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Ershiwuwei Lvxue Pill (ELP, མགྲིན་མཚལ་ཉེར་ལྔ།), a traditional Tibetan medicine preparation, has been used hundreds of years for the clinical treatment of rheumatoid arthritis (RA) in the highland region of Tibet, China. However, the underlying mechanism of its therapeutic effect remains unclear. The present study aimed to investigate the potential pharmacological mechanisms of anti-arthritic effect of ELP. The main chemical constituents of ELP were analyzed by ultra-performance liquid chromatography quadrupole-time-flight mass spectrometry (UPLC-Q-TOF-MS). Forty-eight male Wistar rats (220 ± 20 g) were randomly divided into six groups: normal group, collagen-induced arthritis (CIA) group, methotrexate group (1.05 mg/kg), ELP groups (115, 230 and 460 mg/kg). CIA rat models were assigned to evaluate the anti-RA activity of ELP by determining the paws swelling, arthritis score, organ coefficients of spleen and thymus, and histopathological analysis of knee joints of synovial tissues. The levels of TNF-α, IL-10, IL-6 and IL-17 in serum were measured by ELISA. In addition, mRNA and protein expression levels associated with JAK2/STAT3 signaling pathway in synovial tissues of CIA rats were detected by qRT-PCR, immunohistochemistry and Western blot analyses. Fourteen main chemical constituents of ELP were quantitatively determined by UPLC-Q-TOF-MS analysis. Treatment with ELP reduced the paw swelling, arthritis score and organ coefficients of spleen and thymus. Histopathological examination revealed the protective effects of ELP on CIA rats with knee joint injury. The levels of serum pro-inflammatory cytokines (TNF-α, IL-6 and IL-17) were markedly reduced while the anti-inflammatory cytokine IL-10 was significantly increased with the treatment of ELP. Further investigations showed ELP down-regulated the mRNA and protein expression levels of Bcl-2, whereas up-regulated Bax, SOCS1 and SOCS3. Meanwhile, the ratios of p-JAK2/JAK2 and p-STAT3/STAT3 proteins from synovial tissues were dramatically decreased with the treatment of ELP, whereas no changes of the mRNA and protein expression levels of JAK2 and STAT3 were observed. These results indicated that ELP reduced the severity of arthritis and joint swelling, suggesting an antirheumatic effect on CIA rats. The possible mechanism is related to inhibiting inflammatory response and inducing apoptosis in synovial tissues by regulating JAK2/STAT3 signaling pathway. However, further in vivo and in vitro investigations are still needed to clarify the underlying mechanism of ELP in treating RA. Image 1 [ABSTRACT FROM AUTHOR]

Background: Low-intensity pulsed ultrasound (LIPUS) is a safe and noninvasive rehabilitative physical therapy with anti-inflammatory effects. The current study investigated the effect of LIPUS on the inflammation of nucleus pulposus (NP) cells and its underlying mechanism. Methods: Human NP cells were acquired from lumbar disc herniation tissue samples and cultured for experiments. Human NP cells were treated with LPS and then exposed to LIPUS (15 mW/cm2, 30 mW/cm2 and 60 mW/cm2) for 20 min daily for 3 days to determine the appropriate intensity to inhibit the expression of the inflammatory factors TNF-α and IL-1β. The gene and protein expression of aggrecan, collagen II, MMP-3 and MMP-9 was measured by real‐time PCR and western blotting, respectively. The activity of the nuclear factor‐kappa B (NF‐κB) pathway was examined by western blotting and immunofluorescence. After pretreatment with the NF-κB inhibitor PDTC, the expression of TNF-α, IL-1β, MMP-3 and MMP-9 was measured by real‐time PCR. Results: LIPUS at intensities of 15 mW/cm2, 30 mW/cm2 and 60 mW/cm2 inhibited LPS-induced NP cell expression of the inflammatory factors TNF-α and IL-1β, especially at 30 mW/cm2. LIPUS significantly upregulated the gene and protein expression of aggrecan and collagen II and downregulated the gene and protein expression of MMP-3 and MMP-9 in LPS-induced NP cells. The NF‐κB signaling pathway was inhibited by LIPUS through inhibiting the protein expression of p-P65 and the translocation of P65 into the nucleus in LPS-induced NP cells. In addition, LIPUS had similar effects as the NF-κB inhibitor PDTC by inhibiting the NF-κB signaling pathway, inflammation and catabolism in LPS-induced human degenerative nucleus pulposus cells. Conclusion: LIPUS inhibited inflammation and catabolism through the NF‐κB pathway in human degenerative nucleus pulposus cells. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic inflammatory disease due to immune dysregulation that cannot be cured. The skin conditions of psoriasis negatively impact patients' quality of life worldwide. Qing Dai (Indigo Naturalis), a traditional Chinese medicine (TCM) processed from Strobilanthes cusia is a clinical medicine used for psoriasis patient in Taiwan and the gene overexpression of interleukin (IL)-17A could be notably reduced in skin lesions after using Qing Dai ointment and its alkaloid ingredients. To develop a potential anti-psoriatic phytopharmaceutical, an alkaloid-rich fraction named INM-A was prepared from Qing Dai. The chemical profile and anti-psoriatic activity of INM-A were analyzed and evaluated to define its in vitro mechanism and in vivo efficacy for psoriasis therapy. Dowex® 50WX4 hydrogen form resin was used for column chromatography to prepare INM-A. To track alkaloids, INM-A was conducted with Dragendorff's, Mayer's, and Wagner's reagents. HPLC and UV–Vis spectrophotometer were applied to analyze the chemical profile and relative total alkaloid content in INM-A. A psoriatic mouse model induced by imiquimod (IMQ) was performed to verify in vivo efficacy of INM-A. IL-17A-dominated cellular oxygen consumption rate, oxidative stress, and cytokines in keratinocytes were measured to clarify in vitro mechanism of INM-A. An alkaloid-rich fraction, INM-A, consisted of seven active alkaloid compounds 1 – 7 was obtained from Qing Dai. INM-A improved the skin condition severities in IMQ-induced psoriatic mice and decreased IL-17A in not only psoriatic mice but also polarized Th17 cells. In addition, INM-A targeted IL-17A to inhibit inflammation and OXPHOS-driven oxidative stress in human keratinocytes. Accordingly, INM-A manufactured from Qing Dai may be a promising lead phytopharmaceutical for further IL-17A-related inflammatory disease studies such as psoriasis. [Display omitted] • An alkaloid-rich phytopharmaceutical (INM-A) was prepared from Qing Dai. • INM-A could alleviate the severities of dermatitis in IMQ-induced psoriatic mice. • INM-A could decrease IL-17A productions in psoriatic mice and polarized Th17 cells. • INM-A targeted IL-17A to inhibit inflammation (IL-6 and IL-8) in HaCaT cells. • INM-A targeted IL-17A to inhibit OXPHOS-driven oxidative stress in HaCaT cells. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD) including ulcerative colitis (UC) is one of the risk factors for the development of colitis-associated colon cancer (CAC). CAC is a type of colorectal cancer (CRC), the third leading cause of cancer death. Ziziphus jujuba (ZJ) fruit contains bioactive components such as polysaccharides, triterpenoid acid, and flavonoids, and it has shown anti-inflammatory property. The aim of the study was to investigate the protective effect of dietary ZJ on colitis-associated colorectal tumorigenesis in mice. Mice (n = 42, two sets) were injected with azoxymethane (AOM) followed by three cycles of 2% (w/v) dextran sulfate sodium (DSS) in drinking water to induce CAC. Simultaneously, those mice were fed with ZJ diet for 70 days (5% or 10% w/w). Data were analyzed by ANOVA followed by LSD Bonferroni test. Dietary ZJ decreased fecal blood, diarrhea, disease activity index (DAI), spleen weight (P < 0.001), and the number of tumors (P < 0.001). In addition, dietary ZJ increased colon length (P < 0.001) and suppressed the activation of NF-кB/IL-6/JAK1/STAT3 signaling pathway. In conclusion, we suggest that dietary ZJ attenuates inflammation by interfering NF-κB/IL-6/JAK1/STAT3 signaling pathway, thereby inhibits AOM/DSS-induced colon tumorigenesis in mice. [ABSTRACT FROM AUTHOR]

Rhamnella gilgitica Mansf. et Melch. (སེང་ལྡེང་།, RG) is a traditional Tibetan medicinal plant that is currently grown throughout Tibet. According to the theory of Tibetan medicine, RG is efficient for removing rheumatism, reducing swelling, and relieving pain. Hence, it has been used for the treatment of rheumatoid arthritis (RA) in Tibet for many years. However, there are no previous reports on the anti-RA activities of ethyl acetate extract of RG (RGEA). This study aimed to explore the anti-RA effect and mechanism of RGEA on collagen-induced arthritis (CIA) in rats. The CIA model was established in male Wister rats by intradermal injection of bovine type II collagen and Complete Freund's Adjuvant at the base of the tail and left sole, respectively. The rats were orally administered with RGEA (9.71, 19.43, or 38.85 mg/kg) for 23 days. The body weight, swelling volume, arthritis index score, thymus and spleen indices, and pathological changes were observed to evaluate the effect of RGEA on RA. Furthermore, the inflammatory cytokines in serum, such as interleukin1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), interleukin6 (IL-6), interleukin17 (IL-17), interferon-γ (INF-γ), interleukin4 (IL-4), and interleukin10 (IL-10) were measured by enzyme linked immunosorbent assay (ELISA) to explore the anti-inflammatory effects of RGEA. The terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) staining was used to examine apoptosis. Finally, the protein and gene expression of B-cell lymphoma-2-associated X (Bax), B-cell lymphoma 2 (Bcl-2), Caspase3, janus-activated kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), suppressor of cytokine signaling1 (SOCS1), and 3 (SOCS3) in synovial tissue were detected using immunohistochemistry and real-time quantitative polymerase chain reaction (RT-qPCR). After the treatment with RGEA, the body weight of rats was restored, both the arthritis index and paw swelling were suppressed, and spleen and thymus indices were decreased. RGEA reduced the inflammatory cells and synovial hyperplasia in the synovial tissue of the knee joint, and suppressed bone erosion. Meanwhile, RGEA decreased the levels of IL-1β, IL-6, IL-17, TNF-α, and INF-γ, while increased the levels of IL-4 and IL-10. TUNEL fluorescence apoptosis results confirmed that RGEA obviously promoted the apoptosis of synovial cells. Further studies showed that RGEA inhibited the proteins and mRNAs expression of JAK2 and STAT3 as well as increased the proteins and mRNAs expression of SOCS1 and SOCS3. In addition, RGEA upregulated the expression of Bax and Caspase3, and downregulated the expression of Bcl-2. The anti-RA effectof RGEA might be related to the promotion of apoptosis and inhibition of inflammation, which regulated the JAK-STAT pathway. Image 1 • For the first time, we studied the anti-rheumatoid arthritis effect of RGEA. • For the first time, we have studied the therapeutic effect of RGEA by regulating JAK-STAT pathway. • For the first time, we discussed the pathogenesis of rheumatoid arthritis based on theory of Tibetan medicine. Image 2. [ABSTRACT FROM AUTHOR]