A novel RIPK1 inhibitor reduces GVHD in mice via a nonimmunosuppressive mechanism that restores intestinal homeostasis.

Intestinal epithelial cells (IECs) are implicated in the propagation of T-cell-mediated inflammatory diseases, including graft-versus-host disease (GVHD), but the underlying mechanism remains poorly defined. Here, we report that IECs require receptor-interacting protein kinase-3 (RIPK3) to drive both gastrointestinal (GI) tract and systemic GVHD after allogeneic hematopoietic stem cell transplantation. Selectively inhibiting RIPK3 in IECs markedly reduces GVHD in murine intestine and liver. IEC RIPK3 cooperates with RIPK1 to trigger mixed lineage kinase domain-like protein-independent production of T-cell-recruiting chemokines and major histocompatibility complex (MHC) class II molecules, which amplify and sustain alloreactive T-cell responses. Alloreactive T-cell-produced interferon gamma enhances this RIPK1/RIPK3 action in IECs through a JAK/STAT1-dependent mechanism, creating a feed-forward inflammatory cascade. RIPK1/RIPK3 forms a complex with JAK1 to promote STAT1 activation in IECs. The RIPK1/RIPK3-mediated inflammatory cascade of alloreactive T-cell responses results in intestinal tissue damage, converting the local inflammation into a systemic syndrome. Human patients with severe GVHD showed highly activated RIPK1 in the colon epithelium. Finally, we discover a selective and potent RIPK1 inhibitor (Zharp1-211) that significantly reduces JAK/STAT1-mediated expression of chemokines and MHC class II molecules in IECs, restores intestinal homeostasis, and arrests GVHD without compromising the graft-versus-leukemia (GVL) effect. Thus, targeting RIPK1/RIPK3 in IECs represents an effective nonimmunosuppressive strategy for GVHD treatment and potentially for other diseases involving GI tract inflammation.

Vitamin C promotes ACE2 degradation and protects against SARS-CoV-2 infection.

ACE2 is a major receptor for cellular entry of SARS-CoV-2. Despite advances in targeting ACE2 to inhibit SARS-CoV-2 binding, strategies to flexibly and sufficiently reduce ACE2 levels for the prevention of SARS-CoV-2 infection have not been explored. Here, we reveal vitamin C (VitC) administration as a potent strategy to prevent SARS-CoV-2 infection. VitC reduces ACE2 protein levels in a dose-dependent manner, while even a partial reduction in ACE2 levels can greatly inhibit SARS-CoV-2 infection. Further studies reveal that USP50 is a crucial regulator of ACE2 levels. VitC blocks the USP50-ACE2 interaction, thus promoting K48-linked polyubiquitination of ACE2 at Lys788 and subsequent degradation of ACE2 without affecting its transcriptional expression. Importantly, VitC administration reduces host ACE2 levels and greatly blocks SARS-CoV-2 infection in mice. This study reveals that ACE2 protein levels are down-regulated by an essential nutrient, VitC, thereby enhancing protection against infection of SARS-CoV-2 and its variants.

Rational Manipulation of Active CNT Encapsulated Fe Doped NiCoP Nanoparticles In Situ Grown in Hierarchically Carbonized Wood for High-Current-Density Water Splitting.

Precise morphology design and electronic structure regulation are critically significant to promote catalytic activity and stability for electrochemical hydrogen production at high current density. Herein, the carbon nanotube (CNT) encapsulated Fe-doped NiCoP nanoparticles is in-situ grown in hierarchical carbonized wood (NCF0.5 P@CNT/CW) for water splitting. Coupling merits of porous carbonized wood (CW) substrate, CNT encapsulating and Fe doping, the NCF0.5 P@CNT/CW features remarkable and durable electrocatalytic activity. The overpotentials of NCF0.5 P@CNT/CW at 50 mA cm-2 mV and 205 mV for oxygen evolution reaction (OER) and hydrogen evolution reaction (HER) and features high current density of 800 mA cm-2 within 300 mV for both OER and HER. Moreover, NCF0.5 P@CNT/CW displays outstanding overall water splitting performance (η50 = 1.62 V and η100 = 1.67 V), outperforming Pt/C║RuO2 (η50 = 1.74 V), and can achieve the current density of 700 mA cm-2 at a lower cell voltage of 1.78 V. Overpotential is only 4.0 % decay after 120 h measurement at 50 mA cm-2 . Density functional theory (DFT) calculations reveals Fe doping optimizes the binding energy and Gibbs free energy of intermediates, and regulates d-band center of NCF0.5 P@CNT/CW. Such synergistic strategy of morphology manipulation and electronic structure optimization provides a spark for developing effective and robust bifunctional catalysts.

E3 ubiquitin ligase RNF128 negatively regulates the IL-3/STAT5 signaling pathway by facilitating K27-linked polyubiquitination of IL-3Rα.

IL-3/STAT5 signaling pathway is crucial for the development and activation of immune cells, contributing to the cellular response to infections and inflammatory stimuli. Dysregulation of the IL-3/STAT5 signaling have been associated with inflammatory and autoimmune diseases characterized by inflammatory cell infiltration and organ damage. IL-3 receptor α (IL-3Rα) specifically binds to IL-3 and initiates intracellular signaling, resulting in the phosphorylation of STAT5. However, the regulatory mechanisms of IL-3Rα remain unclear. Here, we identified the E3 ubiquitin ligase RNF128 as a negative regulator of IL-3/STAT5 signaling by targeting IL-3Rα for lysosomal degradation. RNF128 was shown to selectively bind to IL-3Rα, without interacting with the common beta chain IL-3Rß, which shares the subunit with GM-CSF. The deficiency of Rnf128 had no effect on GM-CSF-induced phosphorylation of Stat5, but it resulted in heightened Il-3-triggered activation of Stat5 and increased transcription of the Id1, Pim1, and Cd69 genes. Furthermore, we found that RNF128 promoted the K27-linked polyubiquitination of IL-3Rα in a ligase activity-dependent manner, ultimately facilitating its degradation through the lysosomal pathway. RNF128 inhibited the activation and chemotaxis of macrophages in response to LPS stimulation, thereby attenuating excessive inflammatory responses. Collectively, these results reveal that RNF128 negatively regulates the IL-3/STAT5 signaling pathway by facilitating K27-linked polyubiquitination of IL-3Rα. This study uncovers E3 ubiquitin ligase RNF128 as a novel regulator of the IL-3/STAT5 signaling pathway, providing potential molecular targets for the treatment of inflammatory diseases.

Association between dietary folate intake and severe headache among adults in the USA: a cross-sectional survey.

Folate, also known as vitamin B9, is a water-soluble vitamin. Previous studies on dietary folate intake in severe headache patients were equivocal. Therefore, we conducted a cross-sectional study to elucidate the relationship between folate intake and severe headache. This cross-sectional study used data from participants over 20 years old who participated in the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2004. The diagnosis of severe headache was made through participants' self-report in the NHANES questionnaire section. We performed multivariate logistic regression and restricted cubic spline (RCS) regression to explore the relationship between folate intake and severe headache. A total of 9859 participants took part in the study, 1965 of whom were severe headache patients and the rest were non-severe headache. We found that dietary folate intake was significantly and inversely associated with severe headache. Compared with participants with lower folate intake Q1 (≤ 229·97 ug/d), the adjusted OR values for dietary folate intake and severe headache in Q2 (229·98-337 ug/d), Q3 (337·01-485 ug/d) and Q4 (≥ 485·01 ug/d) were 0·81 (95 % CI: 0·67, 0·98, P = 0·03), 0·93 (95 % CI: 0·77, 1·12, P = 0·41) and 0·63 (95 % CI: 0·49, 0·80, P < 0·001), respectively. For women aged 20-50 years, there was a non-linear association between folate intake and severe headache in the RCS. Women aged 20-50 years should have higher awareness of dietary folate and increase their dietary intake of folate, which may aid in preventing severe headache.

Genetic analysis of a family affected by congenital myasthenic syndrome due to a Novel mutation in the SLC5A7 gene.

BACKGROUND: Mutations in the SLC5A7 gene cause congenital myasthenia, a rare genetic disorder. Mutation points in the SLC5A7 gene differ among individuals and encompass various genetic variations; however, exon deletion variants have yet to be reported in related cases. This study aims to explore the clinical phenotype and genetic traits of a patient with congenital myasthenic syndrome due to SLC5A7 gene variation and those of their family members. CASE PRESENTATION: We describe a case of a Chinese male with congenital myasthenic syndrome presenting fluctuating limb weakness. Genetic testing revealed a heterozygous deletion mutation spanning exons 1-9 in the SLC5A7 gene. QPCR confirmed a deletion in exon 9 of the SLC5A7 gene in the patient's mother and brother. Clinical symptoms of myasthenia improved following treatment with pyridostigmine. CONCLUSION: Exons 1, 5, and 9 of the SLC5A7 gene encode the choline transporter's transmembrane region. Mutations in these exons can impact the stability and plasma membrane levels of the choline transporter. Thus, a heterozygous deletion in exons 1-9 of the SLC5A7 gene could be the pathogenic cause for this patient. In patients exhibiting fluctuating weakness, positive RNS, and seronegativity for myasthenia gravis antibodies, a detailed family history should be considered, and enhanced genetic testing is recommended to determine the cause.

Novel heterogeneous Fe-based catalysts for carbon dioxide hydrogenation to long chain α-olefins-A review.

The thermocatalytic conversion of carbon dioxide (CO2) into high value-added chemicals provides a strategy to address the environmental problems caused by excessive carbon emissions and the sustainable production of chemicals. Significant progress has been made in the CO2 hydrogenation to long chain α-olefins, but controlling C-O activation and C-C coupling remains a great challenge. This review focuses on the recent advances in catalyst design concepts for the synthesis of long chain α-olefins from CO2 hydrogenation. We have systematically summarized and analyzed the ingenious design of catalysts, reaction mechanisms, the interaction between active sites and supports, structure-activity relationship, influence of reaction process parameters on catalyst performance, and catalyst stability, as well as the regeneration methods. Meanwhile, the challenges in the development of the long chain α-olefins synthesis from CO2 hydrogenation are proposed, and the future development opportunities are prospected. The aim of this review is to provide a comprehensive perspective on long chain α-olefins synthesis from CO2 hydrogenation to inspire the invention of novel catalysts and accelerate the development of this process.

Perioperative use of low dose haloperidol safely reduces episodes of postoperative nausea/vomiting and length of stay following elective minimally invasive bariatric surgery.

INTRODUCTION: While total intravenous anesthesia (TIVA) protocols include Dexamethasone and Ondansetron prophylaxis, bariatric patients continue to be considered at particularly high risk for postoperative nausea/vomiting (PONV). A multimodal approach for prophylaxis is recommended by the Bariatric Enhanced Recovery After Surgery (ERAS) Society however, there remains a lack of consensus on the optimal strategy to manage PONV in these patients. Haloperidol has been shown at low doses to have a therapeutic effect in treatment of refractory nausea and in PONV prophylaxis in other high risk surgical populations. We sought to investigate its efficacy as a prophylactic medication for PONV in the bariatric population and to identify which perioperative strategies were most effective at reducing episodes of PONV. METHODS: An institutional bariatric database was created by retrospectively reviewing patients undergoing elective minimally invasive bariatric procedures from 2018 to 2022. Demographic data reviewed included age, gender, preoperative body mass index (BMI), ethnicity, and primary language. Primary endpoints included patient reported episodes of PONV, total doses of Ondansetron administered, need for a second antiemetic (rescue medication), complication rate (most commonly readmission within 30 days), and length of stay. Fisher's exact test, Mann-Whitney test, and ANOVA were used to evaluate the effect of perioperative management on various endpoints. RESULTS: A total of 475 patients were analyzed with Haloperidol being utilized in 15.8% of all patients. Patients receiving Haloperidol were less likely to require Ondansetron outside of the immediate perioperative period (34.7% vs. 49.8%, p = 0.02), experienced less PONV (41.3% vs. 64.3%, p = 0.01) and also had a decreased median length of stay (27.3 vs. 35.8 h, p < 0.0001). CONCLUSIONS: Addition of low dose Haloperidol to Bariatric ERAS protocols decreases incidence of PONV and the need for additional antiemetic coverage resulting in a significantly shorter length of stay, increasing the likelihood of safe discharge on postoperative day 1.

Interaction between diabetes and body mass index on severe headache or migraine in adults: a cross-sectional study.

BACKGROUND: Research on the effects of body mass index (BMI) on severe headache or migraine is limited and controversial. The aim of this study was to explore the association between BMI and the prevalence of migraine, with particular interest in diabetes status difference. METHODS: The present study used analyzed data from people who participated in the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2004. Logistic regression models and restricted cubic spline (RCS) models were applied to investigate the relationship between body mass index and migraine. RESULTS: A total of 10,074 adults aged 20 years or older were included in this study. Body mass index was positively related to migraine, and the corresponding odds ratio (OR; 95% CI) was 1.02 (1.01, 1.03; p < 0.001). And compared to participants in the lowest group of body mass index (< 25 kg/m2), the adjusted ORs for migraine in medium group (25-29.9 kg/m2), and highest group (≥ 30 kg/m2) were 1.14 (95% CI: 0.98-1.32, p = 0.09) and 1.30 (95% CI: 1.11-1.52, p = 0.0022), respectively. The relationship between BMI and migraine exhibited a linear in overall in the RCS. Our findings also suggested an interaction between BMI and diabetes. The relationship between BMI and migraine in adults with diabetes was non-linear. The OR of developing migraine was 1.30 (95% CI: 1.10-1.54) in individuals with BMI ≥ 29.71 kg/m2 in adults with diabetes. CONCLUSION: A higher body mass index is significantly associated with an increased prevalence of migraine, and diabetes status can modify the association between them.

The RNA-binding protein ZFP36 strengthens innate antiviral signaling by targeting RIG-I for K63-linked ubiquitination.

Innate immunity is the first line of defense against infections, which functions as a significant role in resisting pathogen invasion. Rapid immune response is initiated by pattern recognition receptors (PRRs) quickly distinguishing "self" and "non-self." Upon evolutionarily conserved pathogen-associated molecular pattern (PAMP) is recognized by PRRs, innate immune response against infection is triggered via an orchestration of molecular interaction, cytokines cascades, and immune cells. RIG-I plays a critical role in type I interferon (IFN-I) production by direct recognition of cytoplasmic double-stranded viral RNA. However, the activation mechanism of RIG-I is incompletely understood. In this study, we reported RNA-binding protein ZFP36 as a positive regulator of RIG-I-mediated IFN-I production. ZFP36 is a member of Zinc finger proteins (ZFPs) characterized by the zinc finger (ZnF) motif, which broadly involved gene transcription and signal transduction. However, its role in regulating antiviral innate immune signaling is still unclear. We found that ZFP36 associates with RIG-I and potentiates the FN-ß production induced by SeV. Mechanistically, ZFP36 promotes K63-linked polyubiquitination of RIG-I, mostly at K154/K164/K172, thereby facilitating the activation of RIG-I during infection. While the mutant ZFP36 (C118S/C162S) failed to increase polyubiquitination of RIG-I and SeV induced FN-ß. Our findings collectively demonstrated that ZFP36 acts as a positive regulator in antiviral innate immunity by targeting RIG-I for K63-linked ubiquitination, thus improving our understanding of the activation mechanism of RIG-I.

Enantioselective Reductive Cross-Couplings of Olefins by Merging Electrochemistry with Nickel Catalysis.

The merger of electrochemistry and transition metal catalysis has emerged as a powerful tool to join two electrophiles in an enantioselective manner. However, the development of enantioselective electroreductive cross-couplings of olefins remains a challenge. Inspired by the advantages of the synergistic use of electrochemistry with nickel catalysis, we present here a Ni-catalyzed enantioselective electroreductive cross-coupling of acrylates with aryl halides and alkyl bromides, which affords chiral α-aryl carbonyls in good to excellent enantioselectivity. Additionally, this catalytic reaction can be applied to (hetero)aryl chlorides, which is difficult to achieve by other methods. The combination of cyclic voltammetry analysis with electrode potential studies suggests that the NiI species activates aryl halides by oxidative addition and alkyl bromides by single-electron transfer.

Cell damage evaluation by intelligent imaging flow cytometry.

Essential thrombocythemia (ET) is an uncommon situation in which the body produces too many platelets. This can cause blood clots anywhere in the body and results in various symptoms and even strokes or heart attacks. Removing excessive platelets using acoustofluidic methods receives extensive attention due to their high efficiency and high yield. While the damage to the remaining cells, such as erythrocytes and leukocytes is yet evaluated. Existing cell damage evaluation methods usually require cell staining, which are time-consuming and labor-intensive. In this paper, we investigate cell damage by optical time-stretch (OTS) imaging flow cytometry with high throughput and in a label-free manner. Specifically, we first image the erythrocytes and leukocytes sorted by acoustofluidic sorting chip with different acoustic wave powers and flowing speed using OTS imaging flow cytometry at a flowing speed up to 1 m/s. Then, we employ machine learning algorithms to extract biophysical phenotypic features from the cellular images, as well as to cluster and identify images. The results show that both the errors of the biophysical phenotypic features and the proportion of abnormal cells are within 10% in the undamaged cell groups, while the errors are much greater than 10% in the damaged cell groups, indicating that acoustofluidic sorting causes little damage to the cells within the appropriate acoustic power, agreeing well with clinical assays. Our method provides a novel approach for high-throughput and label-free cell damage evaluation in scientific research and clinical settings.

C(sp3)-H Aerobic Alkenylation of Tetrahydroisoquinolines via Organic Electrosynthesis.

A method for the C(sp3)-H alkenylation of N-aryl-tetrahydroisoquinoline (THIQ) has been developed by the combination of electrooxidation and a copper catalyst. The corresponding products were obtained with good to excellent yields under mild conditions. Besides, the addition of TEMPO as an electron mediator is crucial to this transformation, since the oxidative reaction could proceed under a low electrode potential. In addition, the catalytic asymmetric variant has also been demonstrated with good enantioselectivity.

Dodecylation of molybdenum disulfide and its electrochemical properties for hydrogen evolution reaction.

Functionalization of MoS2was achieved by treatment in a strongly reducing sodium naphthalene solution. Dodecyl was grafted onto MoS2nanosheets using alkyl sulphates as electrophiles to obtain dodecylated MoS2without affecting the MoS2crystalline structure. Superior electrocatalytic properties are obtained for dodecylated MoS2. The polarisation curve of this nanomaterial remained constant even after 1000 consecutive cycles. This route provides a new pathway for covalent functionalization of MoS2and might find a variety of applications, such as electrocatalysts.

Design, synthesis, evaluation and optimization of potent IRAK4 inhibitors alleviating production of inflammatory cytokines in LPS-induced SIRS model.

Interleukin-1 receptor associated kinase-4 (IRAK4) has emerged as a therapeutic target for inflammatory and autoimmune diseases. Through reversing the amide of CA-4948 and computer aided structure-activity relationship (SAR) studies, a series of IRAK4 inhibitors with oxazolo[4,5-b]pyridine scaffold were identified. Compound 32 showed improved potency (IC50 = 43 nM) compared to CA-4948 (IC50 = 115 nM), but suffered from hERG inhibition (IC50 = 5.7 µM). Further optimization led to compound 42 with reduced inhibition of hERG (IC50 > 30 µM) and 13-fold higher activity (IC50 = 8.9 nM) than CA-4948. Importantly, compound 42 had favorable in vitro ADME and in vivo pharmacokinetic properties. Furthermore, compound 42 significantly reduced LPS-induced production of serum TNF-α and IL-6 cytokines in the mouse model. The overall profiles of compound 42 support it as a lead for the development of IRAK4 inhibitors for the treatment of inflammatory and autoimmune disorders.

Dietary zinc intake in relation to migraine among adults: a cross sectional study of NHANES 1999-2004.

BACKGROUND: Previous studies have revealed that an antioxidant diet is a protective factor against migraine. However, the association between zinc, an important antioxidant obtained from the diet, and migraine has received little attention. The purpose of this study was to explore the association between zinc intake with migraine. METHODS: The present study used cross-sectional data from individuals who participated in the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2004. Logistic regression models and restricted cubic spline models were performed to explore the association between zinc intake and migraine. RESULTS: A total of 9849 adults aged 20 years or older were included in this study. Zinc intake was negatively associated with migraine. Compared to participants in the lowest group of dietary zinc intake Q1 (≤5.93 mg/day), the adjusted ORs for migraine in Q2 (5.94-8.38 mg/day), Q3 (8.39-11.26 mg/day), Q4 (11.27-15.75 mg/day), and Q5 (≥15.76 mg/day) were 0.73 (95% CI: 0.60-0.89, p = 0.004), 0.72 (95% CI: 0.55-0.95, p = 0.02), 0.76 (95% CI: 0.58-0.99, p = 0.04) and 0.73 (95% CI: 0.50-1.05, p = 0.08), respectively. Our findings also suggested an interaction between zinc intake and age (P for interaction = 0.007). Additionally, the relationship between zinc intake and migraine in adults with 20-50 years was non-linear. CONCLUSIONS: A higher zinc intake is significantly associated with a decreased prevalence of migraine, and age can modify the association between them.

Dietary niacin intake in relation to depression among adults: a population-based study.

BACKGROUND: Previous studies have shown that an antioxidant diet is a protective factor against depression. However, the association between niacin, an important antioxidant consumed from the diet, and depression has received little attention. Therefore, we explored the association between niacin intake and depression through a cross-sectional analysis of the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2016. METHODS: Depression was measured using the Patient Health Questionnaire (PHQ-9, score ≥ 10). Niacin intake was assessed through 24-h dietary recall interviews. The relationship of niacin intake with depression among adults in US was assessed by using a weighted multiple logistic regression model with subgroup analysis. Non-linear associations were explored using restricted cubic spline models. And we used a two-piece-wise logistic regression model with smoothing to explore the threshold for association between them. RESULTS: A total of 16,098 adults were included in this study. Compared with individuals with lowest niacin intake Q1 (≤ 15.96 mg/day), the adjusted OR values for dietary niacin intake and depression in Q2 (15.97-22.86 mg/day), Q3 (22.87-32.28 mg/day) and Q4 (≥ 32.29 mg/day), were 0.92 (95% CI: 0.70-1.20), 0.76 (95% CI: 0.56-0.99,) and 0.68 (95% CI: 0.48-0.98), respectively. The results were not modified by sex, by age and by BMI. Furthermore, the relationship between dietary niacin intake and depression exhibited a U-shaped curve (nonlinear, p < 0.001). And depression risk was lowest when dietary consumption of niacin was around 36 mg/day. CONCLUSIONS: In present study, moderate niacin intake, but not high intake, was associated with lower odds of depression suggesting a U-shaped association.

Identification of autophagy-related genes in neuropathic pain through bioinformatic analysis.

BACKGROUND: Neuropathic pain (NP) is one of the most common types of chronic pain and significantly compromises the quality of life. Autophagy is an intracellular catabolic process that is required to maintain cellular homeostasis in response to various stresses. The role of autophagy-related genes in the diagnosis and treatment of neuropathic pain remains unclear. METHODS: We identified autophagy-related differentially expressed genes (ARDEGs) and differentially expressed miRNAs (DE-miRNAs) in neuropathic pain by bioinformatics analysis of the GSE145226 and GSE145199 datasets. These ARDEGs and their co-expressed genes were subjected to Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, Gene Set Enrichment Analysis (GSEA) and friends analysis. Meanwhile, we constructed TFs-ARDEGs, miRNA-ARDEGs regulatory network through ChIPBase database and the HTFtarget database, multiMir R package. Finally, we performed immune infiltration analysis of ARDEGs by Single Sample Gene Set Enrichment Analysis (ssGSEA). RESULTS: We identified 2 potential autophagy-related differentially expressed genes (Sirt2 and ST7) that may be closely associated with the pathogenesis of neuropathic pain. GO, KEGG and GSEA analysis revealed that these two ARDEGs were mainly enriched in pyridine nucleotide metabolic process, nicotinamide nucleotide metabolic process, Nicotinate and nicotinamide metabolism, NF-κB pathway, KRAS signaling, P53 pathway. In the TFs-ARDEGs and miRNA-ARDEGs regulatory network, miR-140-5p and Cebpb were predicted to be as crucial regulators in the progression of NP. For the ssGSEA results, Sirt2 was positively correlated with Eosinophil and Effector memory CD8+ T cell infiltration, which suggested that it may be involved in the regulation of neuroimmune-related signaling. CONCLUSION: Two autophagy-related differentially expressed genes, especially Sirt2, may be potential biomarkers for NP, providing more evidence about the crucial role of autophagy in neuropathic pain.

The rare-earth yttrium induces cell apoptosis and autophagy in the male reproductive system through ROS-Ca2+-CamkII/Ampk axis.

China has the world's largest reserves of rare earth elements (REEs), but widespread mining and application of REEs has led to an increased risk of potential pollution. Yttrium (Y), the first heavy REEs to be discovered, poses a substantial threat to human health. Unfortunately, little attention has been given to the impact of Y on human reproductive health. In this study, we investigated the toxic effects of YCl3 on mouse testes and four types of testicular cells, including Sertoli, Leydig, spermatogonial and spermatocyte cells. The results showed that YCl3 exposure causes substantial damage to mouse testes and induces apoptosis and autophagy, but not pyroptosis or necrosis, in testicular cells. Genome-wide gene expression analysis revealed that YCl3 induced significant changes in gene expression, with Ca2+ and mitochondria-related genes being the most significantly altered. Mechanistically, YCl3 exposure induced mitochondrial dysfunction in testicular cells, triggering the overproduction of reactive oxygen species (ROS) by impairing the Nrf2 pathway, regulating downstream Ho-1 target protein expression, and increasing Ca2+ levels to activate the CamkII/Ampk signaling pathway. Blocking ROS production or Ca2+ signaling significantly attenuates apoptosis and autophagy, while supplementation with Ca2+ reverses the suppression of apoptosis and autophagy by ROS blockade in testicular cells. Notably, apoptosis and autophagy induced by YCl3 treatment are independent of each other. Thus, our study suggests that YCl3 may impair the antioxidant stress signaling pathway and activate the calcium pathway through the ROS-Ca2+ axis, which promotes testicular cell apoptosis and autophagy independently, thus inducing testicular damage and impairing male reproductive function.

Chinese Expert Consensus on the Use of Biologics in Patients with Chronic Rhinosinusitis (2022, Zhuhai).

BACKGROUND: Chronic rhinosinusitis (CRS) is a common inflammatory disease in otolaryngology, mainly manifested as nasal congestion, nasal discharge, facial pain/pressure, and smell disorder. CRS with nasal polyps (CRSwNP), an important phenotype of CRS, has a high recurrence rate even after receiving corticosteroids and/or functional endoscopic sinus surgery. In recent years, clinicians have focused on the application of biological agents in CRSwNP. However, it has not reached a consensus on the timing and selection of biologics for the treatment of CRS so far. SUMMARY: We reviewed the previous studies of biologics in CRS and summarized the indications, contraindications, efficacy assessment, prognosis, and adverse effects of biologics. Also, we evaluated the treatment response and adverse reactions of dupilumab, omalizumab, and mepolizumab in the management of CRS and made recommendations. KEY MESSAGES: Dupilumab, omalizumab, and mepolizumab have been approved for the treatment of CRSwNP by the US Food and Drug Administration. Type 2 and eosinophilic inflammation, need for systemic steroids or contraindication to systemic steroids, significantly impaired quality of life, anosmia, and comorbid asthma are required for the use of biologics. Based on current evidence, dupilumab has the prominent advantage in improving quality of life and reducing the risk of comorbid asthma in CRSwNP among the approved monoclonal antibodies. Most patients tolerate biological agents well in general with few major or severe adverse effects. Biologics have provided more options for severe uncontrolled CRSwNP patients or patients who refuse to have surgery. In the future, more novel biologics will be assessed in high-quality clinical trials and applied clinically.