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Nitrate (NO3-) in wastewater poses a serious threat to human health and the ecological environment. The electrocatalytic NO3- reduction to ammonia (NH3) reaction (NO3-RR) emerges as a promising carbon-free energy route for enabling NO3- removal and sustainable NH3 synthesis. However, it remains a challenge to achieve high Faraday efficiencies at a wide potential window due to the complex multiple-electron reduction process. Herein, spatially separated dual-metal tandem electrocatalysts made of a nitrogen-doped ordered mesoporous carbon support with ultrasmall and high-content Cu nanoparticles encapsulated inside and large and low-content Ru nanoparticles dispersed on the external surface (denoted as Ru/Cu@NOMC) are designed. In electrocatalytic NO3-RR, the Cu sites can quickly convert NO3- to adsorbed NO2- (*NO2-), while the Ru sites can efficiently produce active hydrogen (*H) to enhance the kinetics of converting *NO2- to NH3 on the Cu sites. Due to the synergistic effect between the Cu and Ru sites, Ru/Cu@NOMC exhibits a maximum NH3 Faradaic efficiency (FENH3) of approximately 100% at -0.1 V vs reversible hydrogen electrode (RHE) and a high NH3 yield rate of 1267 mmol gcat-1 h-1 at -0.5 V vs RHE. Finite element method (FEM) simulation and electrochemical in situ Raman spectroscopy revealed that the mesoporous framework can enhance the intermediate concentration due to the in situ confinement effect. Thanks to the Cu-Ru synergistic effect and the mesopore confinement effect, a wide potential window of approximately 500 mV for FENH3 over 90% and a superior stability for NH3 production over 156 h can be achieved on the Ru/Cu@NOMC catalyst.
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FtsH, a AAA protease, associates with HflK/C subunits to form a megadalton complex that spans the inner membrane and extends into the periplasm of E. coli. How this complex and homologous assemblies in eukaryotic organelles recruit, extract, and degrade membrane-embedded substrates is unclear. Following overproduction of protein components, recent cryo-EM structures reveal symmetric HflK/C cages surrounding FtsH in a manner proposed to inhibit degradation of membrane-embedded substrates. Here, we present structures of native complexes in which HflK/C instead forms an asymmetric nautilus-like assembly with an entryway for membrane-embedded substrates to reach and be engaged by FtsH. Consistent with this nautilus-like structure, proteomic assays suggest that HflK/C enhances FtsH degradation of certain membrane-embedded substrates. The membrane curvature in our FtsHâ¢HflK/C complexes is opposite that of surrounding membrane regions, a property that correlates with lipid-scramblase activity and possibly with FtsH's function in the degradation of membrane-embedded proteins.
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OBJECTIVES: To observe the clinical efficacy of acupuncture intervention at different time for patients with sudden hearing loss. METHODS: According to the timing of acupuncture intervention, 86 patients were divided into early exposure group (n=43) and late exposure group (n=43) . The early exposure group was given acupuncture treatment within 14 days of onset, and the late exposure group was given acupuncture treatment after 14 days of onset. After propensity score matching (PSM, a statistical matching technique for observational data) processing by using SPSS26.0 software, outcomes of 30 cases in the early exposure group and 30 cases in the late exposure group were analyzed. In addition to receiving basic treatment with drugs for vascular dilatation, thrombolysis, nourishing nerve, etc., all patients of the two groups were treated with neck acupuncture ("Neck Seven Meridian Lines" acupuncture), once every other day except Sundays, for a total of 12 time. Before, after the treatment and 3 months after the treatment, the total score of the Tinnitus Handicap Inventory (THI, 0, 2 and 4 points for each of the 25 items, total scores = 100 points) scale was used to evaluate the improvement of tinnitus symptoms caused by hearing loss. The clinical therapeutic effect was evaluated according to the efficacy grading criteria in the Guidelines for Diagnosis and Treatment of Sudden Deafness (2015) and the changes of pure tone audiometry curve. Multivariate Logistic regression was used to analyze the effect of factors that might influence efficacy before propensity score matching. RESULTS: The THI scores of patients in both groups decreased strikingly after the treatment and 3 months' follow-up (P<0.05). Compared with the same time-points of the late exposure group, the total THI scores of post-treatment and 3 months' follow-up were evidently lower in the early exposure group (P<0.05). The effective rate of the early exposure group (22/30, 80.00%) was significantly higher (P<0.05) than that of the late exposure group (16/30, 53.33%). The classification of sudden deafness and the application of traditional Chinese medicine in this study were not independent factors affecting the total effective rate. CONCLUSIONS: The time point of acupuncture intervention is an important factor affecting the effect on hearing and tinnitus disability of patients with sudden deafness. The earlier acupuncture treatment is accepted, the better the therapeutic effect is.
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Terapia por Acupuntura , Perda Auditiva Súbita , Humanos , Perda Auditiva Súbita/terapia , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Resultado do Tratamento , Idoso , Fatores de Tempo , Pontos de Acupuntura , Adulto Jovem , Zumbido/terapiaRESUMO
Lumbar intervertebral disc herniation (LDH) is a common and frequently-occurring disease, which usually causes lumbar and leg pain. Studies have shown that acupuncture can improve the symptoms of LDH patients. In the present paper, we summarize the progress of researches on the mechanisms of acupuncture underlying improvement of symptoms of LDH in recent 10 years from 1) delaying the intervertibral disc degeneration (by down-regulating the expressions of matrix metalloproteinase ï¼»MMPï¼½-3 and MMP-4, up-regulating the expressions of diosaccharides and polyglycoprotein, inhibiting apoptosis and promoting mitochondrial autophagy of nucleus pulposus cells, etc.), 2) maintaining spinal column stability (by relieving rachiasmus and improving lumbar flexor and extensor muscle strength, lowering the degree of polyfidus edema and fat infiltration, and restoring the biomechanics of the spine), 3) regulating inflammation (by inhibiting the production of proinflammatory factors and increasing the production of anti-inflammatory factors, etc.), 4) regulating immune response (by promoting the activity of T cells and other immune cells, lowering serum levels of MMP-3, transforming growth factor-ß1 and prostaglandin E2, raising serum levels of IgA, IgG and IgM to improve immune function ), 5) modulating neural structure and function (by promoting myelin regeneration of sciatic nerve fibers, and reducing the edema of Schwann cells' cytoplasm and mitochondria, and improving neural ultrastructure, and sensory and motor functions of peripheral nerves, etc.), 6) relieving lumbar pain (by down-regulating expression of Ca2+/calmodulin-dependent protein kinase and activation of lumbar spinal cord glial cells, blocking nociceptive signal conduction, regulating the levels of pain-related factors, etc.), and 7) improving local microcirculation. These results may provide scientific evidence for acupuncture treatment of LDH.
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Terapia por Acupuntura , Deslocamento do Disco Intervertebral , Humanos , Deslocamento do Disco Intervertebral/terapia , Animais , Vértebras LombaresRESUMO
BACKGROUND: Inguinal hernia in adults is a common and frequent disease in surgery, prone to occur in the elderly or in those with a weak abdominal wall. Despite its prevalence, Molecular mechanisms underlying inguinal hernia formation are unclear. OBJECTIVE: This study aims to identify potential gene markers for inguinal hernia and available drugs. METHODS: Pubmed2Ensembl text mining was used to identify genes related to "inguinal hernia" keywords. The GeneCodis system was used to specify GO biological process terms and KEGG pathways defined in the Kyoto Encyclopedia of Genes and Genomes (KEGG). The STRING tool was used to construct protein-protein interaction networks, which were then visualized using Cytoscape.CytoHubba and Molecular Complex Detection were utilized to analyze the module (MCODE). A GO and KEGG analysis of gene modules was conducted using the DAVID platform database. Hub genes are those that are concentrated in prominent modules. The druggene interaction database was also used to identify potential drugs for inguinal hernia patients based on their interactions between the hub genes. Finally, a Mendelian randomization study was conducted based on genome-wide association studies to determine whether hub genes cause inguinal hernias. RESULTS: The identification of 96 genes associated with inguinal hernia was carried out using text mining techniques. It was constructed using PPI networks with 80 nodes and 476 edges, and the sequence of the genes was performed using CytoHubba. MCODE analysis identified three gene modules. Three modules contain 37 genes clustered as hub candidate genes associated with inguinal hernia patients. The PI3K-Akt, MAPK, AGE-RAGE, and HIF-1 pathways were found to be enriched in signaling pathways. Sixteen of the 37 genes were found to be targetable by 30 existing drugs. The relationship between hub genes and inguinal hernia was examined using Mendelian randomization. The research revealed nine genes that may be connected with inguinal hernia, such as POMC, CD40LG, TFRC, VWF, LOX, IGF2, BRCA1, TNF, and HGF in the plasma. By inverse variance weighting, ALB was associated with an increased risk of inguinal hernia with an OR of 1.203 (OR [95%] = 1,04 [1.012 to 1.089], p = 0.008). CONCLUSION: We identified potential hub genes for inguinal hernia, predicted potential drugs for inguinal hernia, and reverse-validated potential genes by Mendelian randomization. This may provide further insights into asymptomatic pre-diagnostic methods and contribute to studies to understand the molecular mechanisms of risk genes associated with inguinal hernia.
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To investigate the spatial distribution and source of plutonium isotopes in the Beibu Gulf, surface sediments were collected and analyzed using sector field inductively coupled plasma mass spectrometry (SF-ICP-MS). The activities of 239+240Pu in surface sediments ranged from 0.012 to 0.451 mBq/g (mean: 0.171 ± 0.138 mBq/g, n = 36), indicating a decreasing trend in a counterclockwise direction from the southern bay mouth. The counterclockwise decreasing trend in the south of the bay mouth is similar to the current in the Beibu Gulf. The 240Pu/239Pu atom ratios in surface sediments ranged from 0.156 to 0.283 (mean: 0.236 ± 0.031, n = 36), slightly higher than that of the global fallout value of 0.18. This suggests that the Pu in the Beibu Gulf was a combination of global fallout and Pacific Proving Ground (PPG). The average contribution of the plutonium (Pu) derived from the PPG in the sediment was estimated to be 52 % ± 24 %.
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Plutônio , Monitoramento de Radiação , Cinza Radioativa , Poluentes Radioativos da Água , Sedimentos Geológicos/química , Plutônio/análise , Poluentes Radioativos da Água/análise , China , Cinza Radioativa/análiseRESUMO
Taking the recommendations development of the World Federation of Acupuncture-Moxibustion Societies (WFAS) standard Clinical Practice Guideline for Female Urinary Incontinence as an example, this study analyzed the consensus expert composition, specific consensus process, and results in the development of the guideline's recommendations. It systematically examined the advantages of using the modified Delphi method in the formation of recommendations for acupuncture and moxibustion clinical practice guideline, with the aim of providing reference for the development of acupuncture and moxibustion guidelines in the same field.
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Terapia por Acupuntura , Acupuntura , Moxibustão , Feminino , Humanos , Técnica DelphiRESUMO
AAA+ proteases degrade intracellular proteins in a highly specific manner. E. coli ClpXP, for example, relies on a C-terminal ssrA tag or other terminal degron sequences to recognize proteins, which are then unfolded by ClpX and subsequently translocated through its axial channel and into the degradation chamber of ClpP for proteolysis. Prior cryo-EM structures reveal that the ssrA tag initially binds to a ClpX conformation in which the axial channel is closed by a pore-2 loop. Here, we show that substrate-free ClpXP has a nearly identical closed-channel conformation. We destabilize this closed-channel conformation by deleting residues from the ClpX pore-2 loop. Strikingly, open-channel ClpXP variants degrade non-native proteins lacking degrons faster than the parental enzymes in vitro but degraded GFP-ssrA more slowly. When expressed in E. coli, these open channel variants behave similarly to the wild-type enzyme in assays of filamentation and phage-Mu plating but resulted in reduced growth phenotypes at elevated temperatures or when cells were exposed to sub-lethal antibiotic concentrations. Thus, channel closure is an important determinant of ClpXP degradation specificity.
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Proteínas de Escherichia coli , Escherichia coli , Humanos , ATPases Associadas a Diversas Atividades Celulares/genética , ATPases Associadas a Diversas Atividades Celulares/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas de Escherichia coli/metabolismo , Adenosina Trifosfatases/metabolismo , Endopeptidase Clp/metabolismo , Proteólise , Translocação GenéticaRESUMO
Morphine is a frequently used analgesic that activates the mu-opioid receptor (MOR), which has prominent side effects of tolerance. Although the inefficiency of morphine in inducing the endocytosis of MOR underlies the development of morphine tolerance, currently, there is no effective therapy to treat morphine tolerance. In the current study, we aimed to develop a monoclonal antibody (mAb) precisely targeting MOR and to determine its therapeutic efficacy on morphine tolerance and the underlying molecular mechanisms. We successfully prepared a mAb targeting MOR, named 3A5C7, by hybridoma technique using a strategy of deoxyribonucleic acid immunization combined with cell immunization, and identified it as an immunoglobulin G mAb with high specificity and affinity for MOR and binding ability to antigens with spatial conformation. Treatment of two cell lines, HEK293T and SH-SY5Y, with 3A5C7 enhanced morphine-induced MOR endocytosis via a G protein-coupled receptor kinase 2 (GRK2)/ß-arrestin2-dependent mechanism, as demonstrated by immunofluorescence staining, flow cytometry, Western blotting, coimmunoprecipitation, and small interfering ribonucleic acid (siRNA)-based knockdown. This mAb also allowed MOR recycling from cytoplasm to plasma membrane and attenuated morphine-induced phosphorylation of MOR. We established an in vitro morphine tolerance model using differentiated SH-SY5Y cells induced by retinoic acid. Western blot, enzyme-linked immunosorbent assays, and siRNA-based knockdown revealed that 3A5C7 mAb diminished hyperactivation of adenylate cyclase, the in vitro biomarker of morphine tolerance, via the GRK2/ß-arrestin2 pathway. Furthermore, in vivo hotplate test demonstrated that chronic intrathecal administration of 3A5C7 significantly alleviated morphine tolerance in mice, and withdrawal jumping test revealed that both chronic and acute 3A5C7 intrathecal administration attenuated morphine dependence. Finally, intrathecal electroporation of silencing short hairpin RNA illustrated that the in vivo anti-tolerance and anti-dependence efficacy of 3A5C7 was mediated by enhanced morphine-induced MOR endocytosis via GRK2/ß-arrestin2 pathway. Collectively, our study provided a therapeutic mAb, 3A5C7, targeting MOR to treat morphine tolerance, mediated by enhancing morphine-induced MOR endocytosis. The mAb 3A5C7 demonstrates promising translational value to treat clinical morphine tolerance.
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Cancers originate from a single cell according to Nowell's theory of clonal evolution. The enrichment of the most aggressive clones has been developed and the heterogeneity arises for genomic instability and environmental selection. Multiple myeloma (MM) is a multiple relapse plasma cell cancer generated from bone marrow. Although there were accumulating researches in multiple myeloma pathogenesis, the heterogeneity remains poorly understood. The participants enrolled in this study were 4 EMP+ (EMP, Extramedullary plasmacytoma) and 2 EMP- primarily untreated MM patients. Single cell RNA sequencing and analysis were conducted for the single cell suspension, which was sorted by flow cytometry from peripheral blood mononuclear cells or bone marrow cells. In our research, the results of single cell RNA sequencing show that FAM46C determines MM tumor heterogeneity predicting extramedullary metastasis by influencing RNA stability. Further, we integrated and analyzed 2280 multiple myeloma samples from 7 independent datasets, which uncover that FAM46C mediated tumor heterogeneity predicts poorer survival in multiple myeloma.
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Mieloma Múltiplo , Plasmocitoma , Humanos , Medula Óssea/patologia , Leucócitos Mononucleares , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Recidiva Local de Neoplasia , Plasmocitoma/patologiaRESUMO
With three representative types of gynecological diseases (dysmenorrhea, pelvic inflammation, polycystic ovary syndrome) as examples, the application methods of meridian and acupoint diagnosis for gynecological diseases treated with acupuncture and moxibustion are discussed. During clinical diagnosis and treatment, it is recommended to examine the patient's leg segment along the three yin meridians of foot, aiming to explore the positive reactions of the meridians and acupoints (color, shape, skin temperature, sensory abnormalities, etc.). Acupuncture and moxibustion treatment at this positive reaction place can improve the clinical efficacy. Meridian and acupoint diagnosis could provide basis for meridian syndrome differentiation, thus guiding the selection of acupoint prescriptions; it is also helpful to clarify the deficiency, excess, cold and heat of the disease nature, thus guiding the selection of acupuncture and moxibustion methods. In addition, it is an auxiliary method to estimate the prognosis and outcome of the disease.
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Terapia por Acupuntura , Doenças dos Genitais Femininos , Meridianos , Moxibustão , Feminino , Humanos , Pontos de Acupuntura , Pé , Doenças dos Genitais Femininos/diagnóstico , Doenças dos Genitais Femininos/terapiaRESUMO
Irisin is a muscle-derived hormone that promotes the survival of motor neurons and enhances muscle size following injury. In this study, we investigated the beneficial effects and mechanism(s) of action of irisin in response to cerebral ischemia-reperfusion injury (CIRI). Right-middle cerebral artery occlusion (MCAO) and hypoxia/reoxygenation (H/R) models were generated in C57BL/6 J mice. Mouse neuronal cell lines (NSC-34) were used to confirm the molecular mechanisms of the protection afforded by irisin in response to CIRI. We found that irisin (250 µg/kg) improved cerebral function and reduced the cerebral infarct volume following CIRI. Irisin also protected neuronal cells against ischemia-reperfusion (I/R) induced apoptosis, assessed via TUNEL, and cleaved Caspase-3 staining. Western blotting of neuronal tissue from irisin treated I/R mice showed lower expression of pro-apoptotic Bax and caspase-9 (P < 0.001 and P < 0.01) and increased levels of the pro-survival protein Bcl-2 (P < 0.01 & P < 0.001 vs. I/R). Irisin also reduced the levels of reactive oxygen species (ROS) characterized through malondialdehyde (MDA) assays. Irisin was found to maintain mitochondrial homeostasis through the suppression of mitochondrial fission-linked dynamin-related protein 1 in CIRI mice (P < 0.01 and P < 0.05 v. I/R cohort). Moreover, mitochondrial fusion-related protein (Mfn2) and Opa1 expression were rescued following irisin treatment (P < 0.001 and P < 0.01 v. I/R cohort). Cell-based assays showed that irisin activates PI3K/AKT/mTOR signaling in the neurons of CIRI mice. Furthermore, the beneficial effects of irisin on NSC-34 cell-survival, mitochondrial function, and ROS generation were reversed by VS-5584, a highly specific PI3K/AKT/mTOR inhibitor. Collectively, these data highlight the ability of irisin to alleviate CIRI in vivo and in vitro. The mechanisms of action of irisin include the attenuation of apoptosis through the prevention of mitochondrial fission and increased mitochondrial fusion and the alleviation of oxidative stress through activation of the PI3K/AKT/mTOR axis. We therefore identify irisin as a much-needed therapeutic for CIRI.
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Isquemia Encefálica , Traumatismo por Reperfusão , Camundongos , Animais , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio , Fibronectinas/farmacologia , Camundongos Endogâmicos C57BL , Serina-Treonina Quinases TOR/metabolismo , Traumatismo por Reperfusão/metabolismo , Isquemia Encefálica/metabolismo , Mitocôndrias/metabolismo , ApoptoseRESUMO
Inactivation of horseradish peroxidase (HRP) treatment is a conventional preference to stripping for sequential detections of different proteins of chemiluminescent western blotting (WB). However, little evidence exists on whether other chemical substances treatment can affects the biological activity of HRP during stripping and re-probing of WB blots. Here, we successfully develop 20% crotonic acid (CA) as an alternative to stripping to inhibit HRP used for sequential chemiluminescent WB on polyvinylidene difluoride (PVDF) and Nitrocellulose (NC) membrane. Moreover, NC blots incubation in CA (40 °C, 30min) allow us to perform three round HRP inhibition in sequential detections without losing transferred proteins and damaging membrane. Hence, the method will help us save time and valuable samples without the need to rerun gels.
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Crotonatos , Proteínas , Peroxidase do Rábano Silvestre/química , Western BlottingRESUMO
BACKGROUND: Multiple myeloma (MM) complicated with extramedullary disease (EMD) has a poor prognosis and is a limiting factor in the treatment of MM, and no standard treatment is recommended in international guidelines. Few studies have reported MM with periorbital EMD. CASE SUMMARY: In this paper, the clinical characteristics and survival of seven patients with multiple myeloma and orbital are described and analyzed. The common ocular symptoms were blurred vision, proptosis and/or eye movement disorders, IgG type MM may be a risk factor for orbital involvement. Of them, six patients were treated with bortezomib-based regimens. The median overall survival (OS) and progression free survival for the entire cohort were 48 and 33 mo, respectively, which was much worse than the OS reported for MM patients without orbital EMD. CONCLUSION: Orbital MM may have significantly shortened survival for the entire cohort, so multidisciplinary collaboration is emphasized and recommended in the diagnosis and treatment of these difficult cases.
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Gynecological cancer is one of the most severe diseases that threaten the lives and health of women worldwide. Its incidence rate increases with each passing year and becomes more prevalent among young people. The prognosis of gynecological cancer remains poor despite significant advances in surgical removal and systemic chemotherapy. Several chemokines play a role in the progression of gynecologic cancers. CCL2 (CC-chemokine ligand 2), also termed MCP-1 (monocyte chemotactic protein 1), plays a significant physiological role in monocyte cell migration and the inflammatory response. Recent studies have demonstrated that CCL2 plays a pro-tumorigenic function in the tumor microenvironment. According to previous studies, CCL2 plays a significant role in the occurrence and development of gynecological cancers. Furthermore, recent studies noted that CCL2 could be a potential diagnostic biomarker and prognostic predictor. The purpose of this paper is to review the role of CCL2 in the occurrence and development of gynecological cancers and to discuss the potential therapeutic strategy of CCL2 for gynecological cancers, with a primary focus on breast cancer, ovarian cancer, cervical cancer, and endometrial cancer.
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Opioid abuse and addiction have become a global pandemic, posing tremendous health and social burdens. The rewarding effects and the occurrence of withdrawal symptoms are the two mainstays of opioid addiction. Mu-opioid receptors (MORs), a member of opioid receptors, play important roles in opioid addiction, mediating both the rewarding effects of opioids and opioid withdrawal syndrome (OWS). The underlying mechanism of MOR-mediated opioid rewarding effects and withdrawal syndrome is of vital importance to understand the nature of opioid addiction and also provides theoretical basis for targeting MORs to treat drug addiction. In this review, we first briefly introduce the basic concepts of MORs, including their structure, distribution in the nervous system, endogenous ligands, and functional characteristics. We focused on the brain circuitry and molecular mechanism of MORs-mediated opioid reward and withdrawal. The neuroanatomical and functional elements of the neural circuitry of the reward system underlying opioid addiction were thoroughly discussed, and the roles of MOR within the reward circuitry were also elaborated. Furthermore, we interrogated the roles of MORs in OWS, along with the structural basis and molecular adaptions of MORs-mediated withdrawal syndrome. Finally, current treatment strategies for opioid addiction targeting MORs were also presented.
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Microbial communities play an important role in ecological processes through direct or indirect interactions. However, the interspecific interaction pattern of reservoir microorganisms has still received little attention. The Hengshan Reservoir in Jiangsu province was selected as the research area. Surface and deep water samples were collected to respectively explore the response of planktonic microbial community structure and the molecular ecological network to water depth changes, as well as to identify the key species of planktonic microbial communities in different water depths. The results showed that the richness and evenness of planktonic microorganisms in the surface layer were higher than those in the deep layer, and there were significant differences in the community structure of planktonic microorganisms in different depths. Water depth indirectly affected the planktonic microbial community by changing the environmental heterogeneity, among which the indicators such as TOC, NO3-, NH4+, and PO43- had the most significant impact on the planktonic microbial community structure. In addition, the number of nodes and edges of the deep planktonic microbial molecular ecological network were significantly higher than those on the surface, and the type and number of key species in the deep planktonic microbial community were significantly higher than those on the surface, indicating that the network scale of the deep planktonic microbial community was larger; however, the interspecific cooperative relationship and network connectivity of the surface planktonic microbial community were stronger. These results will provide a scientific basis for the study of interspecific interactions of reservoir microbial communities and are of great significance for predicting the ecological law of microorganisms in reservoir ecosystems and the impact of global material cycles.
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Microbiota , Plâncton , Água , Microbiologia da ÁguaRESUMO
Systemic inflammatory response syndrome (SIRS) is characterized by dysregulated cytokine release, immune responses and is associated with organ dysfunction. IL-6R blockade indicates promising therapeutic effects in cytokine release storm but still remains unknown in SIRS. To address the issue, we generated the human il-6r knock-in mice and a defined epitope murine anti-human membrane-bound IL-6R (mIL-6R) mAb named h-mIL-6R mAb. We found that the h-mIL-6R and the commercial IL-6R mAb Tocilizumab significantly improved the survival rate, reduced the levels of TNF-α, IL-6, IL-1ß, IFN-γ, transaminases and blood urea nitrogen of LPS-induced SIRS mice. Besides, the h-mIL-6R mAb could also dramatically reduce the levels of inflammatory cytokines in LPS-treated THP-1 cells in vitro. RNA-seq analysis indicated that the h-mIL-6R mAb could regulate LPS-induced activation of NF-κB/Ccl2 and NOD-like receptor signaling pathways. Furthermore, we found that the h-mIL-6R mAb could forwardly inhibit Ccl2 expression and NLRP3-mediated pyroptosis by suppressing NF-κB in combination with the NF-κB inhibitor. Collectively, mIL-6R mAbs suppressed NF-κB/Ccl2 signaling and inflammasome activation. IL-6R mAbs are potential alternative therapeutics for suppressing excessive cytokine release, over-activated inflammatory responses and alleviating organ injuries in SIRS.
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The fall armyworm Spodoptera frugiperda (S. frugiperda) (Lepidoptera: Noctuidae) is a worldwide, disruptive, agricultural pest species. The larvae of S. frugiperda feed on seedling, leave, and kernel of crops with chewing mouthparts, resulting in reduced crop yields. Serotonin is an important biogenic amine acting as a neural circuit modulator known to mediate lots of behaviors including feeding in insects. In order to explore the serotonergic neural network in the nervous system of larval S. frugiperda, we performed immunohistochemical experiments to examine the neuropil structure of the brain and the gnathal ganglion with antisynapsin and to examine their serotonergic neurons with antiserotonin serum. Our data show that the brain of larval S. frugiperda contains three neuromeres: the tritocerebrum, the deutocerebrum, and the protocerebrum. The gnathal ganglion also contains three neuromeres: the mandibular neuromere, the maxillary neuromere, and the labial neuromere. There are about 40 serotonergic neurons in the brain and about 24 serotonergic neurons in the gnathal ganglion. Most of these neurons are wide-field neurons giving off processes in several neuropils of the brain and the gnathal ganglion. Serotonergic neuron processes are mainly present in the protocerebrum. A pair of serotonergic neurons associated with the deutocerebrum has arborizations in the contralateral antennal lobe and bilateral superior lateral protocerebra. In the gnathal ganglion, the serotonergic neuron processes are also widespread throughout the neuropil and some process projections extend to the tritocerebrum. These findings on the serotonergic neuron network in larval S. frugiperda allow us to explore the important roles of serotonin in feeding and find a potential approach to modulate the feeding behavior of the gluttonous pest and reduce its damage.
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Objectives: This study aimed to examine the efficacy and safety of acupoint catgut embedding (ACE) for obesity over a 16-week treatment period using sham stimulation as the control. Methods: A multicenter, randomised, parallel, sham-controlled trial was conducted from February 10, 2017, to May 15, 2018. Men with waistlines ≥85 cm and women with ≥80 cm at three sites were randomised to receive eight sessions (over 16 weeks) of ACE (n = 108) or sham ACE (n = 108) with skin penetration at sham acupoints. The catgut was embedded once every two weeks using two alternating sets of acupoints. The follow-up lasted for an additional 24 weeks. The primary outcome was the percentage waistline reduction from baseline to week 16. Results: We included 216 individuals in the intention-to-treat analysis. At 16 weeks, the rate of waistline reduction was 8.80% (95% confidence interval (CI), 7.93% to 9.66%) in the ACE group and 4.09% (95% CI, 3.18% to 5.00%) in the sham control group, with a between-group difference of 4.71% (95% CI, 3.47% to 5.95%; P < 0.0001). This difference persisted throughout the entire follow-up period (between-group difference after 24-week additional weeks, 4.94% (95% CI, 3.58% to 6.30%); P < 0.001). The subgroup analyses of waistline by sex (male/female) revealed treatment effects of 1.93 (95% CI, -0.37 to 4.23, P = 0.1) in the male group and 3.19 (95% CI, 1.99 to 4.39, P < 0.001) in the female group. The adverse event analysis suggested that ACE and laboratory tests confirmed the safety of ACE. Discussion. ACE for 16 weeks could decrease the waistline and weight and was safe for the treatment of obesity. Further research is needed to evaluate the long-term efficacy and sex differences. This trial is registered with NCT02936973.