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Mechanism of action of the bile acid receptor TGR5 in obesity

Acta Pharmaceutica Sinica B 2024年第2期14卷 468-491页

作者： Weijun Lun Qihao Yan Xinghua Guo Minchuan Zhou Yan Bai Jincan He Hua Cao Qishi Che Jiao Guo Zhengquan Su Guangdong Engineering Research Center of Natural Products and New Drugs Guangdong Provincial University Engineering Technology Research Center of Natural Products and DrugsGuangdong Pharmaceutical UniversityGuangzhou 510006China Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine Key Laboratory of Glucolipid Metabolic DisorderMinistry of Education of ChinaGuangdong TCM Key Laboratory for Metabolic DiseasesGuangdong Pharmaceutical UniversityGuangzhou 510006China School of Public Health Guangdong Pharmaceutical UniversityGuangzhou 510310China School of Chemistry and Chemical Engineering Guangdong Pharmaceutical UniversityZhongshan 528458China guangzhou Rainhome Pharm&Tech Co. Ltd.Science CityGuangzhou 510663China

G protein-coupled receptors(GPCRs)are a large family of membrane protein receptors,and Takeda G protein-coupled receptor 5(TGR5)is a member of this family.As a membrane receptor,TGR5 is widely distributed in different parts of the human body and plays a vital role in regulating metabolism,including the processes of energy consumption,weight loss and blood glucose homeostasis.Recent studies have shown that TGR5 plays an important role in glucose and lipid metabolism disorders such as fatty liver,obesity and diabetes.With the global obesity situation becoming more and more serious,a comprehensive explanation of the mechanism of TGR5 and filling the gaps in knowledge concerning clinical ligand drugs are urgently needed.In this review,we mainly explain the anti-obesity mechanism of TGR5 to promote the further study of this target,and show the electron microscope structure of TGR5 and review recent studies on TGR5 ligands to illustrate the specific binding between TGR5 receptor binding sites and ligands,which can effectively provide new ideas for ligand research and promote drug research.

关键词： Obesity TGR5 Bile acids Ligand Appetite Metabolism GLP-1 Inflammation

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A sequential continuous flow synthesis and purification process of calcium dibutyryladenosine cyclophosphate

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Chinese Chemical Letters 2024年第2期35卷 402-406页

作者： Liming Cao Maolin Sun Chaoming Liang Lei Yang Yueyue Ma Ruihua Cheng Yanxiong Ke Wei Yu Jinxing Ye Engineering Research Center of pharmaceutical Process Chemistry Ministry of EducationSchool of PharmacyEast China University of Science and TechnologyShanghai 200237China School of Biomedical and pharmaceutical Sciences Guangdong University of TechnologyGuangzhou 510006China Shanghai No.1 Biochemical& pharmaceutical Co. Ltd.Shanghai 200080China

Calcium dibutyryladenosine cyclophosphate is a widely used cardiovascular drug.The traditional batch synthesis process suffers from long reaction times,tedious operations,and unstable yields.Herein,a sequential continuous flow synthesis combined with a multistage in-line purification process of calcium dibutyryladenosine cyclophosphate was developed.The acylation reaction was completed in a continuous coil reactor at 160℃ in 20 min.And the high toxic solvent pyridine was replaced by acetonitrile.Furthermore,the multistage in-line purification process was integrated into the homemade 3D circular cyclone-type micromixer chip.Combining with the membrane phase separators,the residence time of the purification step was 30 s.The isolated yield of this sequential continuous process was 92%with 99%purity.

关键词： Flow chemistry Calcium dibutyryladenosine cyclophosphate Continuous flow synthesis In-line purification 3D circular cyclone-type micromixer chip

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Ganoderma Lucidum Spore Oil enhances the effect of cyclophosphamide via inhibiting programmed death-1 and prolongs the survival of H22 tumor-bearing mice

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Journal of Traditional Chinese Medicine 2024年第4期 652-659页

作者： JIANG Zhaojian CAI Hongfei YUAN Cheng CAO Lin XU Wendong HAN Yaming ZHANG Qin LI Jing WANG Qin LIU Juyan guangzhou HanFang pharmaceutical Company Limited National Engineering Research Center of Pharmaceutical Processing Technology of Traditional Chinese Medicine and Drug InnovationGuangdong Provincial Key Laboratory of Medicinal Lipids Zhongshan Medical College Sun Yat-sen University guangzhou pharmaceutical holdings Limited National Engineering Research Center of pharmaceutical Processing Technology of Traditional Chinese Medicine and Drug Innovation

OBJECTIVE: To investigate the effect of Ganoderma Lucidum Spore Oil(GLSO) on the tumor growth and survival of H22 tumor-bearing mice treated with cyclophosphamide(CTX), and explore the underlying mechanism.METHODS: Allograft H22 hepatocellular carcinoma mouse model was applied to investigate the effect of GLSO on the tumor growth and survival of animals, and Kaplan-Meier survival analysis was used to analyze the life span. Plasma biochemical examination was used to determine the levels of alanine aminotransferase(ALT),aspartate aminotransferase(AST), urea(UREA) and creatinine(CRE). Western blot analysis was performed to detect Programmed Death-1(PD-1), Programmed Death Ligand 1(PD-L1), Janus Kinase 2(JAK2),phosphorylated Signal Transducer and Activator of Transcription 3(p-STAT3), and Signal Transducer and Activator of Transcription 3(STAT3) expression. RESULTS: GLSO increased the anti-tumor effect of CTX and prolonged the survival of H22 tumor-bearing mice treated with CTX. Meanwhile, GLSO increased the thymus index and showed no obvious toxicity to liver functions of animals. GLSO also decreased the level of UREA in H22 tumor-bearing mice treated with CTX. Furthermore, GLSO could inhibit the expression of PD-1 in spleen, which was independent of JAK2 expression and STAT3 phosphorylation. However, GLSO did not affect the expression of PD-L1, JAK2, and p-STAT3 in tumor tissue. CONCLUSION: GLSO could strengthen the anti-tumor effect of CTX and prolong the life span of H22 tumorbearing mice, while the underlying mechanism might be relevant to the amelioration effect of thymus function and inhibition of PD-1 expression in spleen. Furthermore, these findings implied the promising role of GLSO in combination with CTX to extend the survival of patients in clinical chemotherapy of hepatocellular carcinoma.

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Zhuangyao Jianshen pill(壮腰健肾丸) ameliorates testosterone-induced benign postatic hyperplasia in rats

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Journal of Traditional Chinese Medicine 2024年第4期 694-702页

作者： ZHENG Jingrui CHEN Weijian YE Binbin MO Ziyao DU Qunqun QIN Renan NIE Ke School of Chinese Materia Medica Guangdong Pharmaceutical University Modern Chinese Medicine Research Institute Guangzhou Baiyunshan Chenliji Pharmaceutical Factory Co.Ltd.

OBJECTIVE: To determine the therapeutic effects of the Zhuangyao Jianshen pill(壮腰健肾丸, ZYJSP) against benign prostatic hyperplasia(BPH) and investigate the underlying mechanism. METHODS: Forty-eight male Sprague-Dawley rats were randomly divided into six groups: Control group, BPH model group, finasteride-treated group, ZYJSP low, medium and high dose groups. Except for the control group, 40 rats were castrated and injected with testosterone propionate(TP) for 28 consecutive day to induce BPH. Meanwhile, the corresponding drugs were administered by gavage. The prostate wet weight, prostate index(PI), and the histopathological changes in the prostate were measured as the basis for examining the efficacy of ZYJSP against BPH. Levels of the serum sex hormones, oxidative stress markers, inflammatory markers, renal function markers, growth factors, and Cyclin D1 expression in prostate were measured to characterize the therapeutic mechanism of ZYJSP against BPH. RESULTS: ZYJSP administration significantly reduced prostate wet weight and PI and ameliorated histological changes of the prostate in TP-treated castrated rats. TP markedly increased the levels of creatinine, blood urea nitrogen and growth factors in the serum as well as the expression of the Cyclin D1 in the prostate. Most of these markers were significantly decreased by ZYJSP. ZYJSP significantly restored the dysregulation of testosterone, estradiol, and dihydrotestosterone caused by TP. Furthermore, ZYJSP relieved TP-induced prostate injury and exhibited both anti-inflammatory and anti-oxidant activity by decreasing interleukin-6, interleukin-8, and malondialdehyde levels and increasing the activity of superoxide dismutase in the serum. CONCLUSION: These findings indicate that ZYJSP can effectively ameliorate BPH induced by TP in castrated rats, and the underlying mechanism might be related to regulating sex hormone balance, reducing oxidative stress, and inhibiting the inflammatory response.

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Ganoderma lucidum spore oil enhances the effect of paclitaxel,improves the tolerance to paclitaxel and prolongs the survival in Lewis tumor-bearing mice

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Cancer Advances 2024年第12期7卷 1-6页

作者： Hong-Fei Cai Zhao-Jian Jiang Cheng Yuan Lin Cao Qin Wang Ya-Ming Han Qin Zhang Jing Li Wen-Dong Xu Ju-Yan Liu guangzhou HanFang pharmaceutical Company Limited National Engineering Research Center of Pharmaceutical Processing Technology of Traditional Chinese Medicine and Drug InnovationGuangdong Provincial Key Laboratory of Medicinal LipidsGuangzhou 510240China Nanchang Research Institute Sun Yat-Sen UniversityNanchang 330096China guangzhou pharmaceutical holdings Limited Guangzhou 510130China

Purpose:This study aims to investigate whether Ganoderma lucidum spore oil(GLSO)could enhance the effect of paclitaxel(PTX),improve the tolerance to PTX and prolong the overall survival of Lewis tumor-bearing mice,which has never been reported before.Methods:The tumor,spleen,and thymus were weighed at the end of the experiment.Whole blood was collected for hematological index analysis,and the intact femur was removed to determine the bone marrow nucleated cell count(BMN).The percentage of lymphocytes in the spleen of mice was detected by flow cytometry,the activity of NK cells was detected by LDH assay,and the proliferation index of lymphocytes was determined by CCK-8 assay.The overall and mean survival time and life extension rate were calculated using SPSS software.Results:Our data showed that GLSO could enhance the anti-tumor effect of PTX and prolong the survival of mice.The underlying mechanisms of the above effects might be related to the toxic reduction effect of GLSO by relieving hematotoxicity,myelosuppression and immunosuppression.Specifically,GLSO could increase the number of blood cells and bone marrow cells,alleviate the thymic index,and elevate the number and activity of NK cells in mice treated with PTX.Conclusion:GLSO may enhance the efficacy of PTX by boosting the activity of immune NK cells and prolong survival by counteracting PTX-induced bone marrow alterations and improving hematopoiesis.These findings suggested the promising role of GLSO in combination with PTX to extend the survival and increase the tolerance of patients in clinical chemotherapy of lung cancer.

关键词： Ganoderma lucidum spore oil Traditional Chinese Medicine lung cancer paclitaxel tolerance survival

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QL1706 (anti-PD-1 IgG4/CTLA-4 antibody) plus chemotherapy with or without bevacizumab in advanced non-small cell lung cancer: a multi-cohort, phase II study

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Signal Transduction and Targeted Therapy 2024年第2期9卷 797-806页

作者： Yan Huang Yunpeng Yang Yuanyuan Zhao Hongyun Zhao Ningning Zhou Yaxiong Zhang Likun Chen Ting Zhou Gang Chen Ting Wu Lu Lu Shilin Xue Xiaoyan Kang Li Zhang Wenfeng Fang Department of Medical Oncology Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineNo.651 Dongfeng East RoadGuangzhouGuangdong 510060China Department of Medicine Qilu Pharmaceutical Co.Ltd.JinanChina

First-line chemoimmunotherapy(with or without bevacizumab)has improved outcomes in advanced non-small cell lung cancer(NSCLC).Here,this open-label,multi-cohort phase II study(NCT05329025)was done to investigate the safety and efficacy of QL1706(a single bifunctional MabPair product against PD-1 and CTLA-4)and chemotherapy with or without bevacizumab in this population.Patients were enrolled into five different cohorts based on genotype(cohorts 1-4,epidermal growth factor receptor[EGFR]wild-type;cohort 5,EGFR-mutant and progressed on EGFR-tyrosine kinase inhibitors[TKIs]).Between June 11,2021 and December 29,2021,91 patients were enrolled.Most frequent treatment-related adverse events(TRAEs)included decreased appetite(60[65.9%]),anemia(60[65.9%]),infusion-related reactions(48[52.7%]),and pruritus(44[48.4%]).Grade≥3 TRAEs occurred in 30(33.0%)patients.Twenty-seven(45%)patients with wild-type EGFR achieved partial response(PR)(objective response rate[ORR]=45%)and had a median progression-free survival(mPFS)of 6.8 months(95%CI:5.2-9.7).For 31 patients harboring mutated EGFR,17(54.8%)achieved PR(ORR=54.8%),with an mPFS of 8.5 months(95%CI:5.72-not evaluable).Overall,QL1706 plus chemotherapy,regardless of having bevacizumab,was generally tolerable and had promising antitumor activity for EGFR wild-type advanced NSCLC in first-line setting.Moreover,QL1706 plus chemotherapy and bevacizumab showed favorable antitumor activity for patients who had EGFR mutated NSCLC but failed in TKI therapy,demonstrating a potential for treating this population.

关键词： bevacizumab chemotherapy phase

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A novel dual serotonin transporter and M-channel inhibitor D01 for antidepression and cognitive improvement

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1457-1466页

作者： Yaqin Wei Xiangqing Xu Qiang Guo Song Zhao Yinli Qiu Dongli Wang Wenwen Yu Yani Liu KeWei Wang School of Pharmacy Xuzhou Medical UniversityXuzhou 221004China Institute of pharmaceutical Research Jiangsu Nhwa Pharmaceutical Co.Ltd.&Jiangsu Key Laboratory of Central Nervous System Drug Research and DevelopmentXuzhou 221116China Department of Pharmacology School of PharmacyQingdao University Medical CollegeQingdao 266073China Institute of Innovative Drug Qingdao UniversityQingdao 266021China Center for Brain Science and Brain-Inspired Intelligence Guangdong-Hong Kong-Macao Greater Bay AreaGuangzhou 510515China

Cognitive dysfunction is a core symptom common in psychiatric disorders including depression that is primarily managed by antidepressants lacking efficacy in improving cognition.In this study,we report a novel dual serotonin transporter and voltage-gated potassium Kv7/KCNQ/M-channel inhibitor D01(a 2-methyl-3-aryloxy-3-heteroarylpropylamines derivative)that exhibits both anti-depression effects and improvements in cognition.D01 inhibits serotonin transporters(K_(i)=30.1±6.9 nmol/L)and M channels(IC_(50)=10.1±2.4μmol/L).D01 also reduces the immobility duration in the mouse FST and TST assays in a dose-dependent manner without a stimulatory effect on locomotion.Intragastric administrations of D01(20 and 40 mg/kg)can significantly shorten the immobility time in a mouse model of chronic restraint stress(CRS)-induced depression-like behavior.Additionally,D01 dose-dependently improves the cognitive deficit induced by CRS in Morris water maze test and increases the exploration time with novel objects in normal or scopolamine-induced cognitive deficits in mice,but not fluoxetine.Furthermore,D01 reverses the long-term potentiation(LTP)inhibition induced by scopolamine.Taken together,our findings demonstrate that D01,a dual-target serotonin reuptake and M channel inhibitor,is highly effective in the treatment-resistant depression and cognitive deficits,thus holding potential for development as therapy of depression with cognitive deficits.

关键词： SERT 5-HT Kv7/KCNQ/M current D01 Depression Cognition

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Design and discovery of a highly potent ultralong-acting GLP-1 and glucagon co-agonist for attenuating renal fibrosis

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1283-1301页

作者： Qian Zhao Jiale Dong Han Liu Hui Chen Huan Yu Shuyin Ye Shuangjin Yu Yu Li Longhui Qiu Nazi Song Hongjiao Xu Qi Liu Zhiteng Luo Yuyi Li Rui Wang Guodong Chen Xianxing Jiang School of pharmaceutical Sciences Guangdong Provincial Key Laboratory of Chiral Molecule and Drug DiscoverySun Yat-sen UniversityGuangzhou 510006China Organ Transplant Center the First Affiliated HospitalSun Yat-sen UniversityGuangzhou 510006China Zhongshan School of Medicine Sun Yat-sen UniversityGuangzhou 510006China Shenzhen Turier Biotech.Co. Ltd.Shenzhen 518118China School of Life Sciences Key Laboratory of Preclinical Study for New Drugs of Gansu ProvinceSchool of Basic Medical Sciences&Research Unit of Peptide ScienceChinese Academy of Medical SciencesLanzhou UniversityLanzhou 730000China

The role of co-agonists of glucagon-like peptide-1 receptor(GLP-1R)and glucagon receptor(GCGR)in chronic kidney disease(CKD)remains unclear.Herein we found that GLP-1R and GCGR expression levels were lower in the kidneys of mice with CKD compared to healthy mice and were correlated with disease severity.Interestingly,GLP-1R or GCGR knockdown aggravated the progression of kidney injury in both diabetic db/db mice and non-diabetic mice undergoing unilateral ureteral obstruction(UUO).Based on the importance of GLP-1R and GCGR in CKD,we reported a novel monomeric peptide,1907-B,with dual-agonism on both GLP-1R and GCGR.The data confirmed that 1907-B had a longer half-life than long-acting semaglutide in rats or cynomolgus monkeys(~2-3 fold)and exhibited better therapeutic contribution to CKD than best-in-class monoagonists,semaglutide,or glucagon,in db/db mice and UUO mice.Various lock-of-function models,including selective pharmacological activation and genetic knockdown,confirmed that 1907-B’s effects on ameliorating diabetic nephropathy in db/db mice,as well as inhibiting kidney fibrosis in UUO mice,were mediated through GLP-1 and glucagon signaling.These findings highlight that 1907-B,a novel GLP-1R and GCGR co-agonist,exerts multifactorial improvement in kidney injuries and is an effective and promising therapeutic option for CKD treatment.

关键词： GLP-1 receptor Glucagon receptor Chronic kidney disease Diabetic nephropathy Kidney fibrosis Dual-agonism

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Advances in the Study of Anoectochilus Roxburghii Extracts and Prospects for Cosmetic Application Potentials

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China Detergent & Cosmetics 2024年第1期9卷 45-53页

作者： Liu Xiaochun Chen Laicheng Yang Zhanhong Zou Jie School of Chemistry and Chemical Engineering Guangdong Pharmaceutical UniversityChina guangzhou Hemgathion Biotechnology Co. Ltd.China

Cosmetics made from natural ingredients are becoming more and more common because they contain bioactive compounds that provide many health benefits,are more environmentally friendly and sustainable.Anoectochilus roxburghii(AR)is a precious Chinese herb in China,possessing bioactive components including flavonoids,polysaccharides,volatile oils,kinsenoside,etc.Due to its unique bioactivity and high safety,the prospect of development and utilization is very broad.In this paper,the extraction,separation and purification techniques of AR’s flavonoid,polysaccharides,volatile oils and kinsenoside are briefly summarized.Meanwhile,we discusses their conformational relationships in cosmetics with antioxidant,whitening,antibacterial and soothing effect,and looks forward to the study of Anoectochilus roxburghii in the field of cosmetics,with a view to providing references to the development and utilization of this resource in the field of cosmetics.

关键词： Anoectochilus roxburghii extract Anoectochilus roxburghii polysaccharides Anoectochilus flavonoids cosmetic efficacy

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Two-step continuous flow process of sodium tanshinone ⅡA sulfonate using a 3D circular cyclone-type microreactor

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Chinese Chemical Letters 2024年第1期35卷 290-294页

作者： Maolin Sun Chaoming Liang Liming Cao Yaguo Wang Jiasheng Yang Shiyu Hou Wei Yu Yueyue Ma Ruihua Cheng Jinxing Ye School of Biomedical and pharmaceutical Sciences Guangdong University of TechnologyGuangzhou 510006China School of Pharmacy East China University of Science and TechnologyShanghai 200237China School of Chemical Engineering East China University of Science and TechnologyShanghai 200237China Shanghai No.1 Biochemical&pharmaceutical Co. Ltd.Shanghai 200080China

A sustainable and practical process is presented for the direct synthesis of sodium tanshinone IIA sulfonate(STS).Our approach was inspired by the well-established and industrially applied batch synthetic route for STS production.We constructed a telescoped two-step continuous flow platform.This involved a continuous tanshinone IIA sulfonation and in-line salt formation.For the setup,we constructed a 3D circular cyclone-type microreactor using femtosecond laser micromachining.Compared to the 68%yield for 2 h in batch,the two-step continuous flow had an STS yield of 90%,achieved for a total residence time of<3.0 min under optimal conditions.The proposed continuous flow method vastly simplified the operation and improved procedural safety,while significantly reducing the required acid content and wastewater production.

关键词： Continuous flow Sodium tanshinone IIA sulfonate Cardiovascular Microreactor Green chemistry

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