IRG1/ACOD1 Promotes Neutrophil Reverse Migration and Alleviates Local Inflammation.

Polymorphonuclear neutrophil (PMN) infiltration at inflammatory site plays a critical role in inflammation. PMN reverse migration (rM) describes the phenomenon that PMNs migrate away from inflammatory site back into the vasculature, and its role within inflammatory scenarios remains to be fully determined. This study aimed to investigate the mechanism underlying PMN rM and its role in inflammation. First, we demonstrated PMN rM in a mouse model of LPS-induced acute lung inflammation. By single-cell RNA sequencing (scRNA-seq), we demonstrated that reverse migrated (rM-ed) PMNs in blood expressed high level of immuneresponsive gene 1 (Irg1), the encoding gene of cis-aconitate decarboxylase (ACOD1). Using a mouse air pouch model, which enables us to directly track rM-ed PMNs in vivo, we detected higher expression of ACOD1 in the rM-ed PMNs in circulation. Furthermore, mice with Irg1 knockout exhibited decreased PMN rM and higher levels of inflammatory cytokine in inflammatory site. Mechanistically, we found that itaconate, the product of ACOD1 catalyzation, decreased PMN ICAM-1 expression at the inflammation site. Furthermore, inflammatory site showed a high level of shed CD11a, the ligand of ICAM-1. Neutralization of either ICAM-1 or CD11a leading to increased PMN rM. These findings suggest that the binding of ICAM-1 and shed CD11a serves as a retaining force to hold PMNs in the site of inflammation, and ACOD1-decreased PMN surface expression of ICAM-1 weakens the retaining force, so promoting PMNs to leave the inflammatory site. These results indicate a regulatory role of IRG1 in PMN rM and subsequent contributions to inflammation resolution.

A new three-dimensional (3D) molecularly imprinted polymer fluoroprobe based on green-red dual-emission signals of carbon quantum dots and self-polymerization of dopamine (CDs@PDA-MIPs) for sensitive detection of nifedipine.

Nifedipine (NIF), as one of the dihydropyridine calcium channel blockers, is widely used in the treatment of hypertension. However, misuse or ingestion of NIF can result in serious health issues such as myocardial infarction, arrhythmia, stroke, and even death. It is essential to design a reliable and sensitive detection method to monitor NIF. In this work, an innovative molecularly imprinted polymer dual-emission fluorescent sensor (CDs@PDA-MIPs) strategy was successfully designed for sensitive detection of NIF. The fluorescent intensity of the probe decreased with increasing NIF concentration, showing a satisfactory linear relationship within the range 1.0 × 10-6 M ~ 5.0 × 10-3 M. The LOD of NIF was 9.38 × 10-7 M (S/N = 3) in fluorescence detection. The application of the CDs@PDA-MIPs in actual samples such as urine and Qiangli Dingxuan tablets has been verified, with recovery ranging from 97.8 to 102.8% for NIF. Therefore, the fluorescent probe demonstrates great potential as a sensing system for detecting NIF.

Elderly patients with advanced HER2-positive breast cancer with liver metastases benefit from low dose disitamab vedotin (RC48): case series and literature review.

Currently, although some antibody-drug conjugates have been shown to be safe and effective in the treatment of drug-resistant relapsed human epidermal growth factor receptor 2 (HER2)-positive (IHC 3+ or IHC 2+/fluorescence in situ hybridization+) breast cancer, they are already approved for clinical use in China. But the clinical needs of advanced HER2-positive patients cannot be met due to adverse reactions, drug resistance, drug accessibility and other problems, thus affecting the prognosis of patients. In particular, the representation of elderly and frail patients in randomized clinical trials is significantly under-represented. We report on two elderly women with breast cancer who developed recurrent metastatic lesions after breast cancer surgery and were again confirmed HER2-positive by histopathology and immunohistochemistry. They all developed multiple metastases in the liver after second- or third-line anti-HER2 therapy. Subsequent treatment with RC48 produced good responses and tolerable adverse reactions. One patient obtained progression-free survival for more than 7 months. Based on preliminary evidence, this study shows that RC48 in HER2-positive breast cancer with liver metastases can achieve rapid remission, thereby reducing tumor load and improving patients' quality of life. In particular, RC48 has low side effects and can be well tolerated by elderly patients after dose adjustment, providing them with treatment opportunities. It needs to be further discussed in the future research.

Sex-specific and cell-specific regulation of ER stress and neuroinflammation after traumatic brain injury in juvenile mice.

Endoplasmic reticulum (ER) stress and neuroinflammation play an important role in secondary brain damage after traumatic brain injury (TBI). Due to the complex brain cytoarchitecture, multiple cell types are affected by TBI. However, cell type-specific and sex-specific responses to ER stress and neuroinflammation remain unclear. Here we investigated differential regulation of ER stress and neuroinflammatory pathways in neurons and microglia during the acute phase post-injury in a mouse model of impact acceleration TBI in both males and females. We found that TBI resulted in significant weight loss only in males, and sensorimotor impairment and depressive-like behaviors in both males and females at the acute phase post-injury. By concurrently isolating neurons and microglia from the same brain sample of the same animal, we were able to evaluate the simultaneous responses in neurons and microglia towards ER stress and neuroinflammation in both males and females. We discovered that the ER stress and anti-inflammatory responses were significantly stronger in microglia, especially in female microglia, compared with the male and female neurons. Whereas the degree of phosphorylated-tau (pTau) accumulation was significantly higher in neurons, compared with the microglia. In conclusion, TBI resulted in behavioral deficits and cell type-specific and sex-specific responses to ER stress and neuroinflammation, and abnormal protein accumulation at the acute phase after TBI in immature mice.

Tumor or demyelination? Three tumefactive multiple sclerosis case reports and literature review.

OBJECTIVE: To investigate the clinical diagnosis and treatment of tumefactive multiple sclerosis (TMS). METHODS: Clinical data, laboratory and imaging examinations, and treatment of three patients with TMS were retrospectively analyzed. Data were further analyzed in relation to the literature. RESULTS: All three patients had acute or subacute onset with large lesions on imaging, which were difficult to differentiate from tumors. Two cases had relapses on follow-up and one case had a stereotactic biopsy. CONCLUSION: TMS is difficult to differentiate from brain tumors. It is necessary to improve the understanding of these diseases, to apply the correct diagnosis and treatment and to avoid unnecessary invasive surgery and inappropriate treatment.

Genome-wide identification and characterization of the sweet orange (Citrus sinensis) basic helix-loop-helix (bHLH) family reveals a role for CsbHLH085 as a regulator of citrus bacterial canker resistance.

Citrus bacterial canker (CBC) is a harmful bacterial disease caused by Xanthomonas citri subsp. citri (Xcc), negatively impacting citrus production worldwide. The basic helix-loop-helix (bHLH) transcription factor family plays crucial roles in plant development and stress responses. This study aimed to identify and annotate bHLH proteins encoded in the Citrus sinensis genome and explore their involvement and functional importance in regulating CBC resistance. A total of 135 putative CsbHLHs TFs were identified and categorized into 16 subfamilies. Their chromosomal locations, collinearity, and phylogenetic relationships were comprehensively analyzed. Upon Xcc strain YN1 infection, certain CsbHLHs were differentially regulated in CBC-resistant and CBC-sensitive citrus varieties. Among these, CsbHLH085 was selected for further functional characterization. CsbHLH085 was upregulated in the CBC-resistant citrus variety, was localized in the nucleus, and had a transcriptional activation activity. CsbHLH085 overexpression in Citrus significantly enhanced CBC resistance, accompanied by increased levels of salicylic acid (SA), jasmonic acid (JA), reactive oxygen species (ROS), and decreased levels of abscisic acid (ABA) and antioxidant enzymes. Conversely, CsbHLH085 virus-induced gene silencing resulted in opposite phenotypic and biochemical responses. CsbHLH085 silencing also affected the expression of phytohormone biosynthesis and signaling genes involved in SA, JA, and ABA signaling. These findings highlight the crucial role of CsbHLH085 in regulating CBC resistance, suggesting its potential as a target for biotechnological-assisted breeding citrus varieties with improved resistance against phytopathogens.

Highly Thermally Conductive Flexible Biomimetic APTES-BNNS/BC Nanocomposite Paper by Sol-Gel-Film Technology.

Owing to the evolution of 5G technology, new energy vehicles, flexible electronics, miniaturization and integration of microelectronic devices, high-frequency and high-power devices, and thermal management of materials must consider additional limitations such as electrical insulation, excellent transverse heat transfer, flexibility, and weight. Boron nitride nanosheets (BNNSs) are ideal insulating materials with high thermal conductivity. However, the problem of the 3D thermal conductivity pathway and toughness strength of nanocomposite paper loaded with inorganic thermal conductivity fillers remains a huge challenge. In this study, we propose a new method for preparing ultrathin, large, and uniformly thick BNNS for quantitative production. Bulk hexagonal boron nitride (hBN) layers were exfoliated using a simple and low-cost hydrothermal reaction, and large-scale fewer-layered BNNSs were efficiently prepared by ball milling with a high yield (up to 80%). Based on the aforementioned step, a flexible insulating composite film with high thermal conductivity and a natural "brick-mud" shell structure was constructed via the sol-gel-film conversion method. After prestretching and hot-pressing treatment, the hydrogels became denser, and the modified BNNS formed a three-dimensional (3D) network structure with an ordered orientation and interconnections in the bacterial cellulose (BC) matrix. After 100 folding cycles, the tensile strength of the nanofiber composite film reached 53 MPa, and the strength retention rate exceeded 42%. By optimizing the modified BNNS content, the thermal conductivity reached 24 W/(m·K). This simple approach has wide application potential in the next-generation electronic devices, providing options for designing thermal interface materials with excellent electrical insulation, high thermal stability, and flexibility.

Exosomal mediators in sepsis and inflammatory organ injury: unraveling the role of exosomes in intercellular crosstalk and organ dysfunction.

Sepsis, a severe systemic inflammatory response to infection, remains a leading cause of morbidity and mortality worldwide. Exosomes, as mediators of intercellular communication, play a pivotal role in the pathogenesis of sepsis through modulating immune responses, metabolic reprogramming, coagulopathy, and organ dysfunction. This review highlights the emerging significance of exosomes in these processes. Initially, it provides an in-depth insight into exosome biogenesis and characterization, laying the groundwork for understanding their diverse and intricate functions. Subsequently, it explores the regulatory roles of exosomes in various immune cells such as neutrophils, macrophages, dendritic cells, T cells, and B cells. This analysis elucidates how exosomes are pivotal in modulating immune responses, thus contributing to the complexity of sepsis pathophysiology. Additionally, this review delves into the role of exosomes in the regulation of metabolism and subsequent organ dysfunction in sepsis. It also establishes a connection between exosomes and the coagulation cascade, which affects endothelial integrity and promotes thrombogenesis in sepsis. Moreover, the review discusses the dual role of exosomes in the progression and resolution of sepsis, exploring their complex involvement in inflammation and healing processes. Furthermore, it underscores their potential as biomarkers and therapeutic targets. Understanding these mechanisms presents new opportunities for novel interventions to mitigate the severe outcomes of sepsis, emphasizing the therapeutic promise of exosome research in critical care settings.

Structural and resting-state connection abnormalities of habenula in obsessive-compulsive disorder.

BACKGROUND: Previous studies have suggested that the habenula (Hb) may be involved in the mechanism of obsessive-compulsive disorder (OCD). However, the specific role of Hb in OCD remains unclear. This study aimed to explore the structural and functional abnormalities of Hb in OCD and their relationship with the clinical symptoms. METHODS: Eighty patients with OCD and 85 healthy controls (HCs) were recruited as the primary dataset. The grey matter volume, resting-state functional connectivity (FC), and effective connectivity (EC) of the Hb were calculated and compared between OCD group and HCs. An independent replication dataset was used to verify the stability and robustness of the results. RESULTS: Patients with OCD exhibited smaller Hb volume and increased FC of right Hb-left hippocampus than HCs. Dynamic causal model revealed an increased EC from left hippocampus to right Hb and a less inhibitory causal influence from the right Hb to left hippocampus in the OCD group compared to HCs. Similar results were found in the replication dataset. CONCLUSIONS: This study suggested that abnormal structure of Hb and hippocampus-Hb connectivity may contribute to the pathological basis of OCD.

Asymmetrical positioning of cell organelles reflects the cell chirality of mouse myoblast cells.

Cell chirality is crucial for the chiral morphogenesis of biological tissues, yet its underlying mechanism remains unclear. Cell organelle polarization along multiple axes in a cell body, namely, apical-basal, front-rear, and left-right, is known to direct cell behavior such as orientation, rotation, and migration. Among these axes, the left-right bias holds significant sway in determining the chiral directionality of these behaviors. Normally, mouse myoblast (C2C12) cells exhibit a strong counterclockwise chirality on a ring-shaped micropattern, whereas they display a clockwise dominant chirality under Latrunculin A treatment. To investigate the relationship between multicellular chirality and organelle positioning in single cells, we studied the left-right positioning of cell organelles under distinct cell chirality in single cells via micropatterning technique, fluorescent microscopy, and imaging analysis. We found that on a "T"-shaped micropattern, a C2C12 cell adopts a triangular shape, with its nucleus-centrosome axis pointing toward the top-right direction of the "T." Several other organelles, including the Golgi apparatus, lysosomes, actin filaments, and microtubules, showed a preference to polarize on one side of the axis, indicating the universality of the left-right asymmetrical organelle positioning. Interestingly, upon reversing cell chirality with Latrunculin A, the organelles correspondingly reversed their left-right positioning bias, as suggested by the consistently biased metabolism and contractile properties at the leading edge. This left-right asymmetry in organelle positioning may help predict cell migration direction and serve as a potential marker for identifying cell chirality in biological models.

Impurities in Polymer-Lined Autoclaves Affect Zeolite Synthesis and Si Incorporation Behavior.

Polymer-lined autoclaves are commonly believed to be highly durable and inert in hydrothermal reactions. Herein, we use the hydrothermal synthesis of AlPO-18 zeolite as a case study to demonstrate that the choice of autoclave materials (polytetrafluoroethylene or para-polyphenylene) does significantly affect the product of zeolite synthesis. A small amount of glass fiber in the PPL-lined autoclave unexpectedly functions as a source of silicon and yields SAPO-34 instead of AlPO-18 as the product. The outcomes of 19 successive experiments conducted with a single PPL-lined autoclave exhibit significant variations, further highlighting that the impurities arising from the autoclaves should be considered during the hydrothermal synthesis procedure. In contrast to SAPO-34 synthesized by the conventional method, which displays only Si(4Al) at a low Si/Al ratio, SAPO-34 synthesized in the PPL-lined autoclave exhibits multiple silicon coordination environments. This outcome provides new physical insights into the silicon incorporation mechanism and proposes a viable strategy for regulating the silicon coordination environment at low Si/Al ratios.

Allelochemicals-mediated interaction between algae and bacteria: Direct and indirect contact.

Secondary metabolites with bioactivity are allelochemicals. This study adopted direct contact (R0) and indirect contact (separated by 0.45 µm membrane, R1-A for algae, R1-S for sludge) to reveal the role of metabolites especially allelochemicals on interaction of bacteria and algae. Direct contact exhibited better nutrients removal than indirect contact, due to less antibacterial allelochemicals and oxidative stress. Bacterial signaling molecules were not detected. The major algae-derived allelochemicals were 13-Docosenamide, 9-Octadecenamide, n-Hexadecanoic acid, erucic acid, octadecanoic acid, ß-sitosterol, and E,E,Z-1,3,12-Nonadecatriene-5,14-diol. Furthermore, presence of 13-Docosenamide and 9-Octadecenamide was associated with succession of Flavobacterium and suppression of nitrifying bacteria (Nitrosomonas, Ellin6067, and Nitrospira). Direct contact stimulated denitrifying bacteria Saccharimonadales and algae Scenedesmus, whereas indirect contact is friendly to Dechloromonas, Competibacter, nitrifying bacteria, algae Desmodesmus and Dictyosphaerium. This study highlights the essentiality of cell contact of bacteria-algae in establishing synergy, as cell contact mitigates antagonistic effect induced by metabolites.

Personality and cognition: shoal size discrimination performance is related to boldness and sociability among ten freshwater fish species.

Several studies have reported that animals' personalities are often correlated with individual differences in cognition. Here, we tested whether personality is related to cognition across species, focusing on 10 freshwater fishes and a task relevant for fitness, the ability to discriminate shoal size. Bolder species exhibited more 'shuttle' behavior for information sampling during shoal selection and showed high performance (HP) in the numerical discrimination than shyer species, i.e., low performance (LP) species. Species at both the high and low ends of sociability showed LP, possibly due to loosened selection pressure because of either no need to perform shoal size discrimination tasks frequently in nature for very high sociability species or decreased willingness and motivation to join and stay within shoals for very low sociability species. Notably, the numerical discrimination was sensitive to the numerical contrast ratio in LP species but not in HP species, suggesting that the numerical system used for size discrimination also varied between species. Overall, we demonstrated the interspecies relationship between personality and shoal size discrimination across fish species, suggesting an evolutionary link between numerical abilities and behavior.

Development of a multiplex reverse transcription-quantitative PCR (qPCR) method for detecting common causative agents of swine viral diarrhea in China.

BACKGROUND: Diarrheal diseases caused by viral agents have led to a great morbidity, mortality, and economic loss in global pig industry. Porcine epidemic diarrhea virus (PEDV), transmissible gastroenteritis virus (TGEV), porcine deltacoronavirus (PDCoV), and group A porcine rotavirus (RVA) are main causative agents of swine viral diarrhea with similar clinical signs on Chinese farms and their co-infection is also common. However, it is still lack of a convenient method to detect these four agents. METHODS: A TaqMan multiplex qPCR method was developed to detect PEDV, TGEV, PDCoV, and RVA, simultaneously. This method was then applied to investigate 7,342 swine fecal samples or rectal swabs, as well as 1,246 swine intestinal samples collected from 2075 farms in China in 2022. RESULTS: Minimum detection limits of this method were 3 copies/µL for PEDV, 4 copies/µL for TGEV, 8 copies/µL for RVA, and 8 copies/µL for PDCoV, suggesting a good sensitivity. No signals were observed by using this method detecting other viral agents commonly prevalent in pigs, which is suggestive of a good specificity. Application of this method on investigating clinical samples demonstrated a relatively high positive rate for PEDV (22.21%, 1907/8588) and RVA (44.00%, 3779/8588). In addition, co-infection between PEDV and RVA was observed on 360 investigated farms, accounting for 17.35% (360/2075) of the farms where co-infection events were screened. CONCLUSIONS: A TaqMan multiplex qPCR method targeting PEDV, TGEV, PDCoV, and RVA was developed in this study. This method demonstrated a good specificity and sensitivity on investigating these four common viruses responsible for viral diarrhea on Chinese pig farms, which represents a convenient method for the monitoring and differential diagnosis of swine viral diarrhea.

Effect of supervised exercise training on cardiovascular function in patients with intermittent claudication: a systematic review and meta-analysis of randomized controlled trials.

This study aimed to determine the effect of supervised exercise training (SET) on cardiovascular function in patients with intermittent claudication (IC). A systematic search in MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases was conducted. Primary outcomes were systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), rate pressure product (RPP), cardiac output (CO), peak oxygen consumption (VO2peak), and heart rate variability (HRV). Secondary outcomes were maximum walking distance (MWD) and pain-free walking distance (PFWD). Outcomes were reported as weighted mean difference (WMD) between the SET group and the control group and synthesized by using the random-effects model. Seventeen RCTs with a total of 936 patients were included in this review. SET resulted in significant improvements of SBP (WMD = - 7.40, 95% CI - 10.69 ~ - 4.11, p < 0.001, I2 = 15.2%), DBP (WMD = - 1.92, 95% CI - 3.82 ~ - 0.02, p = 0.048, I2 = 0.0%), HR (WMD = - 3.38, 95% CI - 6.30 ~ - 0.46, p = 0.023, I2 = 0.0%), RPP (WMD = - 1072.82, 95% CI - 1977.05 ~ - 168.59, p = 0.020, I2 = 42.7%), and VO2peak with plantar flexion ergometer exercise (WMD = 5.57, 95% CI 1.66 ~ 9.49, p = 0.005, I2 = 62.4%), whereas CO and HRV remained statistically unaltered. SET also improved MWD (WMD = 139.04, 95% CI 48.64 ~ 229.44, p = 0.003, I2 = 79.3%) and PFWD (WMD = 40.02, 95% CI 23.85 ~ 56.18, p < 0.001, I2 = 0.0%). In conclusion, SET is effective in improving cardiovascular function in patients with IC, which was confirmed on outcomes of cardiovascular function associated with exercise ability. The findings hold out that the standard therapy of SET can improve not only walking distance but also cardiovascular function in patients with IC.

Genome-Wide Identification and Characterization of the Sweet Orange (Citrus sinensis) GATA Family Reveals a Role for CsGATA12 as a Regulator of Citrus Bacterial Canker Resistance.

Citrus bacterial canker (CBC) is a severe bacterial infection caused by Xanthomonas citri subsp. citri (Xcc), which continues to adversely impact citrus production worldwide. Members of the GATA family are important regulators of plant development and regulate plant responses to particular stressors. This report aimed to systematically elucidate the Citrus sinensis genome to identify and annotate genes that encode GATAs and evaluate the functional importance of these CsGATAs as regulators of CBC resistance. In total, 24 CsGATAs were identified and classified into four subfamilies. Furthermore, the phylogenetic relationships, chromosomal locations, collinear relationships, gene structures, and conserved domains for each of these GATA family members were also evaluated. It was observed that Xcc infection induced some CsGATAs, among which CsGATA12 was chosen for further functional validation. CsGATA12 was found to be localized in the nucleus and was differentially upregulated in the CBC-resistant and CBC-sensitive Kumquat and Wanjincheng citrus varieties. When transiently overexpressed, CsGATA12 significantly reduced CBC resistance with a corresponding increase in abscisic acid, jasmonic acid, and antioxidant enzyme levels. These alterations were consistent with lower levels of salicylic acid, ethylene, and reactive oxygen species. Moreover, the bacteria-induced CsGATA12 gene silencing yielded the opposite phenotypic outcomes. This investigation highlights the important role of CsGATA12 in regulating CBC resistance, underscoring its potential utility as a target for breeding citrus varieties with superior phytopathogen resistance.

Variation and disparity in awareness of atrial fibrillation in China: A national cross-sectional study.

BACKGROUND: The latest information regarding the awareness of atrial fibrillation (AF) remains limited in China. OBJECTIVES: The present study aimed to understand the variation and disparity in awareness of AF in China. METHODS: The cross-sectional study used data from the 2020 nationwide epidemiology survey on AF among adults aged 18 years or older in mainland China to assess the prevalence of AF awareness. The awareness of AF diagnostic methods and outcomes was also assessed using an interviewer-administered questionnaire. RESULTS: Of the 114,039 adults responding to the survey, 1463 (age-standardized prevalence, 55.3% (95% confidence interval [CI], 47.7-62.9%) and 10,202 (8.2%, 95%CI 5.4-10.9%) were aware of AF in participants with and without AF, respectively. Of these, 36.4% (95%CI 30.0-42.9%) and 6.3% (95%CI 3.6-9.1%) considered electrocardiogram as a method of diagnosing AF, and 30.0% (95% CI 3.2-8.2%) and 5.2% (95%CI 2.7-7.6%) considered stroke as an outcome of AF. The proportion of participants who being aware of AF varied significantly across sociodemographic and cardiovascular disease subgroups, and was almost consistently lower in rural areas than those in urban areas. Overall, lack of AF awareness was associated with rural areas, geographical region, lower education levels, and without history and had no risk factors of cardiovascular disease. CONCLUSIONS: Nearly half of adults with AF, and >90% non-AF population are unaware of AF in China, with significant variation and disparity. Focused public health initiatives are needed to improve awareness and knowledge of AF among high-risk populations.

CD8+ T cells sustain antitumor response by mediating crosstalk between adenosine A2A receptor and glutathione/GPX4.

Antitumor responses of CD8+ T cells are tightly regulated by distinct metabolic fitness. High levels of glutathione (GSH) are observed in the majority of tumors, contributing to cancer progression and treatment resistance in part by preventing glutathione peroxidase 4-dependent (GPX4-dependent) ferroptosis. Here, we show the necessity of adenosine A2A receptor (A2AR) signaling and the GSH/GPX4 axis in orchestrating metabolic fitness and survival of functionally competent CD8+ T cells. Activated CD8+ T cells treated ex vivo with simultaneous inhibition of A2AR and lipid peroxidation acquire a superior capacity to proliferate and persist in vivo, demonstrating a translatable means to prevent ferroptosis in adoptive cell therapy. Additionally, we identify a particular cluster of intratumoral CD8+ T cells expressing a putative gene signature of GSH metabolism (GMGS) in association with clinical response and survival across several human cancers. Our study addresses a key role of GSH/GPX4 and adenosinergic pathways in fine-tuning the metabolic fitness of antitumor CD8+ T cells.

Pharmacological and mechanistic aspects of quercetin in osteoporosis.

Osteoporosis (OP) is a bone disease associated with increasing age. Currently, the most common medications used to treat OP are anabolic agents, anti-resorptive agents, and medications with other mechanisms of action. However, many of these medications have unfavorable adverse effects or are not intended for long-term use, potentially exerting a severe negative impact on a patient's life and career and placing a heavy burden on families and society. There is an urgent need to find new drugs that can replace these and have fewer adverse effects. Quercetin (Que) is a common flavonol in nature. Numerous studies have examined the therapeutic applications of Que. However, a comprehensive review of the anti-osteoporotic effects of Que has not yet been conducted. This review aimed to describe the recent studies on the anti-osteoporotic effects of Que, including its biological, pharmacological, pharmacokinetic, and toxicological properties. The outcomes demonstrated that Que could enhance OP by increasing osteoblast differentiation and activity and reducing osteoclast differentiation and activity via the pathways of Wnt/ß-catenin, BMP/SMAD/RUNX2, OPG/RANKL/RANK, ERK/JNK, oxidative stress, apoptosis, and transcription factors. Thus, Que is a promising novel drug for the treatment of OP.

ARRDC3 regulates the targeted therapy sensitivity of clear cell renal cell carcinoma by promoting AXL degradation.

AXL plays crucial roles in the tumorigenesis, progression, and drug resistance of neoplasms; however, the mechanisms associated with AXL overexpression in tumors remain largely unknown. In this study, to investigate these molecular mechanisms, wildtype and mutant proteins of arrestin domain-containing protein 3 (ARRDC3) and AXL were expressed, and co-immunoprecipitation analyses were performed. ARRDC3-deficient cells generated using the CRISPR-Cas9 system were treated with different concentrations of the tyrosine kinase inhibitor sunitinib and subjected to cell biological, molecular, and pharmacological experiments. Furthermore, immunohistochemistry was used to analyze the correlation between ARRDC3 and AXL protein expressions in renal cancer tissue specimens. The experimental results demonstrated that ARRDC3 interacts with AXL to promote AXL ubiquitination and degradation, followed by the negative regulation of downstream signaling mechanisms, including the phosphorylation of protein kinase B and extracellular signal-regulated kinase. Notably, ARRDC3 deficiency decreased the sunitinib sensitivity of clear cell renal cell carcinoma (ccRCC) cells in a manner dependent on the regulation of AXL stability. Overall, our results suggest that ARRDC3 is a negative regulator of AXL and can serve as a novel predictor of sunitinib therapeutic response in patients with ccRCC.