Hepatic IRE1α-XBP1 signaling promotes GDF15-mediated anorexia and body weight loss in chemotherapy.

Platinum-based chemotherapy drugs can lead to the development of anorexia, a detrimental effect on the overall health of cancer patients. However, managing chemotherapy-induced anorexia and subsequent weight loss remains challenging due to limited effective therapeutic strategies. Growth differentiation factor 15 (GDF15) has recently gained significant attention in the context of chemotherapy-induced anorexia. Here, we report that hepatic GDF15 plays a crucial role in regulating body weight in response to chemo drugs cisplatin and doxorubicin. Cisplatin and doxorubicin treatments induce hepatic Gdf15 expression and elevate circulating GDF15 levels, leading to hunger suppression and subsequent weight loss. Mechanistically, selective activation by chemotherapy of hepatic IRE1α-XBP1 pathway of the unfolded protein response (UPR) upregulates Gdf15 expression. Genetic and pharmacological inactivation of IRE1α is sufficient to ameliorate chemotherapy-induced anorexia and body weight loss. These results identify hepatic IRE1α as a molecular driver of GDF15-mediated anorexia and suggest that blocking IRE1α RNase activity offers a therapeutic strategy to alleviate the adverse anorexia effects in chemotherapy.

Predictive value of estimated plasma volume for postoperative hypotension in percutaneous intramyocardial septal radiofrequency ablation treating for hypertrophic obstructive cardiomyopathy.

BACKGROUND: Estimated plasma volume status (ePVS) estimated by the Duarte formula is associated with clinical outcomes in patients with heart failure. It remains unclear the predictive value of the ePVS to the postoperative hypotension (POH) in percutaneous intramyocardial septal radiofrequency ablation (PIMSRA) treating hypertrophic obstructive cardiomyopathy (HOCM). METHODS: Data of HOCM patients who underwent PIMSRA were retrospectively collected. Preoperative ePVS was calculated using the Duarte formulas which derived from hemoglobin and hematocrit ratios. Clinical variables including physical assessment, biological and echocardiographic parameters were recorded. Patients were labeled with or without POH according to the medical record in the hospital. Univariable and multivariable logistic regression were performed to evaluate the association between ePVS and POH. Using different thresholds derived from quartiles and the best cutoff value of the receiver operating characteristic curve, the diagnostic performance of ePVS was quantified. RESULTS: Among the 405 patients included in this study, 53 (13.1%) patients were observed with symptomatic POH. Median (IQR) of ePVS in overall patients was 3.77 (3.27~4.40) mL/g and in patients with POH were higher than those without POH. The ePVS was associated with POH, with the odds ratio of 1.669 (95% CI 1.299 ~ 2.144) per mL/g. After adjusted by potential confounders, ePVS remained independently associated with POH, with the approximate odds ratio in different models. CONCLUSION: The preoperative ePVS derived from the Duarte formulas was independently associated with postoperative hypotension in HOCM patients who underwent PIMSRA and showed prognostic value to the risk stratification of postoperative management. TRIAL REGISTRATION: NCT06003478 (22/08/2023).

ATG-101 Is a Tetravalent PD-L1×4-1BB Bispecific Antibody That Stimulates Antitumor Immunity through PD-L1 Blockade and PD-L1-Directed 4-1BB Activation.

Immune checkpoint inhibitors (ICI) have transformed cancer treatment. However, only a minority of patients achieve a profound response. Many patients are innately resistant while others acquire resistance to ICIs. Furthermore, hepatotoxicity and suboptimal efficacy have hampered the clinical development of agonists of 4-1BB, a promising immune-stimulating target. To effectively target 4-1BB and treat diseases resistant to ICIs, we engineered ATG-101, a tetravalent "2+2″ PD-L1×4-1BB bispecific antibody. ATG-101 bound PD-L1 and 4-1BB concurrently, with a greater affinity for PD-L1, and potently activated 4-1BB+ T cells when cross-linked with PD-L1-positive cells. ATG-101 activated exhausted T cells upon PD-L1 binding, indicating a possible role in reversing T-cell dysfunction. ATG-101 displayed potent antitumor activity in numerous in vivo tumor models, including those resistant or refractory to ICIs. ATG-101 greatly increased the proliferation of CD8+ T cells, the infiltration of effector memory T cells, and the ratio of CD8+ T/regulatory T cells in the tumor microenvironment (TME), rendering an immunologically "cold" tumor "hot." Comprehensive characterization of the TME after ATG-101 treatment using single-cell RNA sequencing further revealed an altered immune landscape that reflected increased antitumor immunity. ATG-101 was well tolerated and did not induce hepatotoxicity in non-human primates. According to computational semimechanistic pharmacology modeling, 4-1BB/ATG-101/PD-L1 trimer formation and PD-L1 receptor occupancy were both maximized at around 2 mg/kg of ATG-101, providing guidance regarding the optimal biological dose for clinical trials. In summary, by localizing to PD-L1-rich microenvironments and activating 4-1BB+ immune cells in a PD-L1 cross-linking-dependent manner, ATG-101 safely inhibits growth of ICI resistant and refractory tumors. SIGNIFICANCE: The tetravalent PD-L1×4-1BB bispecific antibody ATG-101 activates 4-1BB+ T cells in a PD-L1 cross-linking-dependent manner, minimizing the hepatotoxicity of existing 4-1BB agonists and suppressing growth of ICI-resistant tumors. See related commentary by Ha et al., p. 1546.

PDGFRß + cell HIF2α is dispensable for white adipose tissue metabolic remodeling and hepatic lipid accumulation in obese mice.

BACKGROUND: Obesity is associated with extensive white adipose tissue (WAT) expansion and remodeling. Healthy WAT expansion contributes to the maintenance of energy balance in the liver, thereby ameliorating obesity-related hepatic steatosis. Tissue-resident mesenchymal stromal cell populations, including PDGFRß + perivascular cells, are increasingly recognized pivotal as determinants of the manner in which WAT expands. However, the full array of regulatory factors controlling WAT stromal cell functions remains to be fully elucidated. Hypoxia-inducible factors (HIFs) are critical regulators in WAT stromal cell populations such as adipocyte precursor cells (APCs). It is revealed that HIF1α activation within PDGFRß + stromal cells results in the suppression of de novo adipogenesis and the promotion of a pro-fibrogenic cellular program in obese animals. However, the role of HIF2α in PDGFRß + cells remains undetermined in vivo. METHODS: New genetic models were employed in which HIF1α (encoded by the Hif1a gene) and HIF2α (encoded by the Epas1 gene) are selectively inactivated in PDGFRß + cells in an inducible manner using tamoxifen (TAM). With these models, both in vitro and in vivo functional analysis of PDGFRß + cells lacking HIF proteins were performed. Additionally, comprehensive metabolic phenotyping in diet-induced mouse models were performed to investigate the roles of PDGFRß + cell HIF proteins in WAT remodeling, liver energy balance and systemic metabolism. RESULTS: Unlike HIF1α inactivation, the new findings in this study suggest that inducible ablation of HIF2α in PDGFRß + cells does not cause apparent effects on WAT expansion induced by obesogenic diet. The adipogenic ability of PDGFRß + APCs is not significantly altered by genetic HIF2α ablation. Moreover, no difference of key parameters associated with healthy WAT remodeling such as improvements of WAT insulin sensitivity, reduction in metabolic inflammation, as well as changes in liver fat accumulation or systemic glucose metabolism, is detected in PDGFRß + cell Epas1-deficient mice. CONCLUSION: The new findings in this study support that, in contrast to HIF1α, PDGFRß + cell HIF2α appears dispensable for WAT metabolic remodeling and the resulting effects on liver metabolic homeostasis in diet-induced obesity, underscoring the isoform-specific roles of HIFα proteins in the regulation of adipose tissue biology.

Percutaneous intramyocardial septal radiofrequency ablation after 5-year follow-up.

OBJECTIVE: The objective is to evaluate the 5-year follow-up results of percutaneous intramyocardial septal radiofrequency ablation (PIMSRA) for hypertrophic obstructive cardiomyopathy (HOCM), including clinical status, electrocardiographic and echocardiographic characteristics. METHODS: 27 patients (age: 44.3±15.5 years; 67% men, 33% women) with severely symptomatic HOCM who underwent PIMSRA from October 2016 to September 2017 were included. Their clinical status, resting and exercise stress echocardiography, electrocardiography and cardiac MRI (CMRI) after long-term follow-up were assessed. RESULTS: One patient died of intracerebral haemorrhage 1 year post procedurally. The New York Heart Association class, Canadian Cardiovascular Society class and exercise-induced syncopal attacks improved significantly in 26 patients (all p<0.01). Left ventricular (LV) outflow tract gradients revealed sustained reduction (resting: from 95.0 to 9.0 mm Hg, p<0.001; post exercise: from 130.5 to 21.0 mm Hg, p<0.001). The echocardiographic evaluation revealed decreased septal thickness, LV posterior wall thickness and left atrial (LA) diameter (all p<0.001). CMRI data revealed decrease in LV mass index and LA volume index and increase in LV end-diastolic volume index and stroke volume index between baseline and long-term follow-up (all p<0.05). The global longitudinal strain of LV improved from (-11.9%±3.7%) before the procedure to (-13.1%±3.9%) at the last check (p<0.001). Malignant ventricular arrhythmia and heart failure events were not observed. CONCLUSIONS: PIMSRA can effectively alleviate symptoms in patients with HOCM and improve their hemodynamics in the long term. TRIAL REGISTRATION NUMBER: NCT02888132.

Clinical phenotypic characteristics in patients carrying MYH7-R143Q mutation with hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) represents one of the most common inherited cardiac conditions, and more than 50 % have a tendency of familial aggregation. However, there is a lack of plenty pedigrees to analyze the clinical characteristics. This study collected 1023 unrelated HCM probands, conducted Sanger sequencing on whom carrying MYH7-R143Q and analyzed the clinical data. The detection rate of MYH7-R143Q was 2.54 % (26/1023). In patients with HCM carrying MYH7-R143Q, the diagnosis age is often concentrated in 31-40 years with moderate hypertrophy and fibrosis, which usually concentrate in the anterior and inferior septum of the basal and mid regions, representing moderate risk of SCD. Besides, this variant represented different genetic characteristics, including incomplete penetrance of autosomal dominant inheritance, polygenic cumulative effect and et al. It is the first time to investigate clinical phenotypes in multiple families carrying the same variant locus MYH7-R143Q, providing a theoretical basis for genetic counseling in clinical practice.

Protocol for quantitative proteomic analysis of heterogeneous adipose tissue-residing progenitor subpopulations in mice.

Recent studies have revealed cellular heterogeneity of mesenchymal stromal cells and immune cells in adipose tissue and emphasized the need for quantitative analysis of small numbers of functionally distinct cells using state-of-the-art "omics" technologies. Here, we present an optimized protocol for precise protein quantification from minute amounts of samples. We describe steps for isolation of mouse adipose progenitor cells, proteomics sample preparation, mass spectrometry measurement, and computational analysis. This protocol can be adapted to other samples with limited amounts. For complete details on the use and execution of this protocol, please refer to Shan et al. (2022).1.

Research status of elderly-care robots and safe human-robot interaction methods.

Faced with the increasingly severe global aging population with fewer children, the research, development, and application of elderly-care robots are expected to provide some technical means to solve the problems of elderly care, disability and semi-disability nursing, and rehabilitation. Elderly-care robots involve biomechanics, computer science, automatic control, ethics, and other fields of knowledge, which is one of the most challenging and most concerned research fields of robotics. Unlike other robots, elderly-care robots work for the frail elderly. There is information exchange and energy exchange between people and robots, and the safe human-robot interaction methods are the research core and key technology. The states of the art of elderly-care robots and their various nursing modes and safe interaction methods are introduced and discussed in this paper. To conclude, considering the disparity between current elderly care robots and their anticipated objectives, we offer a comprehensive overview of the critical technologies and research trends that impact and enhance the feasibility and acceptance of elderly care robots. These areas encompass the collaborative assistance of diverse assistive robots, the establishment of a novel smart home care model for elderly individuals using sensor networks, the optimization of robot design for improved flexibility, and the enhancement of robot acceptability.

Short- and long-term outcomes of laparoscopic versus open gastrectomy after neoadjuvant chemotherapy: A case-control study using a propensity score matching method.

Background: Neoadjuvant chemotherapy (NACT) is increasingly becoming the recommended treatment for locally advanced gastric cancer (LAGC) with promising results. According to previous reports, few studies have evaluated the benefits of laparoscopic gastrectomy (LG) after NACT. Methods: 135 patients from our center who underwent gastrectomy with NACT were available, including 41 patients of LG and 94 OG between July 2018 and July 2022. To reduce selection bias, we used the nearest neighbor method and set caliper = 0.2 for 3:1 matching between LG and OG groups for propensity score matching method (PSM). After PSM, the matched 41 patients with LG and 80 patients with OG formed the cohort, respectively. Univariate and multivariate Cox analyses were performed on all variables to determine independent risk factors associated with survival. Results: LG had a longer operating time compared to OG [260.00 min (220.00 min, 300.00 min) vs. 200.00 min (160.00 min, 260 min), P < 0.001]. The estimated blood loss, metastatic lymph nodes (LN), total LN examined, postoperative hospital stays, blood transfusion (P>0.05) and the incidence of postoperative complications did not show statistical differences from the OG group (P = 0.084). The type of surgery (LG vs. OG) did not show a significant risk propensity in the univariate and multivariate Cox analysis (HR = 0.69, P = 0.36, 95 % CI: 0.31-1.53). Through the Kaplan-Meier curves, a certain trend showed that the LG group had a better long-term survival outcomes than the OG group, although there was no statistical difference between two groups (P>0.05). Conclusion: LG is a promising treatment option for LAGC patients receiving NACT and had an acceptable safety and efficacy compared to OG.

SS-GNN: A Simple-Structured Graph Neural Network for Affinity Prediction.

Efficient and effective drug-target binding affinity (DTBA) prediction is a challenging task due to the limited computational resources in practical applications and is a crucial basis for drug screening. Inspired by the good representation ability of graph neural networks (GNNs), we propose a simple-structured GNN model named SS-GNN to accurately predict DTBA. By constructing a single undirected graph based on a distance threshold to represent protein-ligand interactions, the scale of the graph data is greatly reduced. Moreover, ignoring covalent bonds in the protein further reduces the computational cost of the model. The graph neural network-multilayer perceptron (GNN-MLP) module takes the latent feature extraction of atoms and edges in the graph as two mutually independent processes. We also develop an edge-based atom-pair feature aggregation method to represent complex interactions and a graph pooling-based method to predict the binding affinity of the complex. We achieve state-of-the-art prediction performance using a simple model (with only 0.6 M parameters) without introducing complicated geometric feature descriptions. SS-GNN achieves Pearson's Rp = 0.853 on the PDBbind v2016 core set, outperforming state-of-the-art GNN-based methods by 5.2%. Moreover, the simplified model structure and concise data processing procedure improve the prediction efficiency of the model. For a typical protein-ligand complex, affinity prediction takes only 0.2 ms. All codes are freely accessible at https://github.com/xianyuco/SS-GNN.

Virtual screening-molecular docking-activity evaluation of Ailanthus altissima (Mill.) swingle bark in the treatment of ulcerative colitis.

BACKGROUND: The dried bark of Ailanthus altissima (Mill.) Swingle is widely used in traditional Chinese medicine for the treatment of ulcerative colitis. The objective of this study was to explore the therapeutic basis of the dried bark of Ailanthus altissima (Mill.) Swingle for the treatment of ulcerative colitis based on Virtual Screening-Molecular Docking-Activity Evaluation technology. METHODS: By searching the Traditional Chinese Medicine Systems Pharmacology TCMSP Database and Analysis Platform, 89 compounds were obtained from the chemical components of the dried bark of Ailanthus altissima (Mill.) Swingle. Then, after preliminarily screening the compounds based on Lipinski's rule of five and other relevant conditions, the AutoDock Vina molecular docking software was used to evaluate the affinity of the compounds to ulcerative colitis-related target proteins and their binding modes through use of the scoring function to identify the best candidate compounds. Further verification of the compound's properties was achieved through in vitro experiments. RESULTS: Twenty-two compounds obtained from the secondary screening were molecularly docked with ulcerative colitis-related target proteins (IL-1R, TLR, EGFR, TGFR, and Wnt) using AutoDock Vina. The free energies of the highest scoring compounds binding to the active cavity of human IL-1R, TLR, EGFR, TGFR, and Wnt proteins were - 8.7, - 8.0, - 9.2, - 7.7, and - 8.5 kcal/mol, respectively. The potential compounds, dehydrocrebanine, ailanthone, and kaempferol, were obtained through scoring function and docking mode analysis. Furthermore, the potential compound ailanthone (1, 3, and 10 µM) was found to have no significant effect on cell proliferation, though at 10 µM it reduced the level of pro-inflammatory factors caused by lipopolysaccharide. CONCLUSION: Among the active components of the dried bark of Ailanthus altissima (Mill.) Swingle, ailanthone plays a major role in its anti-inflammatory properties. The present study shows that ailanthone has advantages in cell proliferation and in inhibiting of inflammation, but further animal research is needed to confirm its pharmaceutical potential.

Theabrownin Isolated from Pu-Erh Tea Enhances the Innate Immune and Anti-Inflammatory Effects of RAW264.7 Macrophages via the TLR2/4-Mediated Signaling Pathway.

Theabrownin (TB) is a tea pigment extracted from Pu-erh Tea. The effects of TB on innate immunity and inflammation are not well understood. Herein, the effects of TB on innate immunity are investigated using RAW264.7 macrophages. We found that TB promoted the proliferation of RAW264.7 macrophages, altered their morphology, enhanced their pinocytic and phagocytic ability, and significantly increased their secretion of nitric oxide (NO) and cytokines, all of which enhanced the immune response. Additionally, TB inhibited the release of inflammatory signals in RAW264.7 macrophages primed with lipopolysaccharide (LPS), implying that TB modulates the excessive inflammation induced by bacterial infection. A Western blot showed that TB could activate the toll-like receptor (TLR)2/4-mediated myeloid differentiation factor 88 (MyD88)-dependent mitogen activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) signaling pathway and the TLR2-mediated phosphoinositide 3-kinase (PI3K)-AKT signaling pathway, enhancing the immune functions of RAW264.7 macrophages. TB also inhibited the phosphorylation of core proteins in the MAPK/NF-κB/PI3K-AKT signaling pathway induced by LPS. In addition, we analyzed the transcriptomes of RAW264.7 macrophages, and a Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis revealed that TB modulated thetoll-like receptor signal pathway. A gene ontology (GO) enrichment analysis indicated that TB treatment strongly modulated the immune response and inflammation. As a result, TB-enhanced innate immunity and modulated inflammation via the TLR2/4 signaling pathway.

Screening of rosmarinic acid from Salvia miltiorrhizae acting on the novel target TRPC1 based on the 'homology modelling-virtual screening-molecular docking-affinity assay-activity evaluation' method.

CONTEXT: Salvia miltiorrhizae Bunge (Lamiaceae) is a traditional Chinese medicine (TCM) for the treatment of 'thoracic obstruction'. Transient receptor potential canonical channel 1 (TRPC1) is a important target for myocardial injury treatment. OBJECTIVE: This work screens the active component acting on TRPC1 from Salvia miltiorrhizae. MATERIALS AND METHODS: TCM Systems Pharmacology Database and Analysis Platform (TCMSP) was used to retrieve Salvia miltiorrhiza compounds for preliminary screening by referring to Lipinski's rule of five. Then, the compound group was comprehensively scored by AutoDock Vina based on TRPC1 protein. Surface plasmon resonance (SPR) was used to determine the affinity of the optimal compound to TRPC1 protein. Western blot assay was carried out to observe the effect of the optimal compound on TRPC1 protein expression in HL-1 cells, and Fura-2/AM detection was carried out to observe the effect of the optimal compound on calcium influx in HEK293 cells. RESULTS: Twenty compounds with relatively good characteristic parameters were determined from 202 compounds of Salvia miltiorrhiza. Rosmarinic acid (RosA) was obtained based on the molecular docking scoring function. RosA had a high binding affinity to TRPC1 protein (KD value = 1.27 µM). RosA (50 µM) could reduce the protein levels (417.1%) of TRPC1 after oxygen-glucose deprivation/reperfusion (OGD/R) in HL-1 cells and it could inhibit TRPC1-mediated Ca2+ influx injury (0.07 ΔRatio340/380) in HEK293 cells. DISCUSSION AND CONCLUSIONS: We obtained the potential active component RosA acting on TRPC1 from Salvia miltiorrhizae, and we speculate that RosA may be a promising clinical candidate for myocardial injury therapy.

Regulation of KDM5C stability and enhancer reprogramming in breast cancer.

Abnormality of enhancer regulation has emerged as one of the critical features for cancer cells. KDM5C is a histone H3K4 demethylase and frequently mutated in several types of cancer. It is critical for H3K4me3 and activity of enhancers, but its regulatory mechanisms remain elusive. Here, we identify TRIM11 as one ubiquitin E3 ligase for KDM5C. TRIM11 interacts with KDM5C, catalyzes K48-linked ubiquitin chain on KDM5C, and promotes KDM5C degradation through proteasome. TRIM11 deficiency in an animal model represses the growth of breast tumor and stabilizes KDM5C. In breast cancer patient tissues, TRIM11 is highly expressed and KDM5C is lower expressed, and their expression is negatively correlated. Mechanistically, TRIM11 regulates the enhancer activity of genes involved in cell migration and immune response by targeting KDM5C. TRIM11 and KDM5C regulate MCAM expression and cell migration through targeting H3K4me3 on MCAM enhancer. Taken together, our study reveals novel mechanisms for enhancer regulation during breast cancer tumorigenesis and development.

Adipocyte IRE1α promotes PGC1α mRNA decay and restrains adaptive thermogenesis.

Adipose tissue undergoes thermogenic remodeling in response to thermal stress and metabolic cues, playing a crucial role in regulating energy expenditure and metabolic homeostasis. Endoplasmic reticulum (ER) stress is associated with adipose dysfunction in obesity and metabolic disease. It remains unclear, however, if ER stress-signaling in adipocytes mechanistically mediates dysregulation of thermogenic fat. Here we show that inositol-requiring enzyme 1α (IRE1α), a key ER stress sensor and signal transducer, acts in both white and beige adipocytes to impede beige fat activation. Ablation of adipocyte IRE1α promotes browning/beiging of subcutaneous white adipose tissue following cold exposure or ß3-adrenergic stimulation. Loss of IRE1α alleviates diet-induced obesity and augments the anti-obesity effect of pharmacologic ß3-adrenergic stimulation. Notably, IRE1α suppresses stimulated lipolysis and degrades Ppargc1a messenger RNA through its RNase activity to downregulate the thermogenic gene program. Hence, blocking IRE1α bears therapeutic potential in unlocking adipocytes' thermogenic capacity to combat obesity and metabolic disorders.

Distinct functional properties of murine perinatal and adult adipose progenitor subpopulations.

Adult white adipose tissue (WAT) harbors distinct mesenchymal stromal cell subpopulations that differentially affect WAT function and plasticity. Here we unveil the cellular landscape of the perinatal epididymal WAT primordium using single-cell transcriptomics in male mice. We reveal that adipocyte precursor cells and fibro-inflammatory progenitors (FIPs) emerge as functionally distinct PDGFRß+ subpopulations within the epididymal WAT anlagen prior to adipocyte accrual. We further identify important molecular and functional differences between perinatal and adult FIPs, including differences in their pro-inflammatory response, adipogenic capacity and anti-adipogenic behavior. Notably, we find that transient overexpression of Pparg in PDGFRß+ cells only during postnatal days 0.5 to 7.5 in male mice leads to hyperplastic WAT development, durable progenitor cell reprogramming, and protection against pathologic WAT remodeling and glucose intolerance in adult-onset obesity. Thus, factors that alter the adipogenic capacity of perinatal adipose progenitors can have long-lasting effects on progenitor plasticity, tissue expandability and metabolic health into adulthood.