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Qing-Yu Xiao,1 Ren-Ling Wang,2 Hai-Jun Wu,1 Wen-Bin Kuang,3 Wei-Wei Meng,4 Zhen Cheng5 1Department of Blood Transfusion, Shenzhen Baoan Shiyan People’s Hospital, Shenzhen, 518108, China; 2Department of Oncology, Kaiping Central Hospital, Jiangmen City, Guangdong Province, 529399, People’s Republic of China; 3Department of Laboratory, Longhua District Central Hospital, Shenzhen, 518110, People’s Republic of China; 4Department of Laboratory, Shenzhen Baoan Shiyan People’s Hospital, Shenzhen, 518108, China; 5Guantian Community Healthcare Center, Shenzhen Baoan Shiyan People’s Hospital, Shenzhen, Guangdong province, 518100, People’s Republic of ChinaCorrespondence: Zhen Cheng, Guantian Community Healthcare Center, Shenzhen Baoan Shiyan People’s Hospital, About 50 Meters South of hkc Huike Industrial Park, Dezheng Road, Baoan District, Shenzhen, Guangdong province, 518100, People’s Republic of China, Tel +86 13632854050, Email cheng_3003_zhen@163.comObjective: To probe into the influence of Helicobacter pylori (Hp) infection on glucose metabolism, lipid metabolism, and inflammatory cytokines in patients with nonalcoholic fatty liver disease (MASLD).Methods: A total of 140 MASLD patients admitted to our Hospital between June 2020 and May 2021 were selected as the research objects. Based on the presence or absence of Hp infection, they were divided into the study group (73 cases with infection) and control group (67 cases without infection). Glucose metabolism indicators [fasting blood glucose (FBG), 2-hour postprandial glucose (2hPG), fasting insulin (FINS), glycated hemoglobin (HbAlc)], lipid metabolism indicators [total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C)], and inflammatory indicators [interleukin-37 (IL-37), interleukin-18 (IL-18)] were measured and compared between the two groups.Results: In terms of glucose metabolism indicators, the study group exhibited higher levels of FBG (5.84± 0.49 vs 5.40± 0.51, t=2.535, P=0.012), 2hPG (7.26± 1.30 vs 6.50± 1.53, t=3.321, P< 0.001), and FINS (11.13± 4.13 vs 9.12± 3.72, t=3.224, P< 0.001), and Insulin resistance index (HOMA-IR) (2.97± 0.35 VS 2.13± 0.54, t=3.761, P< 0.001) and a lower level of HbAlc (5.25± 0.56 vs 6.12± 0.57, t=5.473, P< 0.001) compared to the control group. Regarding lipid metabolism indicators, the study group exhibited higher levels of TC (5.64± 1.49 vs 5.01± 1.32, t=3.332, P< 0.001), TG (1.89± 0.34 vs 1.32± 0.43, t=3.411, P< 0.001), and LDL-C (3.31± 0.43 vs 2.12± 0.29, t=4.142, P< 0.001), and a lower level of HDL-C (1.45± 0.21 vs 1.78± 0.42, t=4.347, P< 0.001) compared to the control group. As for the inflammatory indicators, the study group exhibited higher levels of IL-37 (45.56± 6.02 vs 34.02± 3.28, t=9.332, P< 0.001) and IL-18 (73.57± 5.82 vs 60.34± 4.84, t=10.141, P< 0.001) compared to the control group.Conclusion: It is crucial to place appropriate emphasis on the impact of Hp infection on the glucose metabolism, lipid metabolism, and inflammatory response in MASLD patients, warranting careful consideration during the treatment of these patients.Keywords: Helicobacter pylori, infection, nonalcoholic fatty liver disease, glucose metabolism, lipid metabolism, inflammatory indicators

Xue-Jiao Wang,1 Jun Zhang,1 Shu-Qing Wang,1 Wei-Ren Xu,2 Xian-Chao Cheng,1 Run-Ling Wang1 1Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, People’s Republic of China; 2Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin, People’s Republic of China Abstract: The thiazolidinedione class peroxisome proliferator-activated receptor gamma (PPARγ) agonists are restricted in clinical use as antidiabetic agents because of side effects such as edema, weight gain, and heart failure. The single and selective agonism of PPARγ is the main cause of these side effects. Multitargeted PPARα/γ/δ pan agonist development is the hot topic in the antidiabetic drug research field. In order to identify PPARα/γ/δ pan agonists, a compound database was established by core hopping of rosiglitazone, which was then docked into a PPARα/γ/δ active site to screen out a number of candidate compounds with a higher docking score and better interaction with the active site. Further, absorption, distribution, metabolism, excretion, and toxicity prediction was done to give eight compounds. Molecular dynamics simulation of the representative Cpd#1 showed more favorable binding conformation for PPARs receptor than the original ligand. Cpd#1 could act as a PPARα/γ/δ pan agonist for novel antidiabetic drug research. Keywords: PPARs, diabetes, docking, molecular dynamics simulation, ADMET

Xin Jin1,2,* Tian-Hua Yan,3,* Lan Yan,1 Qian Li,4 Rui-Lian Wang,1 Zhen-Lin Hu,1 Yuan-Ying Jiang,1 Qing-Yan Sun,1 Yong-Bing Cao1 1School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China; 2School of Pharmacy, FuJian University of Traditional Chinese Medicine, Fuzhou, People's Republic of China; 3Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, People's Republic of China; 4Diakite Biological Technology Co., Ltd, Shanghai, People's Republic of China *These authors contributed equally to this work Abstract: A series of novel derivatives of phenyl-substituted berberine triazolyls has been designed and synthesized via copper-catalyzed azide-alkyne cycloaddition click chemistry in an attempt to develop antitumor agents. All of the compounds were evaluated for anticancer activity against a panel of three human cancer cell lines, including MCF-7 (breast), SW-1990 (pancreatic), and SMMC-7721 (liver) and the noncancerous human umbilical vein endothelial cell (HUVEC) cell lines. The results indicated that most of the compounds displayed notable anticancer activities against the MCF-7 cells compared with berberine. Among these derivatives, compound 16 showed the most potent inhibitory activity against the SW-1990 and SMMC-7721 cell lines, with half-maximal inhibitory concentration (IC50) values of 8.54±1.97 µM and 11.87±1.83 µM, respectively. Compound 36 exhibited the most potent inhibitory activity against the MCF-7 cell line, with an IC50 value of 12.57±1.96 µM. Compound 16 and compound 36 exhibited low cytotoxicity in the HUVEC cell line, with IC50 values of 25.49±3.24 µM and 30.47±3.47 µM. Furthermore, compounds 14, 15, 16, 17, 18, 32, and 36 exhibited much better selectivity than berberine toward the normal cell line HUVEC. Keywords: berberine, anticancer, click chemistry, structure–activity relationship

Lei Liu,1 Ying Ma,2 Run-Ling Wang,2 Wei-Ren Xu,3 Shu-Qing Wang,2,5 Kuo-Chen Chou4,5 1PET/CT Center, General Hospital of Tianjin Medical University, Tianjin, People’s Republic of China; 2Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, People’s Republic of China; 3Tianjin Institute of Pharmaceutical Research (TIPR), Tianjin, People’s Republic of China; 4Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah, Saudi Arabia; 5Gordon Life Science Institute, Belmont, MA, USA Abstract: The high prevalence of type 2 diabetes mellitus in the world as well as the increasing reports about the adverse side effects of the existing diabetes treatment drugs have made developing new and effective drugs against the disease a very high priority. In this study, we report ten novel compounds found by targeting peroxisome proliferator-activated receptors (PPARs) using virtual screening and core hopping approaches. PPARs have drawn increasing attention for developing novel drugs to treat diabetes due to their unique functions in regulating glucose, lipid, and cholesterol metabolism. The reported compounds are featured with dual functions, and hence belong to the category of dual agonists. Compared with the single PPAR agonists, the dual PPAR agonists, formed by combining the lipid benefit of PPARα agonists (such as fibrates) and the glycemic advantages of the PPARγ agonists (such as thiazolidinediones), are much more powerful in treating diabetes because they can enhance metabolic effects while minimizing the side effects. This was observed in the studies on molecular dynamics simulations, as well as on absorption, distribution, metabolism, and excretion, that these novel dual agonists not only possessed the same function as ragaglitazar (an investigational drug developed by Novo Nordisk for treating type 2 diabetes) did in activating PPARα and PPARγ, but they also had more favorable conformation for binding to the two receptors. Moreover, the residues involved in forming the binding pockets of PPARα and PPARγ among the top ten compounds are explicitly presented, and this will be very useful for the in-depth conduction of mutagenesis experiments. It is anticipated that the ten compounds may become potential drug candidates, or at the very least, the findings reported here may stimulate new strategies or provide useful insights for designing new and more powerful dual-agonist drugs for treating type 2 diabetes. Keywords: diabetes, PPAR-alpha, PPAR-gamma, dual-agonist drug, core hopping, molecular docking, ADME, binding pocket