Quercetin-induced pyroptosis in colon cancer through NEK7-mediated NLRP3 inflammasome-GSDMD signaling pathway activation.

Pyroptosis, a gasdermin-mediated lytic cell death, is a new hotspot topic in cancer research, and induction of tumor pyroptosis has emerged as a new target in cancer management. Quercetin (Que), a natural substance, demonstrates promising anticancer action. However, further information is required to fully comprehend the function and mechanism of Que in pyroptosis in colon cancer. This study revealed the underlying mechanism of Que-induced pyroptosis in colon cancer in vitro and in vivo. Que inhibited colon cancer cell growth through gasdermin D (GSDMD)-mediated pyroptosis. Depletion of GSDMD, rather than gasdermin E (GSDME), reversed the cytotoxic effects of Que on colon cancer cells. Que treatment upregulated NIMA-related kinase 7 (NEK7) protein expression, thus facilitating the assembly of the NLRP3 inflammasome and cleavage of GSDMD. NEK7 silencing resulted in colon cancer cell growth in vitro and in vivo. Mechanistically, NEK7 depression restrained the activation of the NLRP3 inflammasome-GSDMD pathway, thus attenuating pyroptosis triggered by Que in colon cancer cells. Furthermore, lower NEK7 and NLRP3 expression levels indicated colon cancer progression. Our results unveiled a novel pattern of anti-colon cancer activity of Que, and activation of NEK7-mediated pyroptosis is potentially a promising therapeutic target for colon cancer, which provides novel experimental proof for the clinical application of Que.

Icariin inhibits MMP­1, MMP­3 and MMP­13 expression through MAPK pathways in IL­1ß­stimulated SW1353 chondrosarcoma cells.

Osteoarthritis (OA) is the most common type of arthritis and is a leading cause of disability worldwide, resulting in pain, reduced quality of life and socioeconomic burden. Current therapies for OA focus on mitigating the symptoms of advanced disease, but novel therapeutic agents are needed to inhibit the processes leading to OA. The present study aimed to investigate the effects of Icariin on matrix metalloproteinase (MMP)­1, MMP­3 and MMP­13 expression in interleukin (IL)­1ß­stimulated human SW1353 chondrosarcoma cells, and to investigate the possible mechanism underlying the chondroprotective effects of Icariin. In the present study, IL­1ß was applied on SW1353 chondrosarcoma cells to mimic the microenvironment of osteoarthritis. The cells were treated with Icariin and mitogen­activated protein kinase (MAPK) signaling pathway activators or inhibitors. MMP­1, MMP­3, MMP­13, phosphorylated (P)­p38, P­c­Jun N­terminal kinase (JNK) and P­extracellular signal­regulated kinase (ERK) expression was assessed using reverse transcription­quantitative polymerase chain reaction, ELISA and western blot analysis. The results of the present study demonstrated that Icariin inhibited the expression of MMP­1, MMP­3, MMP­13, P­p38, P­ERK and P­JNK. Furthermore, it was revealed that the inhibition of p38 and ERK contributed to the inhibition of MMP­1 and MMP­3 by Icariin, whereas the inhibition of p38 and JNK contributed to the inhibition of MMP­13. The present results suggested that Icariin may have a chondroprotective effect, exerted through the inhibition of MMP­1, MMP­3 and MMP­13 via MAPK pathways. Therefore, Icariin may have potential as a novel therapeutic strategy for the treatment of osteoarthritis.

Chondroprotective Effects and Multitarget Mechanisms of Fu Yuan Capsule in a Rat Osteoarthritis Model.

Fu Yuan Capsule (FYC) has been clinically used for osteoarthritis (OA) and its related diseases for many years in China. However, its pharmacological mechanism remains unclear. This study aimed to investigate the potential chondroprotective effects of FYC on articular cartilage. Rat OA model was induced by anterior cruciate ligament transection. A group of rats was treated with FYC for 12 weeks. Joint structure, types I and II collagen, and proteoglycan were evaluated by histological examination. The expression of C-terminal crosslinking telopeptide of type II collagen, hydroxyproline, a disintegrin and metalloproteinase with thrombospondin motifs, matrix metalloproteinase, interleukin-1 beta, nitric oxide, prostaglandin E2, heat-shock protein 70, transforming growth factor-beta, osteoprotegerin, and receptor activator of nuclear factor κB ligand were detected. Treatment with FYC could protect against articular cartilage injury. FYC treatment significantly decreased the extracellular matrix degradation factors and inflammatory mediators. Moreover, articular cartilage protective factors were increased in the FYC group. The current finding suggests that FYC protects articular cartilage in a rat OA model through various ways. Thus, it may be an effective agent for OA treatment.

Clinical efficacy of 'Spleen-kidney-care' Yiqi Huayu and Jiangzhuo traditional Chinese medicine for the treatment of patients with diabetic nephropathy.

The aim of the present study was to investigate the effect of the traditional Chinese medicine (TCM), 'Spleen-kidney-care' Yiqi Huayu and Jiangzhuo decoction (SKC-YJ), as an adjuvant therapy in diabetic nephropathy (DN) treatment. In total, 72 patients with DN were randomly divided into control (n=54) and experimental (n=18) groups, with the latter administered SKC-YJ treatment. Indicators for determining the condition of the patients included the levels of proteinuria, blood glucose, glycosylated hemoglobin, blood lipids, blood viscosity and C-reactive protein, which were used to analyze the treatment protocols for DN. Following SKC-YJ treatment, the urinary albumin excretion rate, fasting blood glucose, 2 h-postprandial blood glucose, glycosylated hemoglobin, triglyceride, total cholesterol, blood viscosity, fibrinogen and C-reactive protein levels were detected in the two groups, and were all demonstrated to decrease significantly following treatment with SKC-YJ. Furthermore, the results revealed that SKC-YJ treatment exhibited no significant side-effects on the blood, liver and renal functions or gastrointestinal reactions. By contrast, SKC-YJ improved the symptoms of nausea, vomiting and diarrhea in the patients with DN, while showing no allergic reaction during the observation period. Therefore, SKC-YJ treatment was shown to significantly improve the clinical efficacy of DN treatment, illustrating novel roles for TCM in DN treatment.

Ginsenoside Rb1 inhibits matrix metalloproteinase 13 through down-regulating Notch signaling pathway in osteoarthritis.

Mounting evidence suggests that an excess of matrix metalloproteinase-13 (MMP-13) plays an important role in the breakdown of extracellular matrix in osteoarthritis (OA). Here, the effects of ginsenoside Rb1 (GRb1) on the expression of MMP-13 in IL-1ß-induced SW 1353 chondrosarcoma cells and an experimental rat model of OA induced by anterior cruciate ligament transection (ACLT) were investigated. SW1353 chondrosarcoma cells were pretreated with or without GRb1 and Notch signaling pathway inhibitor, DAPT, then were stimulated with IL-1ß. In rats, experimental OA was induced by ACLT. These rats then received intra-articular injections of vehicle, an inhibitor of γ-secretase, DAPT, and/or GRb1. Expression of MMP-13, collagen type II (CII), Notch1, and jagged 1 (JAG1) were verified by western blotting and immunohistochemistry. In addition, levels of MMP-13 mRNA were detected using quantitative real-time PCR. In histological analyses, treatment with DAPT reduced the number of cartilage lesions present and the expressions of MMP-13, CII, Notch1, and JAG1. In addition, treatment with GRb1 was associated with lower levels of Notch1 and JAG1 in both IL-1ß-induced SW1353 chondrosarcoma cells and in the rat OA model. Furthermore, the suppressive effect of GRb1 on MMP-13 was greater than that exhibited by the signaling pathway inhibitor. In conclusion, GRb1 inhibits MMP-13 through down-regulating Notch signaling pathway in OA.

Chondroprotective effects and multi-target mechanisms of Icariin in IL-1 beta-induced human SW 1353 chondrosarcoma cells and a rat osteoarthritis model.

Cartilage degradation is the most predominant pathological change during osteoarthritis (OA). Furthermore, accumulating evidence suggests that an excess of matrix metalloproteinase-13 (MMP-13) plays a critical role in the breakdown of cartilage. Here, the effects of Icariin on the expression of MMP-13 in IL-1ß-induced SW 1353 chondrosarcoma cells were investigated. In addition, the in vivo effects of Icariin on an experimental rat model of OA induced by anterior cruciate ligament transection (ACLT) was examined. SW1353 chondrosarcoma cells were pretreated with or without Icariin and MAPK and Wnt/ß-catenin signaling pathway inhibitors, then were stimulated with IL-1ß. In rats, experimental OA was induced by ACLT. These rats then received intra-articular injections of vehicle, signaling pathway inhibitors, and/or Icariin. Expression of MMP-13, phosphorylated p38, phosphorylated JNK, and ß-catenin were verified by western blotting. In addition, levels of MMP-13 mRNA were detected using quantitative real-time PCR. In histological analyses, treatment with Icariin reduced the number of cartilage lesions present. In addition, treatment with Icariin was associated with lower levels of phosphorylated p38, phosphorylated JNK, and ß-catenin in both IL-1ß-induced SW1353 chondrosarcoma cells and in the rat OA model. Furthermore, the suppressive effect of Icariin on MMP-13 was greater than that exhibited by other signaling pathway inhibitors. Overall, these data suggest that Icariin has therapeutic potential for the treatment of OA.

[Comparison of two methods for establishing rat models of complex regional pain syndrome type 1].

OBJECTIVE: To investigate the difference between two methods for establishing rat models of complex regional pain syndrome type 1. METHODS: Twenty-four adult SD rats were randomly allocated into control group, tibia fracture group and ischemia group (n=8), and complex regional pain syndrome type 1 was simulated in the latter two groups using different methods. The pain behaviors of the rats were observed and serum substance P level was detected with ELISA at different time points after the operations. RESULTS: Limb loss occurred in 3 rats in tibia fracture group, and the other 5 rats showed a lowered pain threshold. At 8 h after modeling, the rats in ischemia group showed more obvious reduction of pain threshold than those in tibia fracture group. Serum substance P levels in the two model groups underwent similar alterations after modeling, both significantly higher than that in the control group (P<0.01). Microcirculation changes were more serious in tibia fracture group than in ischemia group. Ulcer-like lesions were found in the skin of some rats in tibia fracture group. No obvious pathologies were observed microscopically in the sciatic nerve in the two model groups. CONCLUSION: The two methods can both be effective to simulate complex regional pain syndrome type 1, but tibia fracture results in more sustained symptoms and pathological changes in the microcirculation.

[Effect of electroacupuncture on leptin and adiponectin in simple obesity patients].

OBJECTIVE: To probe into the underlying mechanism of electroacupuncture (EA) for simple obesity patients. METHODS: Sixty simple obesity patients were randomly divided into control, manual acupuncture (MA) and EA groups with 20 cases in each group. Acupoint groups (1) Liangqiu (ST 34), Xuehai (SP 10), etc.; (2) Gongsun (SP 4), Neiting (ST 44), etc. were punctured respectively for MA groups (once every other day, 27 times altogether), and in combination with EA (2-5 mA, 0.8-3 Hz, 30 min) of bilateral Tianshu (ST 25), Fujie (SP 14), etc. for EA group. Serum leptin (Lep) and adiponectin (Adi) were measured by enzyme linked immunosorbent assay (ELISA). RESULTS: After the treatment, of the 20 cases in control, MA and EA groups, 0 (0%), 0(0%) and 4 (20. 0%) were cured; 0 (0%), 10 (50.0%) and 14 (70.0%) were improved remarkably; 1 (5.0%), 7 (35.0%) and 1 (5.0%) were effective; 19 (95.0%), 3 (15.0%) and 1 (5.0%) failed, with the effective rates being 5.0%, 85.0% and 95.0% separately. The therapeutic effects of both MA and EA groups were significantly higher than that of control group (P < 0.01). After the treatment, serum Lep levels in both MA and EA groups decreased significantly, and serum Adi contents of these two groups increased considerably compared with their own basic values of pre-treatment (P < 0.05, 0.01), and the effects of EA were markedly better than those of MA and control groups (P < 0.05). No significant changes were found in Lep and Adi levels in control group (P > 0.05). CONCLUSION: Both EA and manual acupuncture can effectively lower blood Lep content and raise blood Adi in simple obesity patients, which may contribute to its effect in reducing body. weight. The effect of EA is significantly superior t o that of manual acupuncture in the treatment of simple obesity.

[Preliminary analysis on the significance of the new edition of pharmacology of Chinese Materia Medica in guiding theoretical research and clinical practice of integrated Chinese and Western medicine].

The new edition of Pharmacology of Chinese Materia Medica has broken through the previous mode of the teaching materials, it classified traditional Chinese drugs distinctly into three categories--the drugs for radical cure depending on syndrome differentiation, the drugs for etiological treatment aimed at pathogenesis, and the drugs for symptomatic treatment, and introduced some new concepts about integrated Chinese and Western medicine, showing active significance in guiding the theoretical research and clinical practice of integrated traditional Chinese and Western medicine.