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Yi-Jin Wu,1– 3,* Sa-Sa Zhang,1,* Qin Yin,1 Ming Lei,2 Qi-Hai Wang,4 Wen-Gang Chen,1 Ting-Ting Luo,1 Peng Zhou,5 Cong-Lan Ji4,6 1Department of Pharmacy, The Second Affiliated Hospital of Wannan Medical College, Wuhu, 241000, People’s Republic of China; 2Xin’an Medical Research Center, The First Affiliated Hospital of Wannan Medical College, Wuhu, 241000, People’s Republic of China; 3Vascular Diseases Research Center of Wannan Medical College, Wuhu, 241000, People’s Republic of China; 4School of Pharmacy, Anhui College of Traditional Chinese Medicine, Wuhu, Anhui, 241000, People’s Republic of China; 5School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, 230000, People’s Republic of China; 6Research Center of Integration of Traditional Chinese and Western Medicine, Wannan Medical College, Wuhu, 241000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Peng Zhou; Cong-Lan Ji, Email zhoupeng@ahtcm.edu.cn; 37709103@qq.comBackground: α-Mangostin (MG) showed the potentials in alleviating experimental arthritis, inhibiting inflammatory polarization of macrophages/monocytes, and regulating peroxisome proliferators-activated receptor γ (PPAR-γ) and silent information regulator 1 (SIRT1) signals. The aim of this study was to analyze the correlations among the above-mentioned properties.Methods: Antigen-induced arthritis (AIA) was established in mouse, which was treated with MG in combination with SIRT1/PPAR-γ inhibitors to clarify the role of the two signals in the anti-arthritic actions. Pathological changes were systematically investigated. Phenotypes of cells were investigated by flow cytometry. Expression and co-localization of SIRT1 and PPAR-γ proteins in joint tissues were observed by the immunofluorescence method. Finally, clinical implications from the synchronous up-regulation of SIRT1 and PPAR-γ were validated by experiments in vitro.Results: SIRT1 and PPAR-γ inhibitors (nicotinamide and T0070097) reduced the therapeutic effects of MG on AIA mice, and abrogated MG-induced up-regulation of SIRT1/PPAR-γ and inhibition of M1 polarization in macrophages/monocytes. MG has a good binding affinity to PPAR-γ, and MG promoted the co-expression of SIRT1 and PPAR-γ in joints. Synchronously activating SIRT1 and PPAR-γ was revealed to be necessary by MG to repress inflammatory responses in THP-1 monocytes.Conclusion: MG binds PPAR-γ and excites this signaling to initiate ligand-dependent anti-inflammatory activity. Due to certain unspecified signal transduction crosstalk mechanism, it then promoted SIRT1 expression and further limited inflammatory polarization of macrophages/monocytes in AIA mice.Graphical Abstract: Keywords: rheumatoid arthritis, mangosteen, metabolism, inflammation, immune

Dan-Dan Wang,1,2,* Chi-Yi He,3,* Yi-Jin Wu,1,2 Liang Xu,4 Chao Shi,1 Opeyemi Joshua Olatunji,5 Jian Zuo,1,6,7 Cong-Lan Ji8 1Xin’an Medicine Research Center, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, 241000, People’s Republic of China; 2The Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, 230032, People’s Republic of China; 3Department of Gastroenterology, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, 241000, People’s Republic of China; 4Department of Rheumatology, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, 241000, People’s Republic of China; 5Traditional Thai Medical Research and Innovation Center, Faculty of Traditional Thai Medicine, Prince of Songkla University, Hat Yai, 90110, Thailand; 6Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu, 241000, People’s Republic of China; 7Anhui Provincial Engineering Laboratory for Screening and Re-evaluation of Active Compounds of Herbal Medicines in Southern Anhui, Wuhu, 241000, People’s Republic of China; 8School of Pharmacy, Anhui College of Traditional Chinese Medicine, Wuhu, 241000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Cong-Lan Ji; Jian Zuo, Email 37709103@qq.com; zuojian8178@163.comBackground: Exact roles of many metabolic regulators in rheumatoid arthritis (RA) are to be clarified. This study aimed to further characterize the impacts of silent information regulator 1 (SIRT1) status changes on this disease.Methods: Fluctuation pattern of SIRT1 expression in adjuvant-induced arthritis (AIA) rats was monitored using periodically collected white blood cells. Another bath of AIA rats were treated by SIRT1 agonist resveratrol. Blood from these rats was used to separate monocytes and plasma, which were subjected to polymerase chain reaction (PCR), enzyme linked immunosorbent assay (ELISA), and biochemical analyses. Clinical implication of SIRT1 activation was verified by treating AIA rat monocytes with SIRT1 agonist and overexpression vector in vitro.Results: SIRT1 deficiency occurred in AIA rats, which was accompanied with down-regulation of interleukin 10 (IL-10) and arginase-1 (ARG-1). Resveratrol eased oxidative stress and increased IL-10 production in vivo. Results of ELISA analysis demonstrated that resveratrol attenuated AIA severity in rats. Furthermore, it restored the altered levels of triglyceride, lactate and pyruvate in blood. Resveratrol promoted IL-10 production, and suppressed glycolysis of AIA monocytes cultured in vitro. SIRT1 overexpression similarly reshaped differentiation profile of AIA monocytes, evidenced by changes in metabolism indicators, IL-10 production and AMP-activated protein kinase (AMPK) pathway status. Although overexpressing SIRT1 in normal cells did not affect glycolysis significantly, it attenuated AMPK antagonist-caused abnormality.Conclusion: SIRT1 deficiency is implicated in AIA-related immune abnormality and metabolism alteration. Activating this signaling with resveratrol would impair the inflammatory polarization of monocytes, and consequently ease the severity of RA.Keywords: inflammation, metabolic reprogramming, monocytes, resveratrol, rheumatoid arthritis

Jian Zuo,1– 3,* Meng-Qing Tao,1,3,* Xin-Yue Wu,4 Tian-Tian Jiang,1 Opeyemi Joshua Olatunji,5 Jiyang Dong,4 Jun Han,6 Cong-Lan Ji7 1Department of Traditional Chinese Medicine, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, 241000, People’s Republic of China; 2Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu, 241000, People’s Republic of China; 3Research Center of Integration of Traditional Chinese and Western Medicine, Wannan Medical College, Wuhu, 241000, People’s Republic of China; 4Department of Electronic Science, Xiamen University, Xiamen, 361005, People’s Republic of China; 5Faculty of Traditional Thai Medicine, Prince of Songkla University, Hat Yai, 90112, Thailand; 6Drug Research and Development Center, School of Pharmacy, Wannan Medical College, Wuhu, 241000, Anhui, People’s Republic of China; 7School of Pharmacy, Anhui College of Traditional Chinese Medicine, Wuhu, 241000, Anhui, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jun HanDrug Research and Development Center, School of Pharmacy, Wannan Medical College, Wuhu, 241000, Anhui, People’s Republic of ChinaEmail hanjun@wnmc.edu.cnCong-Lan JiSchool of Pharmacy, Anhui College of Traditional Chinese Medicine, Wuhu, 241000, Anhui, People’s Republic of ChinaEmail 37709103@qq.comBackground: The bark of Securidaca inappendiculata Hassk. is traditionally used for treating inflammatory diseases and bone fractures in China. We have previously validated the xanthone-enriched fraction (XRF) of S. inappendiculata with anti-rheumatic potentials, but mechanism underlying the joints protective effects is still largely unknown.Materials and Methods: The male rats with collagen-induced arthritis (CIA) were treated with XRF. The therapeutic efficacy of XRF was evaluated by arthritis score changes, morphological observation of paws, histological examinations and serological analyses. Protein expression in tissues and cells was investigated by either immunohistochemical or immunoblotting methods, while levels of mRNA expression were investigated by RT-qPCR. Metabolites in serum were detected by LC-MS approach. The joints homogenates were used for analyzing possible targeted genes by genome microarray analyses.Results: Treatment with XRF and methotrexate (MTX) led to significant decrease in arthritis scores, and alleviated deformation of paws in CIA rats. In addition, XRF and MTX reduced circulating TNF-α, IL-1β and IL-17α in the serum and down-regulated TLR4/NF-κB and JNK pathways in joints of CIA rats. Compared to MTX, XRF-loading microemulsion significantly protected joints, which was accompanied by dramatic decrease in MMP3. Differential genes-based KEGG enrichment and metabolomics analysis suggested that XRF reduced fatty acids biosynthesis by regulating PPAR-γ signaling. S inappendiculata-derived 1,7-dihydroxy-3,4-dimethoxyxanthone (XAN) up-regulated PPAR-γ expression in macrophages, but suppressed it in pre-adipocytes in vitro, which was synchronized with SIRT1 changes. Adiponectin production and SCD-1 expression in pre-adipocytes were also decreased. Aside the direct inhibition on MMP3 expression in synovioblast, the presence of XAN in macrophages-pre-adipocytes co-culture system further reinforced this effect.Conclusion: This study revealed the joint protective advantages of the bioactive fraction from S. inappendiculata in CIA rats over MTX, and demonstrated that S. inappendiculata-derived xanthones suppressed the erosive nature of synovioblast acquired under inflammatory circumstances by regulating PPAR-γ signaling-controlled metabolism-immunity feedback.Keywords: peroxisome proliferators-activated receptor gamma, PPAR-γ, energy metabolism, rheumatoid arthritis, metabolomics, macrophage, inflammation