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Chronic pancreatitis (CP) is a progressive inflammatory disease with an increasing global prevalence. In recent years, a strong association between CP and metabolic bone diseases (MBDs), especially osteoporosis, has been identified, attracting significant attention in the research field. Epidemiological data suggest a rising trend in the incidence of MBDs among CP patients. Notably, recent studies have highlighted a profound interplay between CP and altered nutritional and immune profiles, offering insights into its linkage with MBDs. At the molecular level, CP introduces a series of biochemical disturbances that compromise bone homeostasis. One critical observation is the disrupted metabolism of vitamin D and vitamin K, both essential micronutrients for maintaining bone integrity, in CP patients. In this review, we provide physio-pathological perspectives on the development and mechanisms of CP-related MBDs. We also outline some of the latest therapeutic strategies for treating patients with CP-associated MBDs, including stem cell transplantation, monoclonal antibodies, and probiotic therapy. In summary, CP-associated MBDs represent a rising medical challenge, involving multiple tissues and organs, complex disease mechanisms, and diverse treatment approaches. More in-depth studies are required to understand the complex interplay between CP and MBDs to facilitate the development of more specific and effective therapeutic approaches.
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Enfermedades Óseas Metabólicas , Pancreatitis Crónica , Humanos , Pancreatitis Crónica/epidemiología , Pancreatitis Crónica/metabolismo , Pancreatitis Crónica/complicaciones , Enfermedades Óseas Metabólicas/epidemiología , Enfermedades Óseas Metabólicas/etiología , Enfermedades Óseas Metabólicas/metabolismo , Vitamina D/metabolismo , Vitamina D/uso terapéutico , Vitamina K/metabolismo , AnimalesRESUMEN
In this paper, research was conducted on Deep Learning Wavefront Sensing (DLWS) neural networks using simulated atmospheric turbulence datasets, and a novel DLWS was proposed based on attention mechanisms and Convolutional Neural Networks (CNNs). The study encompassed both indoor experiments and kilometer-range laser transmission experiments employing DLWS. In terms of indoor experiments, data were collected and training was performed on the platform built by us. Subsequent comparative experiments with the Shack-Hartmann Wavefront Sensing (SHWS) method revealed that our DLWS model achieved accuracy on par with SHWS. For the kilometer-scale experiments, we directly applied the DLWS model obtained from the indoor platform, eliminating the need for new data collection or additional training. The DLWS predicts the wavefront from the beacon light PSF in real time and then uses it for aberration correction of the emitted laser. The results demonstrate a substantial improvement in the average peak intensity of the light spot at the target position after closed-loop correction, with a remarkable increase of 5.35 times compared to the open-loop configuration.
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Degenerative disc disease (DDD) is one of the most common skeletal disorders affecting aged populations. DDD is the leading cause of low back/neck pain, resulting in disability and huge socioeconomic burdens. However, the molecular mechanisms underlying DDD initiation and progression remain poorly understood. Pinch1 and Pinch2 are LIM-domain-containing proteins with crucial functions in mediating multiple fundamental biological processes, such as focal adhesion, cytoskeletal organization, cell proliferation, migration, and survival. In this study, we found that Pinch1 and Pinch2 were both highly expressed in healthy intervertebral discs (IVDs) and dramatically downregulated in degenerative IVDs in mice. Deleting Pinch1 in aggrecan-expressing cells and Pinch2 globally (AggrecanCreERT2; Pinch1fl/fl; Pinch2-/-) caused striking spontaneous DDD-like lesions in lumbar IVDs in mice. Pinch loss inhibited cell proliferation and promoted extracellular matrix (ECM) degradation and apoptosis in lumbar IVDs. Pinch loss markedly enhanced the production of pro-inflammatory cytokines, especially TNFα, in lumbar IVDs and exacerbated instability-induced DDD defects in mice. Pharmacological inhibition of TNFα signaling mitigated the DDD-like lesions caused by Pinch loss. In human degenerative NP samples, reduced expression of Pinch proteins was correlated with severe DDD progression and a markedly upregulated expression of TNFα. Collectively, we demonstrate the crucial role of Pinch proteins in maintaining IVD homeostasis and define a potential therapeutic target for DDD.
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OBJECTIVE: The objective of this study is to analyze and verify the main drug components and targets of "Fuzi-Guizhi" in the treatment of osteoarthritis by using the network pharmacology platform. METHODS: The integrated pharmacology of "Fuzi-Guizhi" was analyzed by using the platform of integrated pharmacology of traditional Chinese medicine to explore its mechanism in the treatment of osteoarthritis. By establishing an arthritis model in vitro, the pharmacological effect of "aconitecassia twigs" on articular cartilage was evaluated and conducted for molecular docking. RESULTS: 28 candidate active components, 37 compound targets, and 583 osteoarthritis-related potential targets were screened, and 10 key target processes were screened in the protein interaction network model. Enrichment analysis showed that the 10 core targets involved 958 GO biologic function items and 76 KEGG signal pathways, which were mainly related to apoptosis and mitochondrial functional metabolism and "Fuzi-Guizhi" drug-containing serum inhibited the expression of Caspase-3 mRNA and protein in chondrocytes and promoted the synthesis of ATP. CONCLUSION: Our research is preliminary that the mechanism of action of "Fuzi-Guizhi" may inhibit chondrocyte degeneration by resisting mitochondrial apoptosis, and further experimental research is required to determine.
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Diterpenos , Medicamentos Herbarios Chinos , Osteoartritis , Humanos , Simulación del Acoplamiento Molecular , Farmacología en Red , Osteoartritis/tratamiento farmacológico , Medicina Tradicional China , Medicamentos Herbarios Chinos/farmacologíaRESUMEN
During the last decade, osteoarthritis (OA) has become one of the most prevalent musculoskeletal diseases worldwide. OA is characterized by progressive loss of articular cartilage, abnormal remodeling of subchondral bone, hyperplasia of synovial cells, and growth of osteophytes, which lead to chronic pain and disability. The pathological mechanisms underlying OA initiation and progression are still poorly understood. Non-coding RNAs (ncRNAs) constitute a large portion of the transcriptome that do not encode proteins but function in numerous biological processes. Cumulating evidence has revealed a strong association between the changes in expression levels of ncRNA and the disease progression of OA. Moreover, loss- and gain-of-function studies utilizing transgenic animal models have demonstrated that ncRNAs exert vital functions in regulating cartilage homeostasis, degeneration, and regeneration, and changes in ncRNA expression can promote or decelerate the progression of OA through distinct molecular mechanisms. Recent studies highlighted the potential of ncRNAs to serve as diagnostic biomarkers, prognostic indicators, and therapeutic targets for OA. MiRNAs and lncRNAs are two major classes of ncRNAs that have been the most widely studied in cartilage tissues. In this review, we focused on miRNAs and lncRNAs and provided a comprehensive understanding of their functional roles as well as molecular mechanisms in cartilage homeostasis and OA pathogenesis.
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BACKGROUND: Ropivacaine oil delivery depot (RODD) can be used to treat postoperative incision pain. The aim was to study pharmacodynamics, toxicity and toxicokinetics of RODD. METHODS: The base research of RODD were conducted. Thirty rabbits were randomly divided into saline, solvent, ropivacaine aqueous injection (RAI) 0.9 mg, RODD 0.9 mg and RODD 3 mg groups. The sciatic nerve of rabbits were isolated, dripped with RODD and the effect of nerve block were observed. In toxicity study, the rats were divided into saline, solvent and RODD 75, 150 and 300 mg/kg groups, 30 rats per group. In toxicokinetics, rats were divided into RODD 75, 150 and 300 mg/kg groups, 18 rats per group. The rats were subcutaneously injected drugs. RESULTS: The analgesic duration of RODD 3 mg and RAI 0.9 mg blocking ischiadic nerve lasted about 20 h and 2 h, respectively, and their blocking intensity was similar. The rats in RODD 75 mg/kg did not show any toxicity. Compared with saline group, in RODD 150 mg/kg group neutrophils and mononuclear cells increased, lymphocytes decreased and albumin decreased(P < 0.05), and pathological examination showed some abnormals. In RODD 300 mg/kg group, 10 rats died and showed some abnormalities in central nerve system, hematologic indexes, part of biochemical indexes, and the weights of spleen, liver, and thymus. However, these abnormal was largely recovered on 14 days after the dosing. The results of toxicokinetics of RODD 75 mg/kg group showed that the Cmax was 1.24 ± 0.59 µg/mL and the AUC(0-24 h) was 11.65 ± 1.58 h·µg/mL. CONCLUSIONS: Subcutaneous injection RODD releases ropivacaine slowly, and shows a stable and longer analgesic effect with a large safety range.
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Anestésicos Locales , Ropivacaína , Animales , Conejos , Ratas , Anestésicos Locales/farmacología , Anestésicos Locales/toxicidad , Dolor Postoperatorio/tratamiento farmacológico , Ropivacaína/farmacología , Ropivacaína/toxicidad , Nervio Ciático , Solventes , ToxicocinéticaRESUMEN
BACKGROUND: Persistent pain following back surgery called failed back surgery syndrome remains a major treatment challenge. The aim of this study is to evaluate the efficacy and safety of electroacupuncture on relieving back pain in FBSS patients. METHODS/DESIGN: This is a randomized, single-blind, single-site, placebo-controlled trial. A total of 144 eligible FBSS patients will be randomly assigned to the electroacupuncture, manual acupuncture, or sham acupuncture group in a 1:1:1 ratio. Each group will receive 2 treatment sessions per week for 12 weeks. The primary outcome will be low back pain intensity based on the 11-point numerical rating scale (NRS). The secondary outcomes include Oswestry Disability Index (ODI) questionnaire, Beck Depression Inventory-II (BDI-II), Pittsburgh Sleep Quality Index (PSQI), and analgesic consumption. All clinical outcomes will be collected at baseline, during the treatment phase (at 8 and 12 weeks), and at the 16-, 24- and 36-week follow-ups. All data will be analyzed based on the intention-to-treat principle and adverse events will be assessed during the trial. DISCUSSION: This pilot randomized controlled trial will evaluate the efficacy of electroacupuncture for treating failed back surgery syndrome. The outcomes will determine whether electroacupuncture is efficacious in relieving low back pain as well as improving the quality of life in failed back surgery syndrome patients. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2000040144 . Registered on 22 November 2020.
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Terapia por Acupuntura , Electroacupuntura , Síndrome de Fracaso de la Cirugía Espinal Lumbar , Electroacupuntura/efectos adversos , Humanos , Dimensión del Dolor , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , Método Simple Ciego , Resultado del TratamientoRESUMEN
Damage in COVID-19 results from both the SARS-CoV-2 virus and its triggered overactive host immune responses. Therapeutic agents that focus solely on reducing viral load or hyperinflammation fail to provide satisfying outcomes in all cases. Although viral and cellular factors have been extensively profiled to identify potential anti-COVID-19 targets, new drugs with significant efficacy remain to be developed. Here, we report the potent preclinical efficacy of ALD-R491, a vimentin-targeting small molecule compound, in treating COVID-19 through its host-directed antiviral and anti-inflammatory actions. We found that by altering the physical properties of vimentin filaments, ALD-491 affected general cellular processes as well as specific cellular functions relevant to SARS-CoV-2 infection. Specifically, ALD-R491 reduced endocytosis, endosomal trafficking, and exosomal release, thus impeding the entry and egress of the virus; increased the microcidal capacity of macrophages, thus facilitating the pathogen clearance; and enhanced the activity of regulatory T cells, therefore suppressing the overactive immune responses. In cultured cells, ALD-R491 potently inhibited the SARS-CoV-2 spike protein and human ACE2-mediated pseudoviral infection. In aged mice with ongoing, productive SARS-CoV-2 infection, ALD-R491 reduced disease symptoms as well as lung damage. In rats, ALD-R491 also reduced bleomycin-induced lung injury and fibrosis. Our results indicate a unique mechanism and significant therapeutic potential for ALD-R491 against COVID-19. We anticipate that ALD-R491, an oral, fast-acting, and non-cytotoxic agent targeting the cellular protein with multipart actions, will be convenient, safe, and broadly effective, regardless of viral mutations, for patients with early- or late-stage disease, post-COVID-19 complications, and other related diseases. IMPORTANCE With the Delta variant currently fueling a resurgence of new infections in the fully vaccinated population, developing an effective therapeutic drug is especially critical and urgent in fighting COVID-19. In contrast to the many efforts to repurpose existing drugs or address only one aspect of COVID-19, we are developing a novel agent with first-in-class mechanisms of action that address both the viral infection and the overactive immune system in the pathogenesis of the disease. Unlike virus-directed therapeutics that may lose efficacy due to viral mutations, and immunosuppressants that require ideal timing to be effective, this agent, with its unique host-directed antiviral and anti-inflammatory actions, can work against all variants of the virus, be effective during all stages of the disease, and even resolve post-disease damage and complications. Further development of the compound will provide an important tool in the fight against COVID-19 and its complications, as well as future outbreaks of new viruses.
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Antiinflamatorios/uso terapéutico , Antivirales/uso terapéutico , Tratamiento Farmacológico de COVID-19 , COVID-19/metabolismo , Compuestos Orgánicos/uso terapéutico , Glicoproteína de la Espiga del Coronavirus/metabolismo , Vimentina/metabolismo , Animales , Endocitosis/efectos de los fármacos , Endosomas/efectos de los fármacos , Endosomas/metabolismo , Exosomas/efectos de los fármacos , Exosomas/metabolismo , Células HEK293 , Humanos , Ratones , Células RAW 264.7RESUMEN
A 208 W all-solid-state modulated-longitudinal-mode quasi-continuous-wave sodium guide star (SGS) laser was developed by sum-frequency of a 1064 nm laser and a 1319 nm laser. The laser contained two spectral lines separated by 1.72 GHz for re-pumping the sodium atoms. To suppress absorption saturation effect of the sodium atoms induced by the high light intensity, we used a white noise generator to modulate the 1064 nm single frequency seed laser in the frequency domain. The line width of the modulated-longitudinal-mode 589 nm laser was maximally broadened to 0.74 GHz compared to the initial line width of ~0.30 GHz. A bright SGS with photon return flux of 56800 photons/s/cm2 during the pulse length was obtained.
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BACKGROUND: The purpose of this study was to measure the level of job satisfaction of certified physicians in rural primary health care facilities (PHCFs) in Shandong Province in order to ascertain the key factors affecting their satisfaction and to provide effective information for policy decisions. METHODS: This cross-sectional study was conducted among certified physicians in PHCFs in rural Shandong from June to August 2016. An anonymous questionnaire was completed by 495 participants (valid response rate: 91.6%). Data were analyzed using an exploratory factor analysis (EFA), one-way analysis of variance (ANOVA), and multiple linear regression. RESULTS: The participants consisted of 310 (62.6%) males and 185 (37.4%) females. The overall mean score for job satisfaction among respondents was 3.41 (standard deviation (SD) 0.68), which indicated that certified physicians were partially satisfied with their jobs. Results also indicated that factors for the highest level of satisfaction among certified physicians were the internal environment and job description. Moreover, physicians were more satisfied with competency behaviours and organizational management than with working conditions and job rewards. In contrast, physicians were dissatisfied with the external environment to an extent. Overall job satisfaction decreased with more years of service. Older physicians were less satisfied with their jobs than younger ones. Physicians with a higher level of education or senior professional title were less satisfied with their jobs than those with a lower level of education or junior professional tilte. Organizational management and the external environment were the most important factors influencing job satisfaction. CONCLUSION: Certified physicians working in PHCFs in rural Shandong had a slightly higher level of overall job satisfaciton than usual. After recent healthcare reforms, the job satisfaction of primary health care physicians in Shandong has changed little in comparison to that of physicians in other provinces in China. More attention should be paid to the impacts of these variables (age, educational background, technical title, monthly salary, form of employment, and years of service) on job satisfaction. Numerous recommendations may be considered to enhance organizational management and the external environment. The Government should enhace the formulation, implementation, and evaluation of policies to ensure that physicians continue to enjoy working in PHCFs. In short, the Government should pay more attention to protecting the legitimate rights and interests of primary care physicians when devising medical reforms.
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Certificación , Satisfacción en el Trabajo , Médicos de Atención Primaria/psicología , Población Rural , Adulto , China , Estudios Transversales , Análisis Factorial , Femenino , Reforma de la Atención de Salud , Humanos , Masculino , Persona de Mediana Edad , Encuestas y CuestionariosRESUMEN
It has been reported that 90% of the anti-drug antibody (ADA) to Adalimumab in human patients bound to the TNF-binding area, resulted in the annual loss of responses to Adalimumab up to 24%. It is of urgency to develop a cost-effective and easy-to-use ADA diagnostic kit for diagnosis of potential drug-resistance in patients treated with Adalimumab in clinic hospitals to avoid the tremendous economic and human costs to patients and health-care providers. In this study, we reported the generations of mouse monoclonal and monkey polyclonal antibodies against Adalimumab as assay standards and positive quality controls respectively. A Bridging ELISA assay was successfully developed with a limit of detection (LOD) between 22-80ng/ml. The preliminary validation of assay was carried out first with 50 normal human sera, further validated by screening the ADA in 192 serum samples from monkeys treated with or without Adalimumab. Our data showed that the Bridging ELISA kit is very sensitive, highly specific and ready for study in human clinic trials.
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Adalimumab/inmunología , Antiinflamatorios/inmunología , Anticuerpos Monoclonales/metabolismo , Ensayo de Inmunoadsorción Enzimática/métodos , Adalimumab/uso terapéutico , Animales , Antiinflamatorios/uso terapéutico , Análisis Costo-Beneficio , Resistencia a Medicamentos , Femenino , Humanos , Inmunoglobulina G/metabolismo , Macaca fascicularis , Ratones , Ratones Endogámicos BALB C , Sensibilidad y EspecificidadRESUMEN
Epigenetics play important roles during development progress of tumor. The histone modifications are the most important constituted field. Recently, accumulating research focused on exploring the roles of those modifications in regulating tumorigenesis. Moreover, the dysregulation of histone modifications is supposed to have vital clinical significance. Numerous histone modifications have the potential to be prognostic biomarkers, monitoring response of therapy, early diagnostic markers. Herein, we review the recent advances of histone modifications involving development of gastric cancer.
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Biomarcadores de Tumor/genética , Epigénesis Genética/genética , Histonas/genética , Neoplasias Gástricas/genética , Animales , Transformación Celular Neoplásica/genética , HumanosRESUMEN
BACKGROUND/AIMS: Interleukin-12 (IL-12) is a cytokine that plays an important role in cell-mediated immunity and shows great potential as a therapeutic agent for the treatment of tumors and infectious diseases. METHODS: We investigated the pharmacokinetics (PK) and pharmacodynamics of recombinant human IL-12 (rhIL-12) and rhIL-12 combined with hepatitis B surface antigen (HB(s)Ag) after administration by subcutaneous (s.c.) injection or intravenous infusion in cynomolgus monkeys. RESULTS: After s.c. injection of rhIL-12 at doses of 0.15-1.5 microg/kg, the monkey's metabolism showed linear kinetic characteristics. The intramuscular injection of HB(s)Ag vaccine did not affect the pharmacokinetic profile of rhIL-12. In monkeys administered rhIL-12 in a continuous dosing fashion, serum rhIL-12 was undetectable, probably due to the neutralizing effect of anti-rhIL-12 antibodies. In monkeys receiving high-dose s.c. injection of rhIL-12, the T(max) for serum rhIL-12 concentration was 4-8 h, and the T(max) for serum interferon-gamma (IFN-gamma) concentration was 24-72 h. However, in monkeys receiving continuous dosing of rhIL-12, serum IFN-gamma concentration was very low or even undetectable. CONCLUSION: We found that the PK of rhIL-12 was dose-dependent and its pharmacological effects appeared after T(max) and lasted much longer than mean retention time.