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Chinese drug registration laws and regulations have always reserved a place for the new traditional Chinese medicine(TCM) drugs for syndromes, but so far no such new drugs have been approved for registration. This paper expounded on the relevant policies, regulations, and technologies of new TCM drugs for syndromes in China and pointed out that the application of the animal model of TCM syndromes to carry out pharmacodynamics research and clinical efficacy evaluation criteria of TCM syndromes were the main technical difficulties in the research and development of new TCM drugs for syndromes. Not all syndromes are suitable for developing new drugs, and the indications for new TCM drugs should be constant syndromes. Among the three research and development models of simple syndrome, syndrome-unified disease, and combined disease and syndrome, the research and development model of combined disease and syndrome is recommended. Clinical positioning is the key to new TCM drugs for syndromes. It is encouraged to conduct high-quality human use experience studies to determine the clinical positioning of new TCM drugs for syndromes, as well as the target population, dose, course of treatment, and initial therapeutic and safety, and apply for exemption from non-clinical effectiveness studies. Clinical trials of new TCM drugs for syndromes should take the target symptoms or signs as the main efficacy index and the efficacy of TCM syndromes as the secondary efficacy index. Clinical research program design should implement the "patient-centered" concept and introduce clinical outcome evaluation indicators. In the clinical safety evaluation, special conditions such as characteristic syndromes and changes should be considered. With the construction of the human use experience technology system and the promotion of the TCM registration and evaluation evidence system featuring the "combination of TCM theory, human use experience, and clinical trials", it is believed that many high-quality new TCM drugs for syndromes will be developed in the future.
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Medicamentos Herbarios Chinos , Medicina Tradicional China , Humanos , Investigación , Síndrome , China , Medicamentos Herbarios Chinos/uso terapéuticoRESUMEN
Traditional Chinese medicine(TCM) preparations in medical institutions, as a unique and important form of preparations in China, have a long history of human use and serve as a bridge between clinical experience prescriptions and new Chinese medicine preparations. The state encourages medical institutions to transform their preparations into new traditional Chinese medicines, emphasizing their role as "incubators". Since the proposal of the traditional Chinese medicine registration and evaluation evidence system with the integration of TCM theory, human use experience(HUE), and clinical experience, the idea of transforming preparations used in medical institutions into new drugs based on HUE has been increasingly valued by drug research and development organizations. In the transformation process, pharmaceutical changes should be concerned from multiple aspects. This paper discusses the pharmaceutical changes and countermeasures based on the transformation of traditional Chinese medicine preparations in medical institutions into new drugs based on HUE from the aspects of excipients, dosage forms, production technology, production scale, packaging materials and containers, production sites, and registration standards. It is emphasized that scientific decisions should be made according to the characteristics and clinical needs of drugs to ensure the stability of drug quality. The impacts of pharmaceutical changes on drug quality should be objectively assessed based on appropriate evaluation indexes and detection methods. The layout should be carried out in advance, and the key pharmaceutical information of the preparations should be kept stable, so as to underpin the transformation of traditional Chinese medicine preparations in medical institutions into new drugs based on HUE.
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Medicamentos Herbarios Chinos , Medicina Tradicional China , Humanos , Medicamentos Herbarios Chinos/uso terapéutico , Estándares de Referencia , Control de Calidad , Composición de Medicamentos , Preparaciones FarmacéuticasRESUMEN
The nuclear receptor superfamily RAR is generally considered to play a crucial role in the development of tumors by regulating the transcription of target genes. Nevertheless, whether RARγ performs tumor-promoting or tumor-suppressing functions and its specific mechanism in thyroid carcinoma (TC) remain unknown. Here, our study demonstrated that RARγ was abnormally overexpressed in TC tissues compared with normal thyroid tissues. Moreover, RARγ expression was remarkably correlated with cell phenotypes such as cell proliferation, migration and invasion. Mechanistically, RARγ knockdown effectively decreased the phosphorylation levels of JAK1 and STAT3, leading to decreased expression of the membrane protein CD24. In a coculture system, TC cells with high levels of CD24 in the membrane were more likely to escape phagocytosis by macrophages via the combination of CD24 with the inhibitory receptor Siglec-10 in the membrane of macrophages. In contrast, the ability of macrophages to engulf TC cells was notably elevated through exogenous addition of CD24 antibody. Collectively, our study revealed a previously undiscovered molecular mechanism of RARγ in promoting the development of TC, shedding light on RARγ as a promising therapeutic target for TC.
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Neoplasias de la Tiroides , Humanos , Antígeno CD24 , Línea Celular Tumoral , Proliferación Celular , Janus Quinasa 1 , Factor de Transcripción STAT3 , Neoplasias de la Tiroides/genética , Receptor de Ácido Retinoico gammaRESUMEN
Diabetic cardiomyopathy (DCM) is a prevalent cardiovascular complication of diabetes mellitus, characterized by high morbidity and mortality rates worldwide. However, treatment options for DCM remain limited. For decades, a substantial body of evidence has suggested that the inflammatory response plays a pivotal role in the development and progression of DCM. Notably, DCM is closely associated with alterations in inflammatory cells, exerting direct effects on major resident cells such as cardiomyocytes, vascular endothelial cells, and fibroblasts. These cellular changes subsequently contribute to the development of DCM. This article comprehensively analyzes cellular, animal, and human studies to summarize the latest insights into the impact of inflammation on DCM. Furthermore, the potential therapeutic effects of current anti-inflammatory drugs in the management of DCM are also taken into consideration. The ultimate goal of this work is to consolidate the existing literature on the inflammatory processes underlying DCM, providing clinicians with the necessary knowledge and tools to adopt a more efficient and evidence-based approach to managing this condition.
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Diabetes Mellitus , Cardiomiopatías Diabéticas , Animales , Humanos , Cardiomiopatías Diabéticas/tratamiento farmacológico , Cardiomiopatías Diabéticas/etiología , Células Endoteliales , Inflamación/tratamiento farmacológico , Inflamación/complicaciones , Miocitos Cardíacos , Antiinflamatorios/uso terapéutico , Antiinflamatorios/farmacología , Diabetes Mellitus/tratamiento farmacológicoRESUMEN
PURPOSE: Acupuncture has been widely used in the treatment of knee osteoarthritis (KOA), but the selection of acupoints is indeterminate and lacks biological basis. The skin temperature of acupoints can reflect the state of local tissue and may be a potential factor for guiding acupoint selection. This study aims to compare the skin temperature of acupoints between KOA patients and the healthy population. STUDY DESIGN AND METHODS: This is a protocol for a cross-sectional case-control study with 170 KOA patients and 170 age- and gender-matched healthy individuals. Diagnosed patients aged 45 to 70 will be recruited in the KOA group. Participants in the healthy group will be matched with the KOA group based on mean age and gender distribution. Skin temperature of 11 acupoints (ST35, EX-LE5, GB33, GB34, EX-LE2, ST34, ST36, GB39, BL40, SP9, SP10) will be extracted from infrared thermography (IRT) images of the lower limbs. Other measurements will include demographic data (gender, age, ethnicity, education, height, weight, BMI) and disease-related data (numerical rating scale, pain sites, duration of pain, pain descriptors, pain activities). DISCUSSION: The results of this study will provide biological evidence for acupoint selection. This study is a precondition for follow-up studies, in which the value of optimized acupoint selection will be verified. TRIAL REGISTRATION: ChiCTR2200058867.
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Terapia por Acupuntura , Osteoartritis de la Rodilla , Humanos , Puntos de Acupuntura , Termografía , Estudios de Casos y Controles , Estudios Transversales , Osteoartritis de la Rodilla/terapia , Terapia por Acupuntura/métodos , Dolor , Extremidad Inferior , Resultado del TratamientoRESUMEN
Non-healing diabetic wounds (DW) are a serious clinical problem that remained poorly understood. We recently found that topical application of growth differentiation factor 11 (GDF11) accelerated skin wound healing in both Type 1 DM (T1DM) and genetically engineered Type 2 diabetic db/db (T2DM) mice. In the present study, we elucidated the cellular and molecular mechanisms underlying the action of GDF11 on healing of small skin wound. Single round-shape full-thickness wound of 5-mm diameter with muscle and bone exposed was made on mouse dorsum using a sterile punch biopsy 7 days following the onset of DM. Recombinant human GDF11 (rGDF11, 50 ng/mL, 10 µL) was topically applied onto the wound area twice a day until epidermal closure (maximum 14 days). Digital images of wound were obtained once a day from D0 to D14 post-wounding. We showed that topical application of GDF11 accelerated the healing of full-thickness skin wounds in both type 1 and type 2 diabetic mice, even after GDF8 (a muscle growth factor) had been silenced. At the cellular level, GDF11 significantly facilitated neovascularization to enhance regeneration of skin tissues by stimulating mobilization, migration and homing of endothelial progenitor cells (EPCs) to the wounded area. At the molecular level, GDF11 greatly increased HIF-1É expression to enhance the activities of VEGF and SDF-1É, thereby neovascularization. We found that endogenous GDF11 level was robustly decreased in skin tissue of diabetic wounds. The specific antibody against GDF11 or silence of GDF11 by siRNA in healthy mice mimicked the non-healing property of diabetic wound. Thus, we demonstrate that GDF11 promotes diabetic wound healing via stimulating endothelial progenitor cells mobilization and neovascularization mediated by HIF-1É-VEGF/SDF-1É pathway. Our results support the potential of GDF11 as a therapeutic agent for non-healing DW.
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Diabetes Mellitus Experimental , Células Progenitoras Endoteliales , Factores de Diferenciación de Crecimiento , Cicatrización de Heridas , Animales , Humanos , Ratones , Proteínas Morfogenéticas Óseas/metabolismo , Quimiocina CXCL12/efectos de los fármacos , Quimiocina CXCL12/metabolismo , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Células Progenitoras Endoteliales/metabolismo , Células Progenitoras Endoteliales/patología , Factores de Diferenciación de Crecimiento/uso terapéutico , Factores de Diferenciación de Crecimiento/metabolismo , Neovascularización Fisiológica , Factor A de Crecimiento Endotelial Vascular/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/metabolismo , Cicatrización de Heridas/efectos de los fármacos , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/uso terapéutico , Subunidad alfa del Factor 1 Inducible por Hipoxia/efectos de los fármacos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismoRESUMEN
OBJECTIVE: To assess the efficacy of the combined treatment with electroacupuncture (EA) and intradermal needling on simple obesity and explore its underlying effect mechanism. METHODS: A total number of 116 patients with simple obesity were randomized into an observation group (58 cases, 3 cases dropped off and 2 cases removed) and a control group (58 cases, 4 cases dropped off and 1 cases removed). Patients in the control group received EA at Zhongwan (CV 12), Quchi (LI 11), Zusanli (ST 36), Pishu (BL 20), Weishu (BL 21), etc., for 30 min each time. On the base of the intervention as the control group, the patients in the observation group received the intradermal needling at Tianshu (ST 25), Daheng (SP 15), Zusanli (ST 36), Shangjuxu (ST 37), Quchi (LI 11), Pishu (BL 20) and Weishu (BL 21). In each group, the intervention was given once every two days, 3 times a week, consecutively for 3 months. Before and after treatment, the obesity indexes (body mass [BW], body mass index [BMI], body fat percentage [F%], adiposity [A] and waist circumference [WC]), the serum intestinal lymphatic function-related factors (vascular endothelial growth factor C [VEGF-C], delta-like ligand 4 [DLL4], adrenomedullin [ADM]), blood lipid (total cholesterol [TC], triglyceride [TG] and low density lipoprotein-cholesterol [LDL-C]), and fasting plasma glucose (FPG), fasting insulin (FINS) and insulin resistance index (HOMA-IR) were observed in the patients of both groups; and the efficacy was assessed. RESULTS: The effective rate was 88.7% (47/53) in the observation group, higher than 71.7% (38/53) in the control group (P<0.05). After treatment, except FPG in the control group, BW, BMI, F%, A, WC, and the concentrations of serum VEGF-C, DLL4 and ADM, as well as TC, TG, LDL-C, FBG, FINS and HOMA-IR were all reduced compared with those before treatment in both groups (P<0.05). The reduction ranges of BW, BMI, F%, A, WC, and the concentrations of serum VEGF-C, DLL4 and ADM, and TC, LDL-C, FINS and HOMA-IR in the observation group were all larger than those in the control group (P<0.05). CONCLUSION: Electroacupuncture combined with intradermal needling can reduce body weight and lipid, and improve insulin resistance in treatment of simple obesity, which is achieved probably through inhibiting lymphangiogenesis and promoting lymphatic endothelial permeability.
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Electroacupuntura , Resistencia a la Insulina , Obesidad Mórbida , Puntos de Acupuntura , Glucemia/metabolismo , LDL-Colesterol , Humanos , Intestinos , Lípidos , Linfocitos , Obesidad/metabolismo , Obesidad/terapia , Triglicéridos , Factor C de Crecimiento Endotelial VascularRESUMEN
The opportunistic fungal pathogen Talaromyces marneffei, which is endemic across a narrow band of tropical Southeast Asia and southern China, is an intracellular pathogen that causes systemic and lethal infection through the mononuclear phagocyte system. The mechanisms by which T. marneffei successfully replicates and escapes the immune system remain unclear. To investigate the role of arginine metabolism in the escape of T. marneffei from killer macrophages, we assessed inducible nitric oxide synthase (iNOS) and arginase expression, nitric oxide (NO) production, arginase and phagocytic activity, and the killing of T. marneffei in a coculture system. Our results indicate that T. marneffei induced macrophage polarization toward the M2 phenotype and regulated the arginine metabolism pathway by prolonging infection, thereby reducing antimicrobial activity and promoting fungal survival. Moreover, inhibiting T. marneffei-induced macrophage arginase activity with Nω-hydroxy-nor-arginine restored NO synthesis and strengthened fungal killing. These findings indicate that T. marneffei affects macrophage polarization and inhibits macrophage antimicrobial function via the arginine metabolism pathway.
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Levosimendan and dobutamine are extensively used to treat sepsis-associated cardiovascular failure in ICU. Nevertheless, the role and mechanism of levosimendan in patients with sepsis-induced cardiomyopathy remains unclear. Moreover, previous studies on whether levosimendan is superior to dobutamine are still controversial. More importantly, these studies did not take changes (before-after comparison to the baseline) in quantitative parameters such as ejection fraction into account with the baseline level. Here, we aimed to determine the pros and cons of the two medicines by assessing the changes in cardiac function and blood lactate, mortality, with the standardized mean difference used as a summary statistic. Relevant studies were obtained by a thorough and disciplined literature search in several notable academic databases, including Google Scholar, PubMed, Cochrane Library and Embase until November 2020. Outcomes included changes in cardiac function, lactic acid, mortality and length of hospital stay. A total of 6 randomized controlled trials were included in this study, including 192 patients. Compared with dobutamine, patients treated with levosimendan had a greater improvement of cardiac index (ΔCI) (random effects, SMD = 0.90 [0.20,1.60]; I2 = 76%, P < 0.01) and left ventricular stroke work index (ΔLVSWI) (random effects, SMD = 1.56 [0.90,2.21]; I2 = 65%, P = 0.04), a significant decrease of blood lactate (Δblood lactate) (random effects, MD = - 0.79 [- 1.33, - 0.25]; I2 = 68%, P < 0.01) at 24-h after drug intervention, respectively. There was no significant difference between levosimendan and dobutamine on all-cause mortality in ICU (fixed effect, OR = 0.72 [0.39,1.33]; I2 = 0%, P = 0.99). We combine effect sizes related to different measurement parameters to evaluate cardiac function, which implied that septic patients with myocardial dysfunction might have a better improvement of cardiac function by levosimendan than dobutamine (random effects, SMD = 1.05 [0.69,1.41]; I2 = 67%, P < 0.01). This study suggested a significant improvement of CI, LVSWI, and decrease of blood lactate in septic patients with myocardial dysfunction in ICU after 24-h administration of levosimendan than dobutamine. However, the administration of levosimendan has neither an impact on mortality nor LVEF. Septic patients with myocardial dysfunction may partly benefit from levosimendan than dobutamine, mainly embodied in cardiac function improvement.
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Dobutamina/uso terapéutico , Cardiopatías , Ácido Láctico/sangre , Sepsis , Simendán/uso terapéutico , Volumen Sistólico/efectos de los fármacos , Supervivencia sin Enfermedad , Cardiopatías/sangre , Cardiopatías/tratamiento farmacológico , Cardiopatías/mortalidad , Cardiopatías/fisiopatología , Sepsis/sangre , Sepsis/tratamiento farmacológico , Sepsis/mortalidad , Sepsis/fisiopatología , Tasa de SupervivenciaRESUMEN
BACKGROUND: Talaromyces marneffei (T. marneffei) is a destructive opportunistic dimorphic fungal which can cause lethiferous Talaromycosis, but the clearance of T. marneffei mainly depends on the innate immune response. OBJECTIVE: To investigate whether T. marneffei can inhibit the expression of CD86 in THP-1 cells after infection and discuss the potential mechanisms. METHODS: Western blot and immunoelectron microscopy were used to detect the CD86 expression on T. marneffei cultured on BHI medium at 37°C. Western blot, enzyme-linked immunoassay and immunofluorescence were used to detect the change of CD86 expression on macrophages incubating with T. marneffei. Enzyme-linked immunoassay was used to detect the content of CD86 in supernatant in the co-culture system. Immunohistochemistry and immunoelectron microscopy were used to detect the expression of CD86 on T. marneffei incubating with macrophages. RESULTS: T. marneffei did not express CD86 when cultured separately at 37°C detected by Western blot and immunoelectron microscopy, but it did express CD86 when incubated with macrophages detected by immunohistochemistry and immunoelectron microscopy. The CD86 expression of macrophages significantly decreased at 72 hours when infected with T. marneffei while the content of CD86 in supernatant significantly increased at 72 hours compared with the control group which were detected by Western blot, enzyme-linked immunoassay and immunofluorescence. CONCLUSION: 1) After T. marneffei infection, CD86 expression on THP-1 decreased, and with the progression of infection, insufficient polarization of M1 macrophages gradually appeared; 2) T. marneffei may adsorb or uptake CD86 in supernatant produced by macrophages during the contact with THP-1 cells, thus leading to the consumption of CD86 in macrophages.
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The regulation of mTOR and the dimethylation of histone H3 on lysine 9 (H3K9me2) H3K9me2 by Uhrf1 and the mechanism of autophagy regulation in myocardial ischemia-reperfusion injury (MIRI) were studied in vivo and in vitro. An in vitro I/R injury model was established using the primary mouse cardiomyocytes treated with H2O2. Subsequent analysis by qRT-PCR, western blot, and immunofluorescence indicated that overexpression of Uhrf1 significantly inhibited apoptosis of the H2O2-treated cardiomyocytes, reduced expression of apoptosis factors caspase-3 and Bax, and increased expression of apoptosis inhibitory factor Bcl-2. Furthermore, Uhrf1 was found to increase cardiomyocyte proliferation and promote the expression of mTOR, while the four expression peaks of H3K9me2 on the mTOR gene were inhibited by overexpression of Uhrf1. The expression of autophagy factors LC3, Beclin-1, and p-mTOR in Uhrf1-overexpressed cardiomyocytes was dramatically increased, and P62 expression was dramatically decreased. When an H3K9me2 inhibitor was added to the Uhrf1-knockdown cardiomyocytes, the expression of mTOR was increased, the expression of LC3, Beclin-1, and p-mTOR was decreased, and P62 expression was significantly increased. In the present study, Uhrf1 exhibits a protective function in MIRI, reducing the apoptosis of cardiomyocytes while increasing their proliferation and viability.
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Autofagia/fisiología , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Histonas/metabolismo , Daño por Reperfusión Miocárdica/metabolismo , Miocitos Cardíacos/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Animales , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Autofagia/efectos de los fármacos , Caspasa 3/metabolismo , Proliferación Celular/efectos de los fármacos , Proliferación Celular/fisiología , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Peróxido de Hidrógeno/farmacología , Ratones , Miocitos Cardíacos/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Proteína X Asociada a bcl-2/metabolismoRESUMEN
BACKGROUND: Sepsis-induced myopathy (SIM) is a disease that causes motor dysfunction in patients with sepsis. There is currently no targeted treatment for this disease. Acupuncture has shown considerable efficacy in the treatment of sepsis and muscle weakness. Therefore, our research aims to explore the effects of acupuncture on the improvement of muscle structure and function in SIM patients and on activities of daily living. METHODS: The ACU-SIM pilot study is a single-center, propensity-score stratified, assessor-blinded, prospective pragmatic controlled trial (pCT) with a 1-year follow-up period. This study will be deployed in a multi-professional critical care department at a tertiary teaching hospital in Guangzhou, China. Ninety-eight intensive care unit subjects will be recruited and assigned to either the control group or the acupuncture group. Both groups will receive basic treatment for sepsis, and the acupuncture group will additionally receive acupuncture treatment. The primary outcomes will be the rectus femoris cross-sectional area, the Medical Research Council sum-score and time-to-event (defined as all-cause mortality or unplanned readmission to the intensive care unit due to invasive ventilation). The activities of daily living will be accessed by the motor item of the Functional Independence Measure. Recruitment will last for 2 years, and each patient will have a 1-year follow-up after the intervention. DISCUSSION: There is currently no research on the therapeutic effects of acupuncture on SIM. The results of this study may contribute to new knowledge regarding early muscle atrophy and the treatment effect of acupuncture in SIM patients, and the results may also direct new approaches and interventions in these patients. This trial will serve as a pilot study for an upcoming multicenter real-world study. TRIAL REGISTRATION: Chinese Clinical Trials Registry: ChiCTR-1900026308, registered on September 29th, 2019.
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Terapia por Acupuntura/métodos , Debilidad Muscular/terapia , Atrofia Muscular/terapia , Enfermedades Musculares/terapia , Sepsis/terapia , Actividades Cotidianas , Terapia por Acupuntura/efectos adversos , China/epidemiología , Cuidados Críticos/organización & administración , Estudios de Seguimiento , Humanos , Unidades de Cuidados Intensivos/estadística & datos numéricos , Mortalidad/tendencias , Debilidad Muscular/etiología , Debilidad Muscular/patología , Atrofia Muscular/etiología , Atrofia Muscular/patología , Enfermedades Musculares/etiología , Readmisión del Paciente/tendencias , Proyectos Piloto , Puntaje de Propensión , Estudios Prospectivos , Respiración Artificial/métodos , Respiración Artificial/estadística & datos numéricos , Sepsis/complicaciones , Centros de Atención Terciaria/organización & administración , Resultado del TratamientoRESUMEN
In this study, the mechanism of TDP-43 gene expression on inflammatory factors and Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) signalling pathways in ischaemic hypoxic stress dependence was investigated. Sixty SD rats were selected and divided into the control group, the osteoarthritis (OA) model group, and the TDP-43-mMSCs+OA group. In the OA model group and the TDP-43-mMSCs+OA group, OA was established by collagenase injection. Western blotting assays were used to detect the expression of TDP-43 in cartilage tissues of each rat. The secretion of tumour necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) in the serum of rats was determined by enzyme-linked immunosorbent assay (ELISA). The formation of cytoplasmic stress granules (SGs) and the expression of receptor for activated c-kinase 1 (RACK1) were detected by Western blotting assays in each group of rats. The expression of MTK1 and MAPKKK phosphorylation and changes in the JNK and p38 MAPK signalling pathways were detected by Western blotting assays. Compared with the control group, the expression of TDP-43 in the cartilage tissue of rats in the OA model group was significantly decreased. The expression of TDP-43 in the cartilage tissue of rats in the TDP-43-mMSCs+OA group was significantly higher than that of the control group and the OA model group, which indicates that TDP-43-mMSC transplantation was successful. Enzyme-linked immunosorbent assay results showed that the plasma TNF-α and IL-1ß levels in the OA model group were significantly increased (P < 0.01) when compared with the control group. However, the secretion of TNF-α and IL-1ß in the serum of the TDP-43-mMSCs+OA group was significantly lower than that of the model group (P < 0.01) but still higher than the control group. This indicates that overexpression of TDP-43 reduces the inflammatory response induced by OA. Western blotting assays showed that the amount of cytoplasmic SGs in the cartilage tissue of rats in the OA model group was significantly decreased when compared with the control group. The amount of SGs in the cartilage of rats in the TDP-43-mMSCs+OA group was significantly higher than that of the model group. The expression of RACK1 in the cartilage tissue of rats in the OA model group was significantly higher than that of the control group. Overexpression of the TDP-43 gene can interfere with the secretion of inflammatory factors and inhibit the activation of the JNK and p38 MAPK signalling pathways by ischaemic hypoxia stress. Thus, the molecular mechanism of chondrocytopathic lesions was reversed, which provided a new theoretical basis for the treatment of OA.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas de Unión al ADN/metabolismo , Hipoxia/fisiopatología , Inflamación/genética , Inflamación/fisiopatología , Osteoartritis/genética , Osteoartritis/fisiopatología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Proteínas de Unión al ADN/genética , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Hipoxia/genética , Masculino , Ratas , Ratas Sprague-Dawley , Proteínas Quinasas p38 Activadas por Mitógenos/genéticaRESUMEN
BACKGROUND: This study focused on the mechanisms where icariin inhibited chondrocyte apoptosis and angiogenesis by regulating the TDP-43 signaling pathway. METHODS: A rat osteoarthritis (OA) model was established by collagenase injection. Histological examination of the articular cartilage and synovial tissue was performed 6 weeks after operation. Cartilage cell line overexpressing TDP-43 and mesenchymal stem cell line (TDP43-MSCs) of the rat TDP43 gene were established. RESULTS: In OA rats transplanted with TDP43-mMSCs, TDP43 was highly expressed in chondrocytes (TDP43-HC), while TDP43 expression was low in HC and MSCs-HC (p < 0.05). After the intervention of MSCs-TDP43, high expression of TDP43 induced the apoptosis and death of chondrocytes. After the addition of icariin, late apoptosis and death of TDP43-HC were significantly attenuated. Apoptosis and death of HC, MSCs-HC, and TDP43-HC cells were effectively controlled with icariin, and no apparent cell death was found. ELISA showed that the VEGF and HIF-1 alpha were significantly higher in the rat OA model than the normal control rats. CONCLUSION: TDP43-MSC transplantation interfered with the expression of TDP43 in the articular chondrocytes of OA rats, which may impact on inducing apoptosis of chondrocytes as well as inhibiting the proliferation of chondrocytes. Additionally, TDP43-MSCs appeared to promote the formation of neovascularization in the synovial tissue, which could be significantly attenuated by icariin.
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Apoptosis , Condrocitos/efectos de los fármacos , Proteínas de Unión al ADN/metabolismo , Flavonoides/farmacología , Osteoartritis/metabolismo , Animales , Línea Celular , Células Cultivadas , Condrocitos/metabolismo , Masculino , Trasplante de Células Madre Mesenquimatosas/métodos , Células Madre Mesenquimatosas/metabolismo , Neovascularización Fisiológica , Osteoartritis/terapia , Ratas , Ratas Sprague-Dawley , Transducción de SeñalRESUMEN
BACKGROUND: High-viscosity cement (HVC) has been gradually applied in percutaneous vertebroplasty (PVP) and percutaneous kyphoplasty (PKP). Although HVC has been reported to reduce cement leakage, different opinions exist. To assess the complications of HVC in cement leakage in the treatment of vertebral compression fractures and to evaluate the clinical effect of HVC compared with low-viscosity cement (LVC). METHODS: EMBASE, PubMed, Science Direct, Google Scholar and Cochrane Library databases were comprehensively searched from their inception to August 2017. Two researchers independently searched for articles and reviewed all retrieved studies. Forest plots were used to illustrate the results. The Q-test and I statistic were employed to evaluate between-study heterogeneity. Potential publication bias was assessed by funnel plot. RESULTS: HVC reduced the occurrence of cement leakage (risk ratio (RR) = 0.38, 95% confidence interval (CI) = 0.29 to 0.51, P < 0.00001), especially in the disc space (RR = 0.45, 95% CI = 0.45 to 0.80, P = 0.007) and the vein (RR = 0.54, 95% CI = 0.35 to 0.85, P = 0.008) but not in the intraspinal space (RR = 0.48, 95% CI = 0.19 to 1.23, P = 0.13) or the paravertebral area (RR = 0.63, 95% CI = 0.32 to 1.22, P = 0.17). No significant differences in the visual analogue scale (VAS), Oswestry Disability Index (ODI), injected cement volume or adjacent vertebral fracture were noted between HVC and LVC (P > 0.05). CONCLUSION: Compared with LVC, HVC results in a reduced incidence of cement leakage for the treatment of vertebral compression fractures, especially in the disc space and vein but not in the intraspinal space or the paravertebral area. In addition, HVC yields the same satisfactory clinical effect as LVC.
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Cementos para Huesos/uso terapéutico , Fracturas por Compresión/cirugía , Fracturas de la Columna Vertebral/cirugía , Viscosidad , Cementos para Huesos/química , HumanosRESUMEN
OBJECTIVE: To evaluate the clinical effect of ultra-early injection (before the phase of "tooth-paste-like") of low-viscosity cement in percutaneous vertebroplasty (PVP) for treating osteoporotic vertebral compression fractures (OVCFs). METHODS: Two hundred sixty-one patients who had PVP procedures with low-viscosity cement (ultra-early injection: 145, normal injection: 135) were included from July 2010 to July 2016 in our hospital. Visual Analog Scale (VAS), Oswestry Disability Index (ODI), Cobb angle, cement leakage, and adjacent vertebral fractures were evaluated. The follow-up period was over 12 months. RESULTS: VAS 3.0â¯d after surgery was significantly reduced in the ultra-early injection group compared to that in the control group (Pâ¯=â¯0.00), but no difference was found at the final follow-up (Pâ¯=â¯0.53). Similar results were found for ODI. The Cobb angle in both groups was recovered after PVP (Pâ¯<â¯0.05); however, in the control group, the Cobb angle at the final follow-up was significantly increased compared with that 3.0â¯d after surgery (Pâ¯=â¯0.00). There was a significant difference in the Cobb angle between the two groups at the final follow-up (Pâ¯=â¯0.00). Regarding cement leakage, there were no significant differences in terms of mild (Pâ¯=â¯0.58), moderate (Pâ¯=â¯0.68), or severe leakage (Pâ¯=â¯0.52). Seven patients in the control group had adjacent vertebral fractures, but only one patient in the ultra-early injection group experienced adjacent fractures (Pâ¯=â¯0.03). CONCLUSIONS: Ultra-early injection of low-viscosity cement during PVP procedures in the treatment of OVCFs not only quickly and significantly relieves pain, reduces the incidence of adjacent vertebral fractures, and prevents progressive kyphotic deformity, but also does not increase the risk of cement leakage when compared with that of the traditional injection procedure.
Asunto(s)
Cementos para Huesos/uso terapéutico , Fracturas por Compresión/cirugía , Fracturas Osteoporóticas/cirugía , Fracturas de la Columna Vertebral/cirugía , Vertebroplastia/métodos , Anciano , Dolor de Espalda/cirugía , Cementos para Huesos/efectos adversos , Estudios de Cohortes , Evaluación de la Discapacidad , Femenino , Estudios de Seguimiento , Humanos , Inyecciones , Masculino , Persona de Mediana Edad , Dimensión del Dolor , Estudios Retrospectivos , Factores de Tiempo , Resultado del Tratamiento , Vertebroplastia/efectos adversos , ViscosidadRESUMEN
The myostatin gene (MSTN) is a genetic determinant of skeletal muscle growth. Single nucleotide polymorphisms (SNP) in MSTN are of importance due to their strong associations with horse racing performances. In this study, we screened the SNPs in MSTN gene in 514 horses from 15 Chinese horse breeds. Six SNPs (g.26T>C, g.156T>C, g.587A>G, g.598C>T, g.1485C>T, g.2115A>G) in MSTN gene were detected by sequencing and genotyped using PCR-RFLP method. The g.587A>G and g.598C>T residing in the 5'UTR region were novel SNPs identified by this study. The g.2115A>G which have previously been associated with racing performances were present in Chinese horse breeds, providing valuable genetic information for evaluating the potential racing performances in Chinese domestic breeds. The six SNPs together defined thirteen haplotypes, demonstrating abundant haplotype diversities in Chinese horses. Most of the haplotypes were shared among different breeds with no haplotype restricted to a specific region or a single horse breed. AMOVA analysis indicated that most of the genetic variance was attributable to differences among individuals without any significant contribution by the four geographical groups. This study will provide fundamental and instrumental genetic information for evaluating the potential racing performances of Chinese horse breeds.
Asunto(s)
Caballos/genética , Miostatina/genética , Polimorfismo de Nucleótido Simple , Regiones no Traducidas 5' , Animales , Animales Endogámicos , China , Polimorfismo de Longitud del Fragmento de RestricciónRESUMEN
OBJECTIVE: To assess the therapeutic effect of acupuncture for apoplectic aphasia. METHODS: A systematic review of the relevant randomized controlled trials (RCTs) of acupuncture for apoplectic aphasia was performed with Cochrance system assessment methods. The quality of researches was reviewed one by one, and data was extracted by two reviewers independently. Meta-analysis was conducted with the assistance of RevMan 5.0 software. RESULTS: Eleven randomized controlled trials (RCTs) involving 756 patients were included. Meta-analysis indicated that there was statistical difference between acupuncture and language training groups on cured rate with [RR = 1.74, 95% CI (1.10, 2.74), P = 0.02] at the end of treatment. However, acupuncture combined language training group was statistically superior to language training group on cured rate with [RR = 3.01, 95% CI (1.81, 5.01), P < 0.000 1], language function score with [WMD =10.54, 95% CI (7.86, 13.21), P < 0.000 01], oral expression with [WMD = 8.86, 95% CI (7.38, 10.35), P < 0.000 01]. CONCLUSION: It is approved that acupuncture (or acupuncture combined language training) is effective for apoplectic aphasia. But the quality of inclusive literature is low. Therefore, more RCTs of high methodological quality is requested to be carried out.
Asunto(s)
Terapia por Acupuntura , Afasia/terapia , Accidente Cerebrovascular/complicaciones , Afasia/etiología , Humanos , Terapia del Lenguaje , Metaanálisis como Asunto , Resultado del TratamientoRESUMEN
AIM: The aim of the present study was to investigate the effects of silencing the livin gene by small interfering RNA (siRNA) on the expression of livin and the effects on apoptosis, cell cycle, and proliferation in human malignant melanoma LiBr cells. METHODS: Three chemically-synthetic siRNA duplexes targeting livin were transiently transfected into the LiBr cells, and the effects on livin expression were detected both at the mRNA level by real-time RT-PCR and at the protein level by Western blotting. Apoptosis was evaluated by terminal deoxynucleotidyl transferase-mediated digoxigenin-dUTP nick-end labeling assay, flow cytometric analysis, and the expression of procaspase-3 and activated caspase-3 analysis by Western blotting. Cell cycle was analyzed by flow cytometry. Cell proliferation was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. RESULTS: One of the 3 designed siRNA could effectively knock down the livin expression both at the mRNA and protein levels in dose- and time-dependent manners; 100 nmol/L with maximum downregulation on mRNA at 48 h, and on the protein at 72 h after transfection. Silencing livin could significantly induce apoptosis, arrest cell cycle at the G0/G1 phase, and inhibit proliferation in LiBr cells. Meanwhile, caspase-3 was activated. CONCLUSION: The livin gene could serve as a potential molecular target for gene therapy by siRNA for malignant melanoma.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Apoptosis/genética , Ciclo Celular/genética , Proliferación Celular , Silenciador del Gen , Proteínas Inhibidoras de la Apoptosis/genética , Melanoma/patología , Proteínas de Neoplasias/genética , ARN Interferente Pequeño , Secuencia de Bases , Línea Celular Tumoral , Cartilla de ADN , Citometría de Flujo , Humanos , Melanoma/genéticaRESUMEN
AIM: To investigate the effects of siRNA on expression of livin and dose- and time-response in human malignant melanoma LiBr cells. METHODS: Three chemically synthesized specific siRNAs targeting to livin were transfected to LiBr cells, then the expression of livin was detected both at mRNA level by real-time RT-PCR and at protein level by Western blot, and the effective one was selected for use on observation of dose- and time-response to livin silencing. RESULTS: One of three designed siRNAs could effectively knock down the livin expression both at mRNA and protein levels in dose- and time- dependent manners, 100 nmol/L of which achieved the highest knockdown effect on mRNA at 48 h and on protein at 72 h after transfection. CONCLUSION: Expression of livin in LiBr cells could be efficiently knocked down by siRNA with target site 790-808 of livin mRNA.