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The TRPV3 channel plays vital roles in skin physiology. Dysfunction of TRPV3 causes skin diseases, including Olmsted syndrome. However, the lack of potent and selective inhibitors impedes the validation of TRPV3 as a therapeutic target. In this study, we identified Trpvicin as a potent and subtype-selective inhibitor of TRPV3. Trpvicin exhibits pharmacological potential in the inhibition of itch and hair loss in mouse models. Cryogenic electron microscopy structures of TRPV3 and the pathogenic G573S mutant complexed with Trpvicin reveal detailed ligand-binding sites, suggesting that Trpvicin inhibits the TRPV3 channel by stabilizing it in a closed state. Our G573S mutant structures demonstrate that the mutation causes a dilated pore, generating constitutive opening activity. Trpvicin accesses additional binding sites inside the central cavity of the G573S mutant to remodel the channel symmetry and block the channel. Together, our results provide mechanistic insights into the inhibition of TRPV3 by Trpvicin and support TRPV3-related drug development.
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Canais de Cátion TRPV , Camundongos , Animais , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/química , Mutação , Sítios de LigaçãoRESUMO
High-entropy borides hold potential as electrocatalysts for water oxidation. However, the synthesis of the tailored nanostructures remains a challenge due to the thermodynamic immiscibility of polymetallic components. Herein, a FeCoCuMnRuB nanobox decorated with a nanosheet array was synthesized for the first time by a "coordination-etch-reduction" method. The FeCoCuMnRuB nanobox has various structural characteristics to express the catalytic performance; meanwhile, it combines the high-entropy effect of multiple components with the electron trap effect induced by electron-deficient B, synergistically regulating its electronic structure. As a result, FeCoCuMnRuB nanobox exhibits enhanced OER activity with a low overpotential (η10 = 233 mV), high TOF value (0.0539 s-1), small Tafel slope (61 mV/dec), and a satisfactory stability for 200 h, outperforming the high-entropy alloy and low-entropy borides. This work develops a high entropy and electron-deficient B-driven strategy for motivating the catalytic performance of water oxidation, which broadens the structural diversity and category of high-entropy materials.
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BACKGROUND: Azvudine has been approved for the treatment of coronavirus disease 2019 (COVID-19) patients in China, and this meta-analysis aims to illustrate the safety of azvudine and its effectiveness in reducing mortality. METHODS: PubMed, Embase, Web of science, Cochrane Library and the Epistemonikos COVID-19 Living Overview of Evidence database (L.OVE) were searched to aggregate currently published studies. Cochrane risk of bias tool and ROBINS-I tool were used to assess the risk of bias of randomized controlled study and cohort study respectively. Odds radios (ORs) with 95% confidence interval (CIs) were combined for dichotomous variables. Publication bias was assessed by Egger's test and funnel plots. RESULTS: A total of 184 articles were retrieved from the included databases and 17 studies were included into the final analysis. Pooled analysis showed that azvudine significantly reduced mortality risk in COVID-19 patients compared with controls (OR: 0.41, 95%CI 0.31-0.54, p < 0.001). Besides, either mild to moderate or severe COVID-19 patients could benefit from azvudine administration. There was no significant difference in the incidence of ICU admission (OR: 0.90, 95%CI 0.47-1.72, p = 0.74) and invasive ventilation (OR: 0.94, 95%CI 0.54-1.62, p = 0.82) between azvudine and control group. The incidence of adverse events was similar between azvudine and control (OR: 1.26, 95%CI 0.59-2.70, p = 0.56). CONCLUSIONS: This meta-analysis suggests that azvudine could reduce the mortality risk of COVID-19 patients, and the safety of administration is acceptable. TRIAL REGISTRATION: PROSPERO; No.: CRD42023462988; URL: https://www.crd.york.ac.uk/prospero/ .
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Antivirais , Tratamento Farmacológico da COVID-19 , COVID-19 , SARS-CoV-2 , Humanos , COVID-19/mortalidade , Antivirais/uso terapêutico , Antivirais/efeitos adversos , SARS-CoV-2/efeitos dos fármacos , Resultado do TratamentoRESUMO
BACKGROUND: Examinations based on lung tissue specimen can play a significant role in the diagnosis for critically ill and intubated patients with lung infiltration. However, severe complications including tension pneumothorax and intrabronchial hemorrhage limit the application of needle biopsy. METHODS: A refined needle biopsy technique, named bronchus-blocked ultrasound-guided percutaneous transthoracic needle biopsy (BUS-PTNB), was performed on four intubated patients between August 2020 and April 2021. BUS-PTNB was done at bedside, following an EPUBNOW (evaluation, preparation, ultrasound location, bronchus blocking, needle biopsy, observation, and withdrawal of blocker) workflow. Parameters including procedure feasibility, sample acquisition, perioperative conditions, and complications were observed. Tissue specimens were sent to pathological examinations and microbial tests. RESULTS: Adequate specimens were successfully obtained from four patients. Diagnosis and treatment were correspondingly refined based on pathological and microbial tests. Intrabronchial hemorrhage occurred in patient 1 but was stopped by endobronchial blocker. Mild pneumothorax happened in patient 4 due to little air leakage, and closed thoracic drainage was placed. During the procedure, peripheral capillary hemoglobin oxygen saturation (SPO2), blood pressure, and heart rate of patient 4 fluctuated but recovered quickly. Vital signs were stable for patient 1-3. CONCLUSIONS: BUS-PTNB provides a promising, practical and feasible method in acquiring tissue specimen for critically ill patients under intratracheal intubation. It may facilitate the pathological diagnosis or other tissue-based tests for intubated patients and improve clinical outcomes.
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Biópsia por Agulha , Brônquios , Biópsia Guiada por Imagem , Pneumopatias , Ultrassonografia de Intervenção , Biópsia por Agulha/métodos , Brônquios/diagnóstico por imagem , Brônquios/patologia , Estado Terminal , Humanos , Intubação Intratraqueal , Pneumopatias/patologia , Pneumopatias/terapiaRESUMO
BACKGROUND: COVID-19 is a viral respiratory disease caused by the severe acute respiratory syndrome-Coronavirus type 2 (SARS-CoV-2). Patients with this disease may be more prone to venous or arterial thrombosis because of the activation of many factors involved in it, including inflammation, platelet activation and endothelial dysfunction. Interferon gamma inducible protein-10 (IP-10), monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein 1-alpha (MIP1α) are cytokines related to thrombosis. Therefore, this study focused on these three indicators in COVID-19, with the hope to find biomarkers that are associated with patients' outcome. METHODS: This is a retrospective single-center study involving 74 severe and critically ill COVID-19 patients recruited from the ICU department of the Tongji Hospital in Wuhan, China. The patients were divided into two groups: severe patients and critically ill patients. The serum IP-10, MCP-1 and MIP1α level in both groups was detected using the enzyme-linked immunosorbent assay (ELISA) kit. The clinical symptoms, laboratory test results, and the outcome of COVID-19 patients were retrospectively analyzed. RESULTS: The serum IP-10 and MCP-1 level in critically ill patients was significantly higher than that in severe patients (P < 0.001). However, no statistical difference in MIP1α between the two groups was found. The analysis of dynamic changes showed that these indicators remarkably increased in patients with poor prognosis. Since the selected patients were severe or critically ill, no significant difference was observed between survival and death. CONCLUSIONS: IP-10 and MCP-1 are biomarkers associated with the severity of COVID-19 disease and can be related to the risk of death in COVID-19 patients.
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Quimiocina CCL2/sangue , Quimiocina CXCL10/sangue , Infecções por Coronavirus/complicações , Síndrome da Liberação de Citocina/complicações , Coagulação Intravascular Disseminada/complicações , Pneumonia Viral/complicações , Embolia Pulmonar/complicações , Insuficiência Respiratória/complicações , Proteínas Adaptadoras de Transdução de Sinal/sangue , Idoso , Betacoronavirus/patogenicidade , Biomarcadores/sangue , COVID-19 , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/virologia , Estado Terminal , Síndrome da Liberação de Citocina/diagnóstico , Síndrome da Liberação de Citocina/mortalidade , Síndrome da Liberação de Citocina/virologia , Coagulação Intravascular Disseminada/diagnóstico , Coagulação Intravascular Disseminada/mortalidade , Coagulação Intravascular Disseminada/virologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/mortalidade , Pneumonia Viral/virologia , Prognóstico , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/mortalidade , Embolia Pulmonar/virologia , Insuficiência Respiratória/diagnóstico , Insuficiência Respiratória/mortalidade , Insuficiência Respiratória/virologia , Estudos Retrospectivos , SARS-CoV-2 , Índice de Gravidade de Doença , Análise de SobrevidaRESUMO
BACKGROUND: Immunoglobulin G4-related disease (IgG4-RD) encompasses a group of immune-mediated disorders that are gaining increasing recognition. Pulmonary presentations are common, with four types of patterns been described on radiography, including solid nodular, bronchovascular, ground glass opacities, and alveolar interstitial. Pleural thickening and pleural effusion have also been reported. However, there have been no reports of IgG4-RD that presents as spontaneous hemothorax. CASE PRESENTATION: A 61-year-old Chinese woman experienced recurrent right-sided chest pain and transient syncope. A significant decrease in her hemoglobin level and thick bloody pleural fluid demonstrated spontaneous hemothorax. The elevated serum IgG4 and histopathological analysis of the right pleura and intercostal lymph node specimens all supported the diagnosis of IgG4-RD in this patient. Further diagnostic evaluation did not reveal other causes for spontaneous hemothorax. She received steroids and no recurrent bleeding event occurred during a follow-up period of more than 1 year. CONCLUSION: Recurrent spontaneous hemothorax can be a rare manifestation of IgG4-RD, with pleural involvement as the most probable mechanism.
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Hemotórax/etiologia , Doença Relacionada a Imunoglobulina G4/diagnóstico , Imunoglobulina G/sangue , Pleura/patologia , Feminino , Humanos , Doença Relacionada a Imunoglobulina G4/patologia , Doença Relacionada a Imunoglobulina G4/fisiopatologia , Linfonodos/patologia , Pessoa de Meia-Idade , Recidiva , Tomografia Computadorizada por Raios XRESUMO
Membrane-integrated type II phosphatidic acid phosphatases (PAP2s) are important for numerous bacterial to human biological processes, including glucose transport, lipid metabolism, and signaling. Escherichia coli phosphatidylglycerol-phosphate phosphatase B (ecPgpB) catalyzes removing the terminal phosphate group from a lipid carrier, undecaprenyl pyrophosphate, and is essential for transport of many hydrophilic small molecules across the membrane. We determined the crystal structure of ecPgpB at a resolution of 3.2 Å. This structure shares a similar folding topology and a nearly identical active site with soluble PAP2 enzymes. However, the substrate binding mechanism appears to be fundamentally different from that in soluble PAP2 enzymes. In ecPgpB, the potential substrate entrance to the active site is located in a cleft formed by a V-shaped transmembrane helix pair, allowing lateral movement of the lipid substrate entering the active site from the membrane lipid bilayer. Activity assays of point mutations confirmed the importance of the catalytic residues and potential residues involved in phosphate binding. The structure also suggests an induced-fit mechanism for the substrate binding. The 3D structure of ecPgpB serves as a prototype to study eukaryotic PAP2 enzymes, including human glucose-6-phosphatase, a key enzyme in the homeostatic regulation of blood glucose concentrations.
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Escherichia coli/enzimologia , Modelos Moleculares , Monoéster Fosfórico Hidrolases/química , Clonagem Molecular , Cristalografia por Raios X , Glucose-6-Fosfatase/química , Humanos , Conformação ProteicaRESUMO
The major facilitator superfamily (MFS) is the largest family of secondary active transporters and is present in all life kingdoms. Detailed structural basis of the substrate transport and energy-coupling mechanisms of these proteins remain to be elucidated. YajR is a putative proton-driven MFS transporter found in many Gram-negative bacteria. Here we report the crystal structure of Escherichia coli YajR at 3.15 Å resolution in an outward-facing conformation. In addition to having the 12 canonical transmembrane helices, the YajR structure includes a unique 65-residue C-terminal domain which is independently stable. The structure is unique in illustrating the functional role of "sequence motif A." This highly conserved element is seen to stabilize the outward conformation of YajR and suggests a general mechanism for the conformational change between the inward and outward states of the MFS transporters.
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Motivos de Aminoácidos , Proteínas de Escherichia coli/química , Proteínas de Membrana Transportadoras/química , Estrutura Terciária de Proteína , Sequência de Aminoácidos , Sítios de Ligação/genética , Transporte Biológico , Cristalografia por Raios X , Eletroforese em Gel de Poliacrilamida , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Modelos Moleculares , Dados de Sequência Molecular , Mutação , Conformação Proteica , Estrutura Secundária de Proteína , Homologia de Sequência de AminoácidosRESUMO
YajR is an Escherichia coli transporter that belongs to the major facilitator superfamily. Unlike most MFS transporters, YajR contains a carboxyl terminal, cytosolic domain of 67 amino acid residues termed YAM domain. Although it is speculated that the function of this small soluble domain is to regulate the conformational change of the 12-helix transmembrane domain, its precise regulatory role remains unclear. Here, we report the crystal structure of the YAM domain at 1.07-Å resolution, along with its structure determined using nuclear magnetic resonance. Detailed analysis of the high resolution structure revealed a symmetrical dimer in which a belt of well-ordered poly-pentagonal water molecules is embedded. A mutagenesis experiment and a thermal stability assay were used to analyze the putative role of this dimerization in response to changes in halogen concentration.
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Proteínas de Escherichia coli/química , Proteínas de Membrana Transportadoras/química , Sequência de Aminoácidos , Cristalografia por Raios X , Proteínas de Escherichia coli/genética , Proteínas de Membrana Transportadoras/genética , Modelos Moleculares , Dados de Sequência Molecular , Mutação , Ressonância Magnética Nuclear Biomolecular , Multimerização Proteica , Estabilidade Proteica , Estrutura Terciária de Proteína , Cloreto de Sódio/química , Água/químicaRESUMO
Transient Receptor Potential Vanilloid 1 (TRPV1) plays a central role in pain sensation and is thus an attractive pharmacological drug target. SAF312 is a potent, selective, and non-competitive antagonist of TRPV1 and shows promising potential in treating ocular surface pain. However, the precise mechanism by which SAF312 inhibits TRPV1 remains poorly understood. Here, we present the cryo-EM structure of human TRPV1 in complex with SAF312, elucidating the structural foundation of its antagonistic effects on TRPV1. SAF312 binds to the vanilloid binding pocket, preventing conformational changes in S4 and S5 helices, which are essential for channel gating. Unexpectedly, a putative cholesterol was found to contribute to SAF312's inhibition. Complemented by mutagenesis experiments and molecular dynamics simulations, our research offers substantial mechanistic insights into the regulation of TRPV1 by SAF312, highlighting the interplay between the antagonist and cholesterol in modulating TRPV1 function. This work not only expands our understanding of TRPV1 inhibition by SAF312 but also lays the groundwork for further developments in the design and optimization of TRPV1-related therapies.
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Colesterol , Microscopia Crioeletrônica , Simulação de Dinâmica Molecular , Canais de Cátion TRPV , Canais de Cátion TRPV/metabolismo , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/química , Canais de Cátion TRPV/genética , Colesterol/metabolismo , Humanos , Sítios de Ligação , Células HEK293 , Ligação ProteicaRESUMO
RNA uptake by cells is critical for RNA-mediated gene interference (RNAi) and RNA-based therapeutics. In Caenorhabditis elegans, RNAi is systemic as a result of SID-1-mediated double-stranded RNA (dsRNA) across cells. Despite the functional importance, the underlying mechanisms of dsRNA internalization by SID-1 remain elusive. Here we describe cryogenic electron microscopy structures of SID-1, SID-1-dsRNA complex and human SID-1 homologs SIDT1 and SIDT2, elucidating the structural basis of dsRNA recognition and import by SID-1. The homodimeric SID-1 homologs share conserved architecture, but only SID-1 possesses the molecular determinants within its extracellular domains for distinguishing dsRNA from single-stranded RNA and DNA. We show that the removal of the long intracellular loop between transmembrane helix 1 and 2 attenuates dsRNA uptake and systemic RNAi in vivo, suggesting a possible endocytic mechanism of SID-1-mediated dsRNA internalization. Our study provides mechanistic insights into dsRNA internalization by SID-1, which may facilitate the development of dsRNA applications based on SID-1.
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Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Microscopia Crioeletrônica , RNA de Cadeia Dupla , RNA de Cadeia Dupla/metabolismo , RNA de Cadeia Dupla/química , Animais , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/química , Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/genética , Humanos , Modelos Moleculares , Interferência de RNA , Proteínas de MembranaRESUMO
The nonselective calcium-permeable Transient Receptor Potential Cation Channel Subfamily V Member4 (TRPV4) channel regulates various physiological activities. Dysfunction of TRPV4 is linked to many severe diseases, including edema, pain, gastrointestinal disorders, lung diseases, and inherited neurodegeneration. Emerging TRPV4 antagonists show potential clinical benefits. However, the molecular mechanisms of TRPV4 antagonism remain poorly understood. Here, cryo-electron microscopy (cryo-EM) structures of human TRPV4 are presented in-complex with two potent antagonists, revealing the detailed binding pockets and regulatory mechanisms of TRPV4 gating. Both antagonists bind to the voltage-sensing-like domain (VSLD) and stabilize the channel in closed states. These two antagonists induce TRPV4 to undergo an apparent fourfold to twofold symmetry transition. Moreover, it is demonstrated that one of the antagonists binds to the VSLD extended pocket, which differs from the canonical VSLD pocket. Complemented with functional and molecular dynamics simulation results, this study provides crucial mechanistic insights into TRPV4 regulation by small-molecule antagonists, which may facilitate future drug discovery targeting TRPV4.
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Microscopia Crioeletrônica , Canais de Cátion TRPV , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/metabolismo , Canais de Cátion TRPV/química , Canais de Cátion TRPV/genética , Humanos , Microscopia Crioeletrônica/métodos , Simulação de Dinâmica Molecular , Sítios de LigaçãoRESUMO
In the era of global climate change, the increasingly severe Fusarium head blight (FHB) and deoxynivalenol (DON) contamination have caused economic losses and brought food and feed safety concerns. Recently, an FHB resistance gene Fhb7 coding a glutathione-S transferase (GST) to degrade DON by opening the critical toxic epoxide moiety was identified and opened a new window for wheat breeding and DON detoxification. However, the poor stability of Fhb7 and the elusiveness of the catalytic mechanism hinder its practical application. Herein, we report the first structure of Fhb7 at 2.41 Å and reveal a unique catalytic mechanism of epoxide opening transformation in GST family proteins. Furthermore, variants V29P and M10 showed that 5.5-fold and 266.7-fold longer half-life time than wild-type, respectively, were identified. These variants offer broad substrate scope, and the engineered biosafe Bacillus subtilis overexpressing the variants shows excellent DON degradation performance, exhibiting potential at bacterium engineering to achieve DON detoxification in the feed and biomedicine industry. This work provides a profound mechanistic insight into the enzymatic activities of Fhb7 and paves the way for further utilizing Fhb7-related enzymes in crop breeding and DON detoxification by synthetic biology.
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Bladder cancer (BC) is a common malignant tumor of urinary system, which can be divided into muscle-invasive BC (MIBC) and nonmuscle-invasive BC (NMIBC). The number of BC patients has been gradually increasing currently. At present, bladder tumours are diagnosed and followed-up using a combination of cystoscopic examination, cytology and histology. However, the detection of early grade tumors, which is much easier to treat effectively than advanced stage disease, is still insufficient. It frequently recurs and can progress when not expeditiously diagnosed and monitored following initial therapy for NMIBC. Treatment strategies are totally different for different stage diseases. Therefore, it is of great practical significance to study new biomarkers for diagnosis and prognosis. In this review, we summarize the current state of biomarker development in BC diagnosis and prognosis prediction. We retrospectively analyse eight diagnostic biomarkers and eight prognostic biomarkers, in which CK, P53, PPARγ, PTEN and ncRNA are emphasized for discussion. Eight molecular subtype systems are also identified. Clinical translation of biomarkers for diagnosis, prognosis, monitoring and treatment will hopefully improve outcomes for patients. These potential biomarkers provide an opportunity to diagnose tumors earlier and with greater accuracy, and help identify those patients most at risk of disease recurrence.
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Neoplasias não Músculo Invasivas da Bexiga , Neoplasias da Bexiga Urinária , Humanos , Biomarcadores Tumorais/genética , Estudos Retrospectivos , Recidiva Local de Neoplasia , Neoplasias da Bexiga Urinária/patologiaRESUMO
Biosynthetic enzymes evolutionarily gain novel functions, thereby expanding the structural diversity of natural products to the benefit of host organisms. Diels-Alderases (DAs), functionally unique enzymes catalysing [4 + 2] cycloaddition reactions, have received considerable research interest. However, their evolutionary mechanisms remain obscure. Here, we investigate the evolutionary origins of the intermolecular DAs in the biosynthesis of Moraceae plant-derived Diels-Alder-type secondary metabolites. Our findings suggest that these DAs have evolved from an ancestor functioning as a flavin adenine dinucleotide (FAD)-dependent oxidocyclase (OC), which catalyses the oxidative cyclisation reactions of isoprenoid-substituted phenolic compounds. Through crystal structure determination, computational calculations, and site-directed mutagenesis experiments, we identified several critical substitutions, including S348L, A357L, D389E and H418R that alter the substrate-binding mode and enable the OCs to gain intermolecular DA activity during evolution. This work provides mechanistic insights into the evolutionary rationale of DAs and paves the way for mining and engineering new DAs from other protein families.
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Morus , Morus/genética , Morus/química , Terpenos , Catálise , Reação de CicloadiçãoRESUMO
Background: Patient-ventilator asynchrony (PVA) frequently occurs in mechanically ventilated patients within the ICU and has the potential for harm. Depending solely on the health care team cannot accurately and promptly identify PVA. To address this issue, our team has developed a cloud-based platform for monitoring mechanical ventilation (MV), comprising the PVA-RemoteMonitor system and the 24-h MV analysis report. We conducted a survey to evaluate physicians' satisfaction and acceptance of the platform in 14 ICUs. Methods: Data from medical records, clinical information systems, and ventilators were uploaded to the cloud platform and underwent data processing. The data were analyzed to monitor PVA and displayed in the front-end. The 24-h analysis report for MV was generated for clinical reference. Critical care physicians in 14 hospitals' ICUs that involved in the platform participated in a questionnaire survey, among whom 10 physicians were interviewed to investigate physicians' acceptance and opinions of this system. Results: The PVA-RemoteMonitor system exhibited a high level of specificity in detecting flow insufficiency, premature cycle, delayed cycle, reverse trigger, auto trigger, and overshoot, with sensitivities of 90.31 %, 98.76 %, 99.75 %, 99.97 %, 100 %, and 99.69 %, respectively. The 24-h analysis report supplied essential data about PVA and respiratory mechanics. 86.2 % (75/87) of physicians supported the application of this platform. Conclusions: The PVA-RemoteMonitor system accurately identified PVA, and the MV analysis report provided guidance in controlling PVA. Our platform can effectively assist ICU physicians in the management of ventilated patients.
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BACKGROUND: Severe acute respiratory syndrome coronavirus 2 will coexist with humans for a long time, and it is therefore important to develop effective treatments for coronavirus disease 2019 (COVID-19). Recent studies have demonstrated that antiviral therapy is a key factor in preventing patients from progressing to severe disease, even death. Effective and affordable antiviral medications are essential for disease treatment and are urgently needed. Azvudine, a nucleoside analogue, is a potential low-cost candidate with few drug interactions. However, validation of high-quality clinical studies is still limited. METHODS: This is a multicentre, randomized, double-blind, placebo-controlled phase III clinical trial involving 1096 adult patients with mild-to-moderate symptoms of COVID-19 who are at high risk for progression to severe COVID-19. Patients will be randomized to (1) receive azvudine tablets 5 mg daily for a maximum of 7 days or (2) receive placebo five tablets daily. All participants will be permitted to use a standard treatment strategy except antiviral therapy beyond the investigational medications. The primary outcome will be the ratio of COVID-19-related critical illness and all-cause mortality among the two groups within 28 days. DISCUSSION: The purpose of this clinical trial is to determine whether azvudine can prevent patients at risk of severe disease from progressing to critical illness and death, and the results will identify whether azvudine is an effective and affordable antiviral treatment option for COVID-19. TRIAL REGISTRATION: ClinicalTrials.gov NCT05689034. Registered on 18 January 2023.
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Azidas , COVID-19 , Desoxicitidina/análogos & derivados , Adulto , Humanos , Estado Terminal , SARS-CoV-2 , Antivirais/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Multicêntricos como Assunto , Ensaios Clínicos Fase III como AssuntoRESUMO
The sodium-activated Slo2.2 channel is abundantly expressed in the brain, playing a critical role in regulating neuronal excitability. The Na+-binding site and the underlying mechanisms of Na+-dependent activation remain unclear. Here, we present cryoelectron microscopy (cryo-EM) structures of human Slo2.2 in closed, open, and inhibitor-bound form at resolutions of 2.6-3.2 Å, revealing gating mechanisms of Slo2.2 regulation by cations and a potent inhibitor. The cytoplasmic gating ring domain of the closed Slo2.2 harbors multiple K+ and Zn2+ sites, which stabilize the channel in the closed conformation. The open Slo2.2 structure reveals at least two Na+-sensitive sites where Na+ binding induces expansion and rotation of the gating ring that opens the inner gate. Furthermore, a potent inhibitor wedges into a pocket formed by pore helix and S6 helix and blocks the pore. Together, our results provide a comprehensive structural framework for the investigation of Slo2.2 channel gating, Na+ sensation, and inhibition.
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Canais de Potássio , Sódio , Humanos , Canais de Potássio/metabolismo , Microscopia Crioeletrônica , Canais de Potássio Ativados por Sódio , Sódio/metabolismoRESUMO
Cisplatin (Cp), a chemotherapeutic agent, interacts with purines on tumor DNA, causing tumor cell apoptosis. However, cisplatin has the characteristics of non-specific distribution and lack of selectivity, resulting in systemic toxicity. Moreover, it cannot maintain the drug's high concentration in the tumor-weak acid environment. These flaws of cisplatin restrict its use in clinical applications. Therefore, a pH-responsive carbon nanotube-modified nano-drug delivery system (CNTs/Gel/Cp) was constructed in this study using gelatin (Gel)-modified carbon nanotubes (CNTs/Gel) loaded with cisplatin to release drugs precisely and slowly, preventing premature inactivation and maintaining an effective concentration. When MCp:MCNTs/Gel = 1:1, the drug reaches the highest loading rate and entrapment efficiency. To achieve the sustained-release effect, CNTs/Gel/Cp can release the medicine steadily for a long time in a pH environment of 6.0. Additionally, CNTs/Gel/Cp display antitumor properties comparable to cisplatin in a manner that varies with the dosage administered. These findings indicate that CNTs/Gel/Cp have an effective, sustained release of cisplatin and a good antitumor effect, providing a theoretical and experimental basis for the clinical application of modified carbon nanotubes (CNTs) as a new drug delivery system.
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OBJECTIVES: To determine the prognostic factors of dermatomyositis with anti-melanoma differentiation-associated gene 5 (MDA5) antibody, a rare disease and often complicated by life-threatening, rapidly progressive interstitial lung disease. METHODS: Herein, we searched the Medline, Embase, and Cochrane Library databases and extracted studies published before August 23, 2022. Pooled analysis of hazard ratios (HRs) or odds ratios was used to identify prognostic factors for mortality among patients with anti-MDA5 antibody-positive dermatomyositis (MDA5+ DM). RESULTS: Twenty-nine cohorts with 2,645 patients were included in this meta-analysis. Factors related to poor prognosis included old age (HR 1.54, 95% confidence interval (CI) 1.41-1.69, p < 0.01), male sex (HR 2.07, 95% CI 1.34-3.18, p < 0.01), rapidly progressive interstitial lung disease (RP-ILD) (HR 9.34, 95% CI 6.39-13.6, p < 0.01), high levels of ferritin (HR 1.05, 95% CI 1.01-1.08, p < 0.01), C-reactive protein (CRP) (HR 1.12, 95% CI 1.06-1.19, p < 0.01), creatine kinase (HR 1.05, 95% CI 1.03-1.07, p < 0.01), and lactate dehydrogenase (LDH) (HR 1.27, 95% CI 1.12-1.45, p < 0.01), whereas oxygen index (HR 0.990, 95% CI 0.988-0.992, p < 0.01), partial pressure of oxygen (HR 0.933, 95% CI 0.906-0.961, p < 0.01), forced vital capacity (HR 0.962, 95% CI 0.928-0.998, p = 0.038), and lymphocyte count (HR 0.421, 95% CI 0.282-0.629, p < 0.01) were associated with better outcomes. CONCLUSIONS: Old age, male sex, hypoxemia, low forced vital capacity, lymphocytopenia, and high levels of ferritin, CRP, creatine kinase, and LDH are risk factors for mortality in patients with MDA5+ DM. However, a cautious interpretation of these results and further quality investigation are warranted.