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Gallic acid (GA), also known as 3,4,5-trihydroxybenzoic acid, is a natural secondary metabolite and widely isolated from various fruits, plants and nuts. In recent years, GA has received increasing attention for its powerful anti-inflammatory properties. The purpose of this review is to clearly illuminate the pharmacological activities and related molecular mechanisms of GA in inflammatory diseases. After consulting a large number of literatures, we made a comprehensive exposition on the chemical characteristics, plant origins, pharmacokinetics and toxicity of GA, especially its pharmacological activities and mechanisms of action. Although the plant source of GA is very rich, its lower extraction rate limits the application of GA in development. It is worth mentioning that GA can not only be separated from many plants, but also be produced in large quantities through biological and chemical synthesis. According to pharmacokinetic studies, the absorption and elimination of GA after oral administration are fast, while the structural optimization or dosage form adjustment of GA is beneficial to increase its bioavailability. Promisingly, toxicity studies have shown that GA scarcely has obvious toxicity or side effects in a variety of animal experiments and clinical trials. The results show that the anti-inflammatory mechanisms of GA mainly involved MAPK and NF-κB signaling pathways. It thus weakens the inflammatory response by reducing the release of inflammatory cytokines, chemokines, adhesion molecule and cell infiltration. Due to its excellent pharmacological activities, GA is expected to be a potential candidate for the treatment of various inflammation-related diseases. This paper will provide theoretical basis for the clinical application of GA and guide the future research and medicinal development of GA., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Acute lung injury (ALI) is life-threatening disease characterized by uncontrolled inflammatory response. IKKα/β, the key kinases in the activation of NF-κB pathway, are implicated in inflammatory pulmonary injury, and represent attractive targets for ALI therapy. Brevilin A (BVA) is a sesquiterpene lactone from Centipeda minima , a Chinese herb used to treat inflammatory diseases. This study aims to investigate the inhibition of BVA on ALI, with focus on clarifying the molecular mechanisms involved in BVA-mediated anti-inflammatory activity in macrophages. Briefly, BVA significantly inhibited the production of NO and PGE2 by suppressing iNOS and COX2 expression, and suppressed the mRNA expression of IL-1β, IL-6, and TNFα in LPS/IFNγ-stimulated RAW264.7 macrophages. The anti-inflammatory activity of BVA was further confirmed in LPS/IFNγ-stimulated BMDMs and TNFα/IFNγ-exposed RAW264.7 cells. In vivo , BVA effectively attenuated LPS-induced lung damage, inflammatory infiltration, and production of pro-inflammatory cytokines, including MPO, IL-1β, IL-6, TNFα, and PGE2. Mechanistically, BVA could covalently bind to the cysteine 114 of IKKα/β, and effectively inhibiting the activity and function of IKKα/β, thereby resulting in the suppression of phosphorylation and degradation of IκBα and the subsequent activation of NF-κB signaling. Furthermore, pretreatment of DTT, a thiol ligand donor, significantly abolished BVA-mediated effects in LPS/IFNγ-stimulated RAW264.7 cells, suggesting the crucial role of the electrophilic α, β-unsaturated ketone of BVA on its anti-inflammatory activity. These results suggest that BVA ameliorates ALI through inhibition of NF-κB signaling via covalently targeting IKKα/β, raising the possibility that BVA could be effective in the treatment of ALI and other diseases harboring aberrant NF-κB signaling. [ABSTRACT FROM AUTHOR]

To better understand the acute inflammatory mechanisms, the modulation, and to investigate the key node in predicting inflammatory diseases, high-sensitivity LC-MS/MS-based proteomics and phosphoproteomics approaches were used to identify differential proteins in RAW264.7 macrophages with lipopolysaccharide (LPS). Furthermore, differential proteins and their main biological process, as well as signaling pathways, were analyzed through bioinformatics techniques. The biological process comparison revealed 219 differential proteins and 405 differential phosphorylation proteins, including major regulatory factors of metabolism (PFKL, PGK1, GYS1, ACC, HSL, LDHA, RAB14, PRKAA1), inflammatory signaling transduction (IKKs, NF-κB, IRAK, IKBkb, PI3K, AKT), and apoptosis (MCL-1, BID, NOXA, SQSTM1). Label-free proteome demonstrated canonical inflammation signaling pathways such as the TNF signaling pathway, NF-κB signaling pathway, and NOD-like receptor signaling pathway. Meanwhile, phosphoproteome revealed new areas of acute inflammation. Phosphoproteomics profiled that glycolysis was enhanced and lipid synthesis was increased. Overall, the AMPK signaling pathway is the key regulatory part in macrophages. These revealed that the early initiation phase of acute inflammation primarily regulated the phosphoproteins of glucose metabolic pathway and lipid synthesis to generate energy and molecules, along with the enhancement of pro-inflammatory factors, and further induced apoptosis. Phosphoproteomics provides new evidence for a complex network of specific but synergistically acting mechanisms confirming that metabolism has a key role in acute inflammation. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: Rheum rhabarbarum (rhubarb) has long been used for the treatment of inflammation in China and other Asian countries. However, the mechanism underlying the anti-inflammatory activity of this medicinal plant is not fully understood. The present study was designed to investigate the anti-inflammatory effects of anthraquinones, the major constituents in rhubarb, and the molecular mechanism involved in their anti-inflammatory effects. Materials and methods: RAW264.7 cells were stimulated by lipopolysaccharide (LPS) in the presence or absence of the compounds examined. The proliferation of RAW264.7 cells was assayed by the Alamar-Blue method. The quantity of nitric oxide (NO) was determined by Griess assay. The expression of pro-inflammatory cytokines was determined by enzyme-linked immunosorbent assay (ELISA) and quantitative real-time PCR. Inducible nitric oxide synthase (iNOS), inhibitor of nuclear factor ?B? (I?B?), extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (MAPK), c-Jun NH2-terminal kinase (JNK), and Akt/phosphoinositide 3-kinase (PI3K) protein expression levels were determined by Western blotting. Results: Aloe-emodin markedly suppressed the production of NO, interleukin-6 (IL-6), and interleukin-1? (IL-1?) in LPS-stimulated RAW264.7 cells with no apparent cytotoxicity. The mRNA expression levels of iNOS, IL-6, and IL-1? genes were also significantly inhibited by aloe-emodin. Western blot analysis showed that aloe-emodin suppressed LPS-induced iNOS protein expression, I?B? degradation, and the phosphorylation of ERK, p38, JNK, and Akt. Conclusions: These results demonstrate that aloe-emodin is the bioactive component of rhubarb that confers an anti-inflammatory effect through a likely mechanism involving a decrease in pro-inflammatory cytokine production in LPS-induced RAW264.7 macrophages via inhibition of NF-?B, MAPK, and PI3K pathways. [Copyright &y& Elsevier]

Numerous studies have demonstrated that various traditional Chinese medicines (TCMs) exhibit potent anti-inflammatory effects against inflammatory diseases mediated through macrophage polarization and metabolic reprogramming. The objective of this review was to assess and consolidate the current understanding regarding the pathogenic mechanisms governing macrophage polarization in the context of regulating inflammatory diseases. We also summarize the mechanism action of various TCMs on the regulation of macrophage polarization, which may contribute to facilitate the development of natural anti-inflammatory drugs based on reshaping macrophage polarization. We conducted a comprehensive review of recently published articles, utilizing keywords such as "macrophage polarization" and "traditional Chinese medicines" in combination with "inflammation," as well as "macrophage polarization" and "inflammation" in conjunction with "natural products," and similar combinations, to search within PubMed and Google Scholar databases. A total of 113 kinds of TCMs (including 62 components of TCMs, 27 TCMs as well as various types of extracts of TCMs and 24 Chinese prescriptions) was reported to exert anti-inflammatory effects through the regulation of key pathways of macrophage polarization and metabolic reprogramming. In this review, we have analyzed studies concerning the involvement of macrophage polarization and metabolic reprogramming in inflammation therapy. TCMs has great advantages in regulating macrophage polarization in treating inflammatory diseases due to its multi-pathway and multi-target pharmacological action. This review may contribute to facilitate the development of natural anti-inflammatory drugs based on reshaping macrophage polarization. [Display omitted] • Macrophage types M1/M2 dictate inflammation outcome via phenotypic shift. • Macrophage polarization pathways are vital targets for treating inflammation-related diseases. • Modulating macrophage metabolism is a novel approach for inflammation-related diseases. • Traditional Chinese medicine aids inflammation by regulating macrophage polarization through multi-pathway, multi-target effects. [ABSTRACT FROM AUTHOR]

Tibetan medicine Qi-Sai-Er-Sang-Dang-Song Decoction(QSD, ཆུ་སེར་སེང་ལྡེང་སུམ་ཐང་།)is a traditional Tibetan medical formulation with demonstrated clinical benefits in atopic dermatitis (AD). However, its potential mechanism and molecular targets remain to be elucidated. This study aims to explore the activity and mechanism of QSD on AD in multiple dimensions by combining in vitro and in vivo experiments with network pharmacology. The AD effect of QSD was investigated by evaluating the levels of nitric oxide (NO) and interleukin-6 (IL-6) in the lipopolysaccharide (LPS) stimulated RAW264.7 cells. AD-like skin lesions in female BALB/c mice were induced by 2,4-dinitrochlorobenzene (DNCB). QSD or dexamethasone (positive control) were gavagely administered daily for 15 consecutive days. The body weight and skin lesion severity were recorded throughout the study. Enzyme-linked immunosorbent assay (ELISA) and Western blot (WB) analysis were used to illuminate the molecular targets associated with the anti-AD effects of QSD. Meanwhile, the ingredients of QSD in the blood were revealed and analyzed by Ultra performance liquid chromatography tandem quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) method. Network pharmacology was used to predict the targets and mechanism of active ingredient therapy for AD. In addition, the network pharmacology outcomes were further verified by molecular docking. After treatment with QSD, the levels of NO and IL-6 were decreased in the cell supernatant. Herein, QSD markedly decreased the eosinophil and mast cells infiltration in the dorsal skin of the 2,4-dinitrochlorobenzene. Moreover, QSD reconstructed the epidermal barrier by increasing the content of collagen fibers and changing the arrangement of DNCB-treated mice. QSD not only inhibited the levels of tumor necrosis factor-α (TNF-α) and interleukin-12 (IL-12) but also inhibited phosphorylation of p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK) proteins in the dorsal skin. Four active ingredients were identified through UPLC-Q-TOF/MS, including (−)-epicatechin, kaempferol-7-O-glucoside, cassiaside, and questin. After the network pharmacological analysis, six core targets of QSD closely related to AD were obtained, including TNF-α, IL-6, Caspase-3 (CASP3), Epidermal growth factor (EGFR), Peroxisome proliferator-activated receptor gamma (PPARG), and Neurotrophic Receptor Tyrosine Kinase 1 (NTRK1). Meanwhile, through Gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, the Mitogen-activated protein kinase (MAPK) signaling pathway occupies an important position in the QSD treatment of AD. The molecular docking results showed that the six core targets are stable in binding to the four active ingredients as indicated by the molecular docking results. The anti-AD effect of QSD might be related to the reconstruction of the epidermal barrier and inhibition of inflammation, which regulated the MAPK pathway. Hence, it provided a promising idea for the study of Tibetan medicine prescriptions for the treatment of AD. [Display omitted] • The mechanisms of QSD for atopic dermatitis (AD) were explored from multiple dimensions. • QSD alleviates AD-like symptoms in mice and regulates MAPK pathway to treat AD. • The theory of Tibetan medicine was combined with modern medicine to explore the pathogenesis of AD. [ABSTRACT FROM AUTHOR]

Coptis chinensis has been used for the treatment of inflammatory diseases in China and other Asian countries for centuries. However, the chemical constituents and mechanism underlying the anti-inflammatory activity of this medicinal plant are poorly understood. Here, coptisine, the main constituent of C. chinensis, was shown to potently inhibit the production of nitric oxide (NO) by suppressing the protein and mRNA expressions of inducible nitric oxide synthase (iNOS) in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Coptisine also inhibited the production of the pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-6 (IL-6) by suppressing expression of cytokine mRNA. Coptisine suppressed the degradation of inhibitor of nuclear factor κBα (IκBα) and phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase/Akt (PI3K/Akt). Coptisine had no effect on the expression of toll-like receptor 4 (TLR-4) and myeloid differentiation factor 88 (MyD88) as well as LPS binding to TLR-4. Coptisine also inhibited carrageenan-elicited rat paw edema and reduced the release of TNF-α and NO in rat inflamed tissue. These results suggest that coptisine inhibits LPS-stimulated inflammation by blocking nuclear factor-kappa B, MAPK, and PI3K/Akt activation in macrophages, and can be used as an agent for the prevention and treatment of inflammatory diseases. [ABSTRACT FROM AUTHOR]

Salidroside (Sal), an active ingredient from Rhodiola crenulate , has been reported to exert neuroprotection in cerebral injury from hypobaric hypoxia (HH) at high altitude. However, it remains to be understood whether its protective effects are related to inflammation suppression. In the present work, we aimed to reveal the mechanism of Sal attenuating HH-induced brain injury in mice caused by an animal hypobaric and hypoxic chamber. Our results provided that Sal could attenuate HH-evoked pathological injury and oxidative stress response by decreasing the content of ROS and MDA, and elevating the activities of SOD and GSH-Px. Sal treatment could partly enhance the energy metabolism, evidenced by increasing the activities of Na+-K+-ATPase, Ca2+-Mg2+-ATPase, ATP, SDH, HK and PK, while decreasing the release of LDH and LD. Meanwhile, Sal administration reversed the degradation of tight junction proteins ZO-1, Occludin and Claudin-5. Further, the increased levels of TNF-α, IL-1β and IL-6 were confined with Sal administration under the HH condition. Importantly, Sal could downregulate the proteins expression of p–NF–κB-p65, NLRP3, cleaved-Caspase-1 and ASC. Sal also decreased the protein expression of iNOS and COX2 with the increased CD206 and Arg1 expression. Taken together, these data provided that the inhibited NF-κB/NLRP3 pathway by Sal could attenuate HH-induced cerebral oxidative stress injury, inflammatory responses and the blood brain barrier (BBB) damage, attributing to the improved energy metabolism and the microglial phenotype of anti-inflammatory M2. The findings suggested that Sal was expected to be a promising anti-inflammatory agent for high altitude HH-induced brain injury. [ABSTRACT FROM AUTHOR]

Cantleyoside (CA) is a kind of iridoid glycosides in Pterocephalus hookeri (C. B. Clarke) Höeck. The purpose of this study was to investigate the effects of CA on human rheumatoid arthritis fibroblast synovial cells (HFLS-RA). Cell proliferation of HFLS-RA was assessed by CCK-8. ELISA was used to detect cytokines NO, TNF-α, IL-1β/6, MCP-1, MMP-1/3/9 and metabolism-related ATPase activities and ATP levels. JC-1, DCFH-DA, Fluo-3 AM and Calcein AM probes were used to detect mitochondrial membrane potential (MMP), reactive oxygen species (ROS), Ca2+ and mitochondrial permeability conversion pore (MPTP), respectively. Isolated mitochondria assay was used to detect mitochondrial swelling. Oxygen consumption rate (OCR), extracellular acidification rate (ECAR) and real-time ATP production were measured using a Seahorse analyzer. Apoptosis was detected by TUNEL and Hoechst staining. Western blot was used to detect the expressions of AMPK/p-AMPK, Sirt 1, IκBα, NF-κB p65/p-NF-κB p65, Bcl-2 and Bax. Cytoplasmic nuclear isolation was also performed to detect the translocation of NF-κB. CA significantly suppressed cell proliferation and the levels of NO, TNF-α, IL-1β/6, MCP-1 and MMP-1/3/9 in HFLS-RA. In addition, CA promoted the apoptosis of HFLS-RA by increasing TUNEL and Hoechst positive cells and the ratio of Bax/Bcl-2. Inhibition of energy metabolism in HFLS-RA by CA reduced OCR, ECAR and real-time ATP generation rate. Importantly, CA promoted p-AMPK and Sirt 1 expression, inhibited IκBα degradation to reduce p-NF-κB and translocation. The results suggest that CA activates the AMPK/Sirt 1/NF-κB pathway by promoting mitochondrial dysfunction, thereby exerting anti-inflammatory and pro-apoptotic effects. [Display omitted] • CA could inhibit inflammatory responses by weakening the expression of inflammatory cytokines, chemokines and MMPs. • CA could induce mitochondrial dysfunction by overloading intracellular ROS and Ca2+ in HFLS-RA. • CA could reduce mitochondrial energy metabolism by restraining OCR, ECAR and real-time ATP production rates in HFLS-RA. • CA could promote apoptosis of HFLS-RA by the activation of AMPK/Sirt 1/NF-κB pathway. [ABSTRACT FROM AUTHOR]

Rhubarb (Rhei Radix et Rhizoma) is a traditional Chinese medicine, has been used as a strong astringent in China to treat inflammation-related diseases, such as acute pancreatitis, acute cholecystitis, appendicitis and so on. Rhein, emodin and aloe-emodin are the important active anthraquinone in rhubarb, and are considered to be the main ingredients contributing to anti-inflammatory. Rhein, emodin and aloe-emodin, anthraquinones with the same parent structure that are found in rhubarb, have beneficial anti-inflammatory effects in vitro and in vivo. Anthraquinone derivatives also have important clinical roles. However, their pharmacodynamic differences and the structure-activity relationships associated with their anti-inflammatory properties have not been systematically explored. The present study was designed to quantify the effects of three rhubarb anthraquinones on inflammation and to explore the structure-activity relationships of these compounds. In this study, we detected NF-κB phosphorylation, iNOS protein expression, and IL-6 and NO production in LPS-stimulated RAW264.7 cells and then calculated median effect equations and built a dynamic pharmacodynamic model to quantitatively evaluate the efficacy of these three anthraquinones. Additionally, to determine the structure-activity relationships, we investigated the physicochemical properties and molecular electrostatic potentials of the drug molecules. We found that rhein, emodin, and aloe-emodin exerted at least dual-target (NF-κB, iNOS) inhibition of LPS-induced inflammatory responses. Compared with rhein and emodin, aloe-emodin had a stronger anti-inflammatory effect, and its inhibition of iNOS protein expression was approximately twice that of NF-κB phosphorylation. In addition, aloe-emodin had the strongest hydrophobic effect among the three anthraquinones. Overall, we concluded that the receptor binding the rhubarb anthraquinones had a hydrophobic pocket. Anthraquinone molecules with stronger hydrophobic effects had higher affinity for the receptor, resulting in greater anti-inflammatory activity. These results suggest that the addition of a hydrophobic group is a potential method for structural modification to design anti-inflammatory anthraquinone derivatives with enhanced potency. [Display omitted] • Rhein, emodin, and aloe-emodin exerted at least dual-target (NF-κB, iNOS) inhibition of LPS-induced inflammatory responses. • Compared with rhein and emodin, aloe-emodin had a stronger anti-inflammatory effect, and its inhibition of iNOS protein expression was approximately twice that of NF-κB phosphorylation. • Anthraquinone molecules with stronger hydrophobic effects had higher affinity for the receptor, resulting in greater anti-inflammatory activity. [ABSTRACT FROM AUTHOR]

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]

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]

• We summarized and analyzed the prescriptions, herbs and identified compounds of TCM on the treatment of DR from the aspects of anti-inflammation, anti-oxidative stress, anti-angiogenesis and anti-apoptosis. • The detailed mechanisms and involved network pathways of herbs-compounds-targets of TCM in treating DR were reviewed and visualized by Cytoscape software. • We discussed the limitations or deficiencies of TCM on the treatment of DR, and gave the further suggestions. As a common ocular complication and microangiopathy of type 2 diabetic mellitus, diabetic retinopathy (DR) can lead to vision loss or even blindness in diabetic patients. At present, the treatment methods of DR mainly include laser and anti-VEGF therapies. Nevertheless, the higher cost and obvious side effects seriously disturb the normal life of DR patients. Promisingly, traditional Chinese medicine (TCM) has been demonstrated to be effective in treating DR by tonifying Qi and nourishing Yin, as well clearing heat and breeding body fluids, thus activating blood and removing blood stasis. Therefore, we screened the literatures on TCM treatment of DR through the web of science, ScienceDirect, PubMed, Google scholar and CNKI online databases. The representative prescriptions, herbs and extracts, and identified compounds for treatment of DR were further summarized and analyzed. Moreover, the detailed mechanisms and involved network pathways of herbs-compounds-targets were visualized by Cytoscape software. Meanwhile, we discussed the existing limitations and deficiencies of TCM on treatment of DR and gave corresponding measures. In conclusion, TCM could significantly ameliorate DR via anti-inflammation, anti-oxidative stress, anti-angiogenesis and anti-apoptosis. [ABSTRACT FROM AUTHOR]

• Targeting macrophage polarization is a potential therapeutic strategy for atherosclerosis. • Inhibiting foam cell formation is a promising way to suppress the developmentof atherosclerosis. • Rhubarbmaybe a potentialcandidate forthe treatment of lipid metabolic diseases and inflammatory diseases. Atherosclerosis, a chronic inflammatory disease associated with high morbidity and mortality, is characterized by the accumulation of foam cells in the arterial wall. It has long been acknowledged that the formation of foam cells is caused by excess lipid uptake and abnormal cholesterol metabolism function. And increasing evidence shows that inhibiting foam cell formation is a promising way to suppress the development of atherosclerotic lesions. In addition to excess foam cells accumulation, inflammation is another major contributor of atherosclerotic lesions. Recently, macrophage polarization has been demonstrated to play a vital role in the regulation of inflammatory response. Generally, macrophages mainly polarized into two phenotypes: either classically activated pro-inflammatory M1 or alternatively activated anti-inflammatory M2. And targeting macrophage polarization has been considered as a feasible approach to prevent the development of atherosclerosis. At present, the anti-atherosclerosis drugs mainly classified into two types: lipid-lowering drugs and anti-inflammatory drugs. A large part of those drugs belong to western medicine, and various side effects are unavoidable. Interestingly, in recent years, Traditional Chinese medicine has attracted growing attention because of its good efficacy and low negative effects. Rhubarb (called Da Huang in Chinese) is a famous folk medicine with a wide spectrum of pharmacological effects, such as lipid-lowering and anti-inflammatory effects. In this review, we summarized current findings about the regulatory effects of Rhubarb on foam cell formation and macrophage polarization, with emphasis on the molecular mechanisms of action that have been revealed during the past two decades, to better understand its pivotal role in the treatment and prevention of atherosclerosis. [ABSTRACT FROM AUTHOR]

Jikan Mingmu Drops (JMD), a traditional Tibetan medicine containing six herbs, has been used to treat dry eye syndrome (DES) in individuals with diabetes mellitus. However, the activity of JMD ameliorates DES with diabetes mellitus has not been previously examined. The aim of the study is to investigate the molecular mechanism of JMD on db/db mice. The main chemical constituents of JMD were analyzed by high-performance liquid chromatography and gas chromatography–mass spectrometry. DES was then induced in db/db mice by applying 0.2% benzalkonium chloride to the ocular surface for 7 days. Eye drops containing JMD (0.25, 0.5, or 1 g/mL) or vehicle subsequently were administered three times daily for another 7 days, and the therapeutic effects were evaluated by phenol red thread tear and sodium fluorescein tests. Conjunctival specimens were subjected to hematoxylin and eosin staining and periodic acid–Schiff staining to examine pathological changes and number of goblet cells. ELISA was performed to assess the levels of various inflammatory cytokines. JMD contains hydroxysafflor yellow A, magnoflorine, jatrorrhizine hydrochloride, palmatine hydrochloride, berberine hydrochloride, gallic acid, ellagic acid, tauroursodeoxycholic acid, camphor, isoborneol, borneol, trans-cinnamic acid, and muscone. JMD treatment significantly increased the tear volume, decreased the corneal fluorescein staining score, restored the morphology and structure of conjunctival epithelial cells, and markedly downregulated the levels of interleukin (IL)-6, IL-17α, IL-1β, tumor necrosis factor-α, and vascular endothelial growth factor in the conjunctiva. Further data showed that these protective effects were accompanied by inhibition of inflammation in a dose-dependent manner. Amelioration of DES in db/db mice with diabetes mellitus by treatment with Tibetan medicine formula JMD maybe related to its anti-inflammatory effects. Image 1 [ABSTRACT FROM AUTHOR]