Overall, this work has contributed to the knowledge of the diversity of life in the enigmatic marine benthic ciliate and its symbioses.

Efficacy evaluation of chimeric antigen receptor-modified human peritoneal macrophages in the treatment of gastric cancer.

BACKGROUND: Gastric cancer is one of the most common cancers. Peritoneal carcinomatosis (PC) appears to be the most common pattern of recurrence, and more than half of the GC patients eventually die from PC. Novel strategies for the management of patients with PC are urgently needed. Recently, rapid progress has been made in adoptive transfer therapy by using macrophages as the effector cells due to their capabilities of phagocytosis, antigen presentation, and high penetration. Here, we generated a novel macrophage-based therapy and investigated anti-tumoral effects on GC and potential toxicity. METHODS: We developed a novel Chimeric Antigen Receptor-Macrophage (CAR-M) based on genetically modifying human peritoneal macrophages (PMs), expressing a HER2-FcεR1γ-CAR (HF-CAR). We tested HF-CAR macrophages in a variety of GC models in vitro and in vivo. RESULTS: HF-CAR-PMs specifically targeted HER2-expressed GC, and harboured the FcεR1γ moieties to trigger engulfment. Intraperitoneal administration of HF-CAR-PMs significantly facilitated the HER2-positive tumour regression in PC mouse model and prolonged the overall survival rate. In addition, the combined use of oxaliplatin and HF-CAR-PMs exhibited significantly augment anti-tumour activity and survival benefit. CONCLUSIONS: HF-CAR-PMs could represent an exciting therapeutic option for patients with HER2-positive GC cancer, which should be tested in carefully designed clinical trials.

Chitosan-Based Hydrogels for Infected Wound Treatment.

Wound infections slow down the healing process and lead to complications such as septicemia, osteomyelitis, and even death. Although traditional methods relying on antibiotics are effective in controlling infection, they have led to the emergence of antibiotic-resistant bacteria. Hydrogels with antimicrobial function become a viable option for reducing bacterial colonization and infection while also accelerating healing processes. Chitosan is extensively developed as antibacterial wound dressings due to its unique biochemical properties and inherent antibacterial activity. In this review, the recent research progress of chitosan-based hydrogels for infected wound treatment, including the fabrication methods, antibacterial mechanisms, antibacterial performance, wound healing efficacy, etc., is summarized. A concise assessment of current limitations and future trends is presented.

Targeting CD44 Variant 5 with an Antibody-Drug Conjugate Is an Effective Therapeutic Strategy for Intrahepatic Cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) is the second most frequent type of primary liver cancer. ICC is among the deadliest malignancies, highlighting that novel treatments are urgently needed. Studies have shown that CD44 variant isoforms, rather than the CD44 standard isoform, are selectively expressed in ICC cells, providing an opportunity for the development of an antibody-drug conjugate (ADC)-based targeted therapeutic strategy. In this study, we observed the specific expression of CD44 variant 5 (CD44v5) in ICC tumors. CD44v5 protein was expressed on the surface of most ICC tumors (103 of 155). A CD44v5-targeted ADC, H1D8-DC (H1D8-drug conjugate), was developed that comprises a humanized anti-CD44v5 mAb conjugated to the microtubule inhibitor monomethyl auristatin E (MMAE) via a cleavable valine-citrulline-based linker. H1D8-DC exhibited efficient antigen binding and internalization in cells expressing CD44v5 on the cell surface. Because of the high expression of cathepsin B in ICC cells, the drug was preferentially released in cancer cells but not in normal cells, thus inducing potent cytotoxicity at picomolar concentrations. In vivo studies showed that H1D8-DC was effective against CD44v5-positive ICC cells and induced tumor regression in patient-derived xenograft models, whereas no significant adverse toxicities were observed. These data demonstrate that CD44v5 is a bona fide target in ICC and provide a rationale for the clinical investigation of a CD44v5-targeted ADC-based approach. SIGNIFICANCE: Elevated expression of CD44 variant 5 in intrahepatic cholangiocarcinoma confers a targetable vulnerability using the newly developed antibody-drug conjugate H1D8-DC, which induces potent growth suppressive effects without significant toxicity.

Interaction of bioactive kaempferol with HMGB1: Investigation by multi-spectroscopic and molecular simulation methods.

Chronic and persistent inflammation associated with excessive high mobility group protein 1 (HMGB1) is a risk factor for various diseases. Dietary intake of kaempferol has been proven to be effective in reducing HMGB1 levels and the degree of inflammation, but the structural mechanism remains unclear. In this context, we first investigated the interaction between bioactive kaempferol and HMGB1 using multi-spectroscopic and molecular simulation techniques. The surface plasmon resonance (SPR) data indicated that kaempferol binds directly to HMGB1 with a Kd value of 2.89 × 10-5 M. Binding of kaempferol with HMGB1 led to the intrinsic fluorescence quenching and modest secondary structure change of HMGB1 supported by fluorescence spectrometry and circular dichroism (CD). Using dynamic light scattering (DLS), it was found that kaempferol induced the aggregation of HMGB1 protein complex to form larger particles. On HMGB1-activated RAW264.7 cells, kaempferol co-incubation exhibited a remarkable inhibitory effect on nitric oxide (NO) release with an IC50 value of 5.02 µM, which was lower than that of quercetin. In silico, kaempferol binds to HMGB1 mainly through hydrogen bonds and hydrophobic forces. Collectively, our study showed kaempferol as a potential HMGB1 inhibitor, mainly acting by direct binding to HMGB1 and inducing its conformational changes, which provides clues for the treatment of chronic inflammation by kaempferol.

Porous Silicon Nanocarriers Boost the Immunomodulation of Mitochondria-Targeted Bovine Serum Albumins on Macrophage Polarization.

The development of nanosystems with intrinsic immunomodulatory effects on macrophage polarization is important for the macrophage-targeted immunotherapy. Here, mitochondria-targeted bovine serum albumins (BSAs) via the conjugation of fluorescent, lipophilic, and cationic rhodamine 110 molecules can efficiently enhance the gene expression of the proinflammatory phenotype of macrophages and correspondingly inhibit the gene expression of their anti-inflammatory phenotype. On this basis, porous silicon nanocarriers can further boost the immunomodulation of these mitochondria-targeted BSAs in vitro or in vivo, accompanied by the secretion of proinflammatory mediators including tumor necrosis factor α, nitric oxide, and reactive oxygen species (ROS). Meanwhile, BSA coatings can also improve the biocompatibility of porous silicon nanoparticulate cores on macrophages. Finally, the mechanism investigations demonstrate that porous silicon nanocarriers can efficiently deliver mitochondria-targeted BSA into macrophages to generate mitochondrial ROS via the interference with mitochondrial respiratory chains, which can further trigger the downstream signaling transduction pathways for the proinflammatory transition. Considering the good biosafety and versatile loading capability, this developed porous silicon@BSA nanosystem with a strong proinflmmatory regulatory effect has important potential on the combinatorial chemoimmunotherapy against cancer or viral/bacterial-related infectious diseases.

Treatment outcomes of tendinitis of long head of the biceps brachii tendon by different surgeries based on the concept of enhanced recovery after surgery.

OBJECTIVES: This study aims to evaluate the therapeutic effects of tenotomy and tenodesis of the long head of the biceps brachii tendon (LHBT) under shoulder arthroscopy based on the concept of enhanced recovery after surgery (ERAS) on long head of the biceps (LHB) tendinitis. PATIENTS AND METHODS: Between January 2019 and January 2021, a total of 80 LHB tendinitis patients (44 males, 36 females; mean age: 55.3±4.5 years; range, 45 to 72 years) were included. The patients were randomly divided into the group of tenotomy of LHBT under shoulder arthroscopy (tenotomy group, n=40) and group of tenodesis of LHBT under shoulder arthroscopy (tenodesis group, n=40). Tenotomy group was randomly subdivided into Tenotomy-1 and Tenotomy-2 groups including 20 patients in each group to receive conventional treatment and treatment plan guided by ERAS concept, respectively. Similarly, the tenodesis group was randomly subdivided into Tenodesis-1 and Tenodesis-2 groups including 20 patients in each group. Their postoperative shoulder joint functions and pain were compared. RESULTS: The Visual Analog Scale score showed a significant difference between Tenotomy-1 group and Tenodesis-1 group at one, three, and six months after surgery (p<0.05). However, there was no significant difference at nine months after surgery (p>0.05). In the tenotomy group, although the operation time was shorter, the patients were more prone to develop Popeye deformity after surgery. The American Shoulder and Elbow Surgeon score, Western Ontario Rotator Cuff Index, Constant-Murley shoulder score had no significant differences between the tenotomy and tenodesis groups; however, there was a significant difference between the conventional treatment group (Tenotomy-1 group and Tenodesis-1 group) and ERAS treatment group (Tenotomy-2 group and Tenodesis-2 group) (p<0.05). CONCLUSION: The clinical efficacy is similar between tenotomy and tenodesis of LHBT under shoulder arthroscopy. While selecting surgical approaches, comprehensive assessment should be performed based on all conditions of patients. Besides, therapeutic schedules should be upgraded and optimized with the help of the ERAS concept after admission to minimize the pain of patients, reduce the potential risk of surgery, and help patients recover quickly.

Blockage of PPARγ T166 phosphorylation enhances the inducibility of beige adipocytes and improves metabolic dysfunctions.

Beige adipocytes in mammalian white adipose tissue (WAT) can reinforce fat catabolism and energy expenditure. Promoting beige adipocyte biogenesis is a tantalizing tactic for combating obesity and its associated metabolic disorders. Here, we report that a previously unidentified phosphorylation pattern (Thr166) in the DNA-binding domain of PPARγ regulates the inducibility of beige adipocytes. This unique posttranslational modification (PTM) pattern influences allosteric communication between PPARγ and DNA or coactivators, which impedes the PPARγ-mediated transactivation of beige cell-related gene expression in WAT. The genetic mutation mimicking T166 phosphorylation (p-T166) hinders the inducibility of beige adipocytes. In contrast, genetic or chemical intervention in this PTM pattern favors beige cell formation. Moreover, inhibition of p-T166 attenuates metabolic dysfunction in obese mice. Our results uncover a mechanism involved in beige cell fate determination. Moreover, our discoveries provide a promising strategy for guiding the development of novel PPARγ agonists for the treatment of obesity and related metabolic disorders.

Integrating Bioinformatics and Network Pharmacology to Explore the Therapeutic Target and Molecular Mechanisms of Schisandrin on Hypertrophic Cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease and is currently the leading cause of sudden death in adolescent athletes. Schisandrin is a quality marker of the traditional Chinese medicine Schisandra chinensis, which has an excellent therapeutic effect on HCM, but its pharmacological mechanism remains unclear. OBJECTIVE: This study aimed to explore the potential and provide scientific evidence for schisandrin as a lead compound against hypertrophic cardiomyopathy. METHODS: The drug-like properties of schisandrin were predicted using the SwissADME website. Then, the PharmMapper database was used to predict potential drug targets and match gene names in the Uniprot database. HCM targets were collected from NCBI, OMIM, and Genecards databases and intersected with drug targets. The intersection targets were imported into the STRING database for PPI analysis, and core targets were identified. KEGG and GO enrichment analysis was performed on the core targets through the DAVID database, and all network maps were imported into Cytoscape software for visualization optimization. HCM-related datasets were downloaded from the GEO database to analyze core targets and screen differentially expressed target genes for molecular docking. RESULTS: After the PPI network analysis of the intersection targets of drugs and diseases, 12 core targets were screened out. The KEGG analysis results showed that they were mainly involved in Rap1, TNF, FoxO, PI3K-Akt, and other signaling pathways. After differential analysis, PPARG, EGFR, and MMP3 targets were also screened. The molecular docking results showed that schisandrin was well bound to the protein backbone of each target. CONCLUSION: This study used network pharmacology combined with differential expression and molecular docking to predict that schisandrin may treat HCM by acting on PPARG, EGFR, and MMP3 targets, and the regulatory process may involve signaling pathways, such as Rap1, TNF, FoxO, and PI3K-Akt, which may provide a valuable reference for subsequent studies.

PFKFB4 facilitates palbociclib resistance in oestrogen receptor-positive breast cancer by enhancing stemness.

BACKGROUND: ER+ breast cancer (ER+ BC) is the most common subtype of BC. Recently, CDK4/6 inhibitors combined with aromatase inhibitors have been approved by FDA as the first-line therapy for patients with ER+ BC, and showed promising therapeutic efficacy in clinical treatment. However, resistance to CDK4/6 inhibitors is frequently observed. A better understanding of the drug resistance mechanism is beneficial to improving therapeutic strategies by identifying optimal combinational treatments. METHODS: Western blotting, qPCR, flow cytometry and a series of cell experiments were performed to evaluate the phenotype of MCF-7/R cells. RNA sequencing, non-targeted metabolomics, shRNA knockdown and tumour cell-bearing mouse models were used to clarify the drug resistance mechanism. RESULTS: Here, we found that ER+ BC cells have shown an adaptive resistance to palbociclib-induced cell cycle arrest by activating an alternative signal pathway, independent of the CDK4/6-RB signal transduction. Continuing treatment of palbociclib evoked cellular senescence of ER+ BC cells. Subsequently, the senescence-like phenotype promoted stemness of ER+ BC cells, accompanied by increased chemoresistance and tumour-initiating potential. Based on transcriptome analysis, we found that PFKFB4 played an important role in stemness transformation and drug resistance. A close correlation was determined between PFKFB4 expression by ER+ BC cells and cell senescence and stemness. Mechanistically, metabolomic profiling revealed that PFKFB4 reprogramed glucose metabolism and promoted cell stemness by enhancing glycolysis. Strikingly, diminishing PFKFB4 levels improved drug sensitivity and overcame chemoresistance during palbociclib treatment in ER+ BC. CONCLUSIONS: These findings not only demonstrated the novel mechanism underlying which ER+ BC cells resisted to palbociclib, but also provided a possible therapeutic strategy in the intervention of ER+ BC to overcome drug resistance.