Curcumin ameliorates IL-1ß-induced apoptosis by activating autophagy and inhibiting the NF-κB signaling pathway in rat primary articular chondrocytes.

Articular cartilage damage and chondrocyte apoptosis are common features of rheumatoid arthritis and osteoarthritis. Recently, curcumin has been reported to exhibit protective effects on degeneration in articular cartilage diseases. However, the effects and mechanisms of curcumin on articular chondrocyte injury remain to be elucidated. The aim of the present study is to investigate the chondroprotective mechanisms of curcumin on interleukin-1ß (IL-1ß)-induced chondrocyte apoptosis in vitro. The results revealed that IL-1ß decreased cell viability and induced apoptosis in primary articular chondrocytes. Curcumin pretreatment reduced IL-1ß-induced articular chondrocyte apoptosis. In addition, treatment with curcumin increased autophagy in articular chondrocytes and protected against IL-1ß-induced apoptosis. The curcumin-mediated protection against IL-1ß induced apoptosis was abolished when cells were treated with the autophagy inhibitor 3-methyladenine or transfected with Beclin-1 small interfering RNA. Furthermore, IL-1ß stimulation significantly increased the phosphorylation levels of nuclear factor (NF)-κB p65 and glycogen synthase kinase-3ß, and decreased the phosphorylation levels of ß-catenin in articular chondrocytes, and these alterations to the phosphorylation levels were partly reversed by treatment with curcumin. Dual-luciferase and electrophoretic mobility shift assays demonstrated that IL-1ß increased NF-κB p65 promoter activity in chondrocytes, and this was also reversed by curcumin. Pretreatment with the NF-κB inhibitor pyrrolidine dithiocarbamate enhanced the protective effects of curcumin on chondrocyte apoptosis, but Wnt/ß-catenin inhibitor, XAV-939, did not exhibit this effect. Molecular docking and dynamic simulation studies results showed that curcumin could bound to RelA (p65) protein. These results indicate that curcumin may suppress IL-1ß-induced chondrocyte apoptosis through activating autophagy and restraining NF-κB signaling pathway.

Effect of volatile oil from Blumea Balsamifera (L.) DC. leaves on wound healing in mice.

OBJECTIVE: To assess the effectiveness of violate oil from Blumea Balsamifera (L.) DC. leaves (BB oil) on wound healing in mice. METHODS: Undiluted BB oil and its diluted solutions with olive oil to 1/5 and 1/10 to yield BB oil1/5 and BB oil1/10 were applied to the wounded skin before wound healing conditions were assessed by healing rate, histopathology, and contents of collagen, hydroxyproline, and Neuropeptide Substance P (SP). All above results were compared with the efficacies of the control, pure olive oil, basic fibroblast growth factor (BFGF), and cream of Jing Wan Hong (JWH). RESULTS: BB oil1/5 and BB oil1/10 improved wound contraction and closure. Histopathology study further confirmed a desirable histological organization of wound tissues. BB oil1/5 and BB oil1/10 reduced the number of inflammatory cells, increased wound-healing rates, and significantly increased the hydroxyproline content. Both BB oil1/5 and BB oil1/10 improved formation of collagen, and reduced the frequency of fibroblasts. Moreover, BB oil1/5 and BB oil1/10 markedly promoted SP expression. However, undiluted BB oil may induce skin thickening and hardening, inhibite collagen synthesis and delay complete skin wound healing. CONCLUSION: The BB oil1/5 and BB oil1/10 promoted capillary regeneration, blood circulation, collagen deposition, granular tissue formation, epithelial deposition, and wound contraction. The mechanism underlying the action might be related to induction of SP secretion, and the proliferation and differentiation of mesenchymal cells.

A Siamese ResNeXt network for predicting carotid intimal thickness of patients with T2DM from fundus images.

Objective: To develop and validate an artificial intelligence diagnostic model based on fundus images for predicting Carotid Intima-Media Thickness (CIMT) in individuals with Type 2 Diabetes Mellitus (T2DM). Methods: In total, 1236 patients with T2DM who had both retinal fundus images and CIMT ultrasound records within a single hospital stay were enrolled. Data were divided into normal and thickened groups and sent to eight deep learning models: convolutional neural networks of the eight models were all based on ResNet or ResNeXt. Their encoder and decoder modes are different, including the standard mode, the Parallel learning mode, and the Siamese mode. Except for the six unimodal networks, two multimodal networks based on ResNeXt under the Parallel learning mode or the Siamese mode were embedded with ages. Performance of eight models were compared via the confusion matrix, precision, recall, specificity, F1 value, and ROC curve, and recall was regarded as the main indicator. Besides, Grad-CAM was used to visualize the decisions made by Siamese ResNeXt network, which is the best performance. Results: Performance of various models demonstrated the following points: 1) the RexNeXt showed a notable improvement over the ResNet; 2) the structural Siamese networks, which extracted features parallelly and independently, exhibited slight performance enhancements compared to the traditional networks. Notably, the Siamese networks resulted in significant improvements; 3) the performance of classification declined if the age factor was embedded in the network. Taken together, the Siamese ResNeXt unimodal model performed best for its superior efficacy and robustness. This model achieved a recall rate of 88.0% and an AUC value of 90.88% in the validation subset. Additionally, heatmaps calculated by the Grad-CAM algorithm presented concentrated and orderly mappings around the optic disc vascular area in normal CIMT groups and dispersed, irregular patterns in thickened CIMT groups. Conclusion: We provided a Siamese ResNeXt neural network for predicting the carotid intimal thickness of patients with T2DM from fundus images and confirmed the correlation between fundus microvascular lesions and CIMT.

Pharmacokinetics, Safety, and Bioequivalence of 2 Lopinavir/Ritonavir (200/50 mg) Tablets in Healthy Chinese Volunteers: Effect of Food on Absorption.

Lopinavir/ritonavir is an important protease inhibitor for treating HIV-1 infection in patients aged >2 years in combination with other antiretrovirals. The antiviral activity of lopinavir/ritonavir in vivo is mainly derived from lopinavir, while ritonavir improves the bioavailability of lopinavir. This study compared the bioequivalence and safety of 2 lopinavir/ritonavir (200/50 mg) formulations under fasted and fed conditions in healthy Chinese volunteers and compared the pharmacokinetic parameters of lopinavir and ritonavir. A randomized, open-label, single-dose, 4-period, crossover bioequivalence was conducted in 72 subjects under fasted and fed conditions. Lopinavir and ritonavir plasma concentrations were analyzed using validated liquid chromatography with tandem mass spectrometry. Noncompartmental analysis was used to evaluate pharmacokinetic parameters. The 90% confidence intervals of test/reference geometric mean ratio for lopinavir and ritonavir area under the plasma concentration-time curve and maximum drug concentration meets the bioequivalence criteria based on the average bioequivalence method. A high-fat meal delayed the time to the maximum concentration of lopinavir and ritonavir. Therefore, these formulations were bioequivalent in healthy Chinese volunteers under fasting and fed conditions. Moreover, adverse events were more frequent in the fed state, but all were mild.

TRPM7 channel inhibition attenuates rheumatoid arthritis articular chondrocyte ferroptosis by suppression of the PKCα-NOX4 axis.

A role for ferroptosis in articular cartilage destruction associated with rheumatoid arthritis (RA) has not been identified. We previously reported transient receptor potential melastatin 7 (TRPM7) expression was correlated with RA cartilage destruction. Herein, we further characterized a role for TRPM7 in chondrocyte ferroptosis. The expression of TRPM7 was found to be elevated in articular chondrocytes derived from adjuvant arthritis (AA) rats, human RA patients, and cultured chondrocytes treated with the ferroptosis inducer, erastin. TRPM7 knockdown or pharmacological inhibition protected primary rat articular chondrocytes and human chondrocytes (C28/I2 cells) from ferroptosis. Moreover, TRPM7 channel activity was demonstrated to contribute to chondrocyte ferroptosis by elevation of intracellular Ca2+. Mechanistically, the PKCα-NOX4 axis was found to respond to stimulation with erastin, which resulted in TRPM7-mediated chondrocyte ferroptosis. Meanwhile, PKCα was shown to directly bind to NOX4, which could be reduced by TRPM7 channel inhibition. Adeno-associated virus 9-mediated TRPM7 silencing or TRPM7 blockade with 2-APB alleviated articular cartilage destruction in AA rats and inhibited chondrocyte ferroptosis. Collectively, both genetic and pharmacological inhibitions of TRPM7 attenuated articular cartilage damage and chondrocyte ferroptosis via the PKCα-NOX4 axis, suggesting that TRPM7-mediated chondrocyte ferroptosis is a promising target for the prevention and treatment of RA.

Systemic pharmacological investigation of the Feng Shi Gu Tong capsule in the treatment of rheumatoid arthritis.

Feng Shi Gu Tong (FSGT) capsule is a commonly used Chinese Traditional Patent Medicine in clinical practice, which has been proven to be effective for the treatment of active rheumatoid arthritis (RA). However, due to its complex composition, the precise molecular mechanism of the FSGT capsule in the treatment of RA is still indistinct. Therefore, the method of systemic pharmacology was used to obtain candidate compounds through absorption, distribution, metabolism, elimination (ADME) parameters, and supplementation of references. Network construction and analysis were also included to reveal the potential mechanism of FSGT capsule in treating RA. A total of 119 compounds were obtained in FSGT capsule, and a total of 107 compounds with targets were included in the study. These compounds acted on 267 targets in total. In addition, there were 317 targets related to RA disease. All constructed networks included four major networks and four minor networks. In addition, the clusters of RA disease protein-protein interaction (PPI) network and FSGT capsule-RA disease targets network revealed that the biological process involved in these clusters including immune response and apoptosis, etc. The pathways enriched by the direct targets of FSGT capsule acted on RA also highly overlapped with the pathways enriched by the RA PPI network, such as the TNF signaling pathway. Our research has managed to predict and explain the pharmacological effects and the molecular mechanisms of the FSGT capsule in RA, and provided a realistic exploration method for studying the potentially active ingredients of traditional Chinese medicines simultaneously.

Network pharmacology-based study on the mechanism of Yiganling capsule in hepatitis B treatment.

BACKGROUND: Yiganling (YGL) capsule is a traditional Chinese medicine preparation consisting of eight herbs that has been clinically proven to have a favorable treatment effect on Hepatitis B (HB). However, due to its multiple targets and multi-pharmacological effects, the mechanisms of YGL capsule in the treatment of HB are unknown. METHODS: First, the chemical constituents of YGL capsules were obtained from the Chinese medicine database, and YGL capsules were constructed. Second, active compounds were screened by the ADME model. The target fishing model was used to screen the corresponding targets of active compounds and to construct a compounds and compound targets network. Using human disease databases and literature mining, we systematically identified genes associated with HB, constructed disease-specific protein-protein interaction networks, and performed clustering and enrichment analyses of these networks. These networks were then merged to obtain a compound-disease target network, and cluster and enrichment analyses were performed on the compound-disease target network to acquire a compounds-disease targets-mechanism network and a clustering network. RESULTS: We successfully built eight pharmacological network diagrams, including four primary networks and other network maps. The four dominating network maps included a HB disease-associated protein-protein interaction network, a YGL capsule compounds-target network, a YGL capsule ingredient target-HB disease target network, and a YGL-HB disease mechanism network. Other networks included a pathway of HB disease targets, the HB disease protein-protein interaction cluster analysis network, and the YGL-HB target clustering network. CONCLUSION: This study successfully forecasted, illuminated, and confirmed the synergistic effects of HB disease molecules and discovered the potential of HB relevant targets, clusters, and target-related biological processes and signaling pathways. Our research not only provides theoretical support for the molecular and pharmacological mechanisms of YGL capsule in HB treatment, but also provides new research methods for the study of the other traditional Chinese medicinal compounds.

A Network Pharmacology Study on the Active Ingredients and Potential Targets of Tripterygium wilfordii Hook for Treatment of Rheumatoid Arthritis.

Traditional Chinese medicine has specific effect on some chronic diseases in clinic, especially in rheumatic diseases. Tripterygium wilfordii Hook (TWH) is a traditional Chinese medicine commonly used in the treatment of rheumatoid arthritis (RA); the unique therapeutic effect has been confirmed by a large number of research papers. TWH has many compounds that lead to its active compounds. However, the potential targets and pharmacological and molecular mechanism of its action treatment of rheumatic diseases are not entirely clear. Therefore, the network pharmacology approach is needed to further study and explore its treatment mechanism. We have successfully set up 10 networks, including four major networks and other networks. Four major networks include rheumatoid arthritis disease network, compound-compound target network of TWH, TWH compound target-rheumatoid arthritis disease network, and TWH-rheumatoid arthritis disease-mechanism network. Other networks consist of RA disease and TWH related targets clusters, biological processes, and pathways network. Our study successfully predicted, explained, and confirmed the TWH of RA disease molecular synergy and found the potential of RA related targets, cluster, biological process, and pathways. This study not only provides prompts to the researcher who explores pharmacological and biological molecular mechanism of TWH applying to RA disease, but also proves a feasible method for discovering potential activated compounds from Chinese herbs.