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Puhua Wu,1,2 Zhicheng Zhang,1 Yan Zhou,2 Quan Liu,2 Kin-Yip Tam,2 Zhenhong Su1 1Hubei Key Laboratory for Kidney Disease Pathogenesis and Intervention, School of Medicine, Hubei Polytechnic University, Huangshi, People’s Republic of China; 2Cancer Centre, Faculty of Health Sciences, University of Macau, Macau, People’s Republic of ChinaCorrespondence: Puhua Wu, Email wph75000@hotmail.comBackground: Pyruvate dehydrogenase kinases (PDHKs), important metabolic and abnormally expressed enzymes in cancer cells, are promising targets for cancer therapy, especially for non-small-cell lung cancer (NSCLC).Methods: In this study, a new hit, dichloroacetophenone (DAP) analog 9, was postulated to bind to the PDHK1 allosteric pocket, guided by molecular modeling and kinase biochemical experiments. Based on this binding mode, novel DAP analogs were designed and synthesized to confirm the importance of Phe180, Tyr411, and the hydrophobic core at the bottom of the pocket.Results: This structure–activity relationship (SAR) study led to the discovery of a novel potent hybrid scaffold, dichloroacetophenone biphenylsulfone ether. Dichloroacetophenone biphenylsulfone ether 31 and 32 inhibited PDHK1 with IC50 values of 86 and 140 nM, respectively.Conclusion: Compound 32 with acceptable in vitro metabolic stability, predicted drug-likeness properties and ADME/T profiles, showed promising therapeutic efficacy in a lung cancer xenograft mouse model. Keywords: PDHK1, dichloroacetophenone, allosteric pocket, anti-NSCLC activity, tumor xenograft mouse model

Ziwei Huang,1 Shanli Zhang,1 Zehui Qin,1 Gaoxiang Ai,1 Minhua Li,1 Shiting Gong,1 Yuhong Liu,1 Huifang Zeng,2 Jiannan Chen,1 Ziren Su,1 Zhengquan Lai3 1School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China; 2The First Affiliated Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China; 3Department of Pharmacy, Shenzhen University General Hospital/Shenzhen University Clinical Medical Academy, Shenzhen University, Shenzhen, Guangdong, People’s Republic of ChinaCorrespondence: Zhengquan Lai, Department of Pharmacy, Shenzhen University General Hospital/Shenzhen University Clinical Medical Academy, Shenzhen University, Shenzhen, Guangdong, People’s Republic of China, Email cruise0303@163.com Ziren Su, School of pharmaceutical sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China, Email suziren@gzucm.edu.cnPropose: Oxyberberine (OBB), one of the main metabolites of berberine derived from intestinal and erythrocyte metabolism, exhibits appreciable anti-hyperuricemic activity. However, the low water solubility and poor plasma concentration–effect relationship of OBB hamper its development and utilization. Therefore, an OBB-hydroxypropyl-β-cyclodextrin (HP-β-CD) supersaturated drug delivery system (SDDS) was prepared and characterized in this work.Methods: OBB-HP-β-CD SDDS was prepared using the ultrasonic-solvent evaporation method and characterized. Additionally, the in vitro and in vivo release experiments were conducted to assess the release kinetics of OBB-HP-β-CD SDDS. Subsequently, the therapeutic efficacy of OBB-HP-β-CD SDDS on hyperuricemia (HUA) was investigated by means of histopathological examination and evaluation of relevant biomarkers.Results: The results of FT-IR, DSC, PXRD, NMR and molecular modeling showed that the crystallized form of OBB was transformed into an amorphous OBB-HP-β-CD complex. Dynamic light scattering indicated that this system was relatively stable and maintained by formation of nanoaggregates with an average diameter of 23 nm. The dissolution rate of OBB-HP-β-CD SDDS was about 5 times higher than that of OBB raw material. Furthermore, the AUC0-t of OBB-HP-β-CD SDDS (10.882 μg/mL*h) was significantly higher than that of the raw OBB counterpart (0.701 μg/mL*h). The oral relative bioavailability of OBB-HP-β-CD SDDS was also enhanced by 16 times compared to that of the raw material. Finally, in vivo pharmacodynamic assay showed the anti-hyperuricemic potency of OBB-HP-β-CD SDDS was approximately 5– 10 times higher than that of OBB raw material.Conclusion: Based on our findings above, OBB-HP-β-CD SDDS proved to be an excellent drug delivery system for increasing the solubility, dissolution, bioavailability, and anti-hyperuricemic potency of OBB. Keywords: oxyberberine, cyclodextrin, supersaturated drug delivery systems, pharmacokinetics, hyperuricemia

Ting Su, Wentong Wang, Xixi Xiong, Meihua Zhang, Yan Lu,* Zhonglan Su* Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yan Lu; Zhonglan Su, Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu Province, People’s Republic of China, Email luyan6289@163.com; alice_su2595@126.comBackground: Cytophagic histiocytic panniculitis (CHP) is a rare panniculitis associated with systemic features characterized by the infiltration of subcutaneous adipose tissue by benign-appearing T lymphocytes and phagocytic histiocytes, mimicking hemophagocytic lymphohistiocytosis (HLH) and subcutaneous panniculitis-like T-cell lymphoma (SPTCL).Purpose: To establish the clinicopathological features and response to treatment of CHP and evaluate the prognosis of patients and guide therapy based on the current state of knowledge.Material and Methods: Clinical, laboratory, histopathological, and outcome data of 12 patients with CHP were retrospectively collected between 2009 and 2022.Results: All the patients presented with plaques or nodules, mostly located in the lower extremities (11/12). Fewer cases involved systemic symptoms (9/12) and laboratory abnormalities (6/12), and none were positive for serum Epstein-Barr virus (EBV)-DNA. Histopathological examination revealed mixed septal and lobular inflammatory infiltration of histiocytes and lymphocytes. Large or atypical lymphocytes were rarely present (2/12). In some patients, varying proportions of plasma cells, neutrophils, and eosinophils were observed. The extent of histocytophagy was mild (9/12), moderate (2/12), and severe (1/12). HLH was not observed in any of our cases, none of which were fatal.Conclusion: The uniqueness of our study lies in the presence of neutrophil-rich dermal and subcutaneous infiltrates, associated with connective tissue disorders (CTD) and streptococcal infections. Our study reveals that EBV-negative CHP tends to a better prognosis than previously research, filling the gap in the much-needed details of CHP in the Chinese population. Moreover, CHP may present as a reactive process in combined primary diseases; further studies are required to validate these findings.Plain Language Summary: Cytophagic histiocytic panniculitis (CHP) is a rare panniculitis associated with systemic features characterized by the infiltration of subcutaneous adipose tissue by benign-appearing T lymphocytes and phagocytic histiocytes, also may be present in hemophagocytic lymphohistiocytosis and subcutaneous panniculitis-like T-cell lymphoma.The presence of neutrophil-rich dermal and subcutaneous infiltrates, associated with connective tissue disorders and streptococcal infections. In addition, EBV-negative CHP has a better prognosis than previously thought and provides knowledge of its prognosis in the Chinese population.With changes in the disease pedigree supported by the development of medical technology, CHP may present as a reactive process of a combined primary disease.Keywords: Cytophagic histiocytic panniculitis, Epstein-Barr virus, hemophagocytic lymphohistiocytosis, retrospective study

Mei Ieng Lam,1,2 Hong Cai,2,3 Pan Chen,2,3 Ka-In Lok,4 Ines Hang Iao Chow,2 Tong Leong Si,2 Zhaohui Su,5 Chee H Ng,6 Feng-Rong An,7 Yu-Tao Xiang2,3 1Education Department, Kiang Wu Nursing College of Macau, Macau SAR, People’s Republic of China; 2Unit of Psychiatry, Department of Public Health and Medicinal Administration, & Institute of Translational Medicine, University of Macau, Macao SAR, People’s Republic of China; 3Centre for Cognitive and Brain Sciences, University of Macau, Macao SAR, People’s Republic of China; 4Faculty of Health Sciences and Sports, Macao Polytechnic University, Macao, People’s Republic of China; 5School of Public Health, Southeast University, Nanjing, People’s Republic of China; 6Department of Psychiatry, The Melbourne Clinic and St Vincent’s Hospital, University of Melbourne, Richmond, Victoria, Australia; 7Beijing Key Laboratory of Mental Disorders, National Clinical Research Center for Mental Disorders & National Center for Mental Disorders, Beijing Anding Hospital; Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence: Chee H Ng, Department of Psychiatry, The Melbourne Clinic and St Vincent’s Hospital, University of Melbourne, Richmond, Victoria, Australia, Email cng@unimelb.edu.au Yu-Tao Xiang, Faculty of Health Sciences, University of Macau, 1/F, Building E12, Macau, People’s Republic of China, Email xyutly@gmail.comBackground: Suicidality is a global public health problem which has increased considerably during the coronavirus disease 2019 (COVID-19) pandemic. This study examined the inter-relationships between depressive symptoms and suicidality using network analysis among Macau residents after the “relatively static management” COVID-19 strategy.Methods: An assessment of suicidal ideation (SI), suicide plan (SP), suicide attempt (SA) and depressive symptoms was conducted with the use of individual binary response items (yes/no) and Patient Health Questionnaire (PHQ-9). In the network analysis, central and bridge symptoms were identified in the network through “Expected Influence” and “Bridge Expected Influence”, and specific symptoms that were directly associated with suicidality were identified via the flow function. Network Comparison Tests (NCT) were conducted to examine the gender differences in network characteristics.Results: The study sample included a total of 1008 Macau residents. The prevalence of depressive symptoms and suicidality were 62.50% (95% CI = 59.4– 65.5%) and 8.9% (95% CI = 7.2– 10.9%), respectively. A network analysis of the sample identified SI (“Suicidal ideation”) as the most central symptom, followed by SP (“Suicide plan”) and PHQ4 (“Fatigue”). SI (“Suicidal ideation”) and PHQ6 (“Guilt”) were bridge nodes connecting depressive symptoms and suicidality. A flow network revealed that the strongest connection was between S (“Suicidality”) and PHQ6 (“Guilt”), followed by S (“Suicidality”) and PHQ 7 (“Concentration”), and S (“Suicidality”) and PHQ3 (“Sleep”).Conclusion: The findings indicated that reduction of specific depressive symptoms and suicidal thoughts may be relevant in decreasing suicidality among adults. Further, suicide assessment and prevention measures should address the central and bridge symptoms identified in this study.Keywords: COVID-19, depression, suicidality, adults, network analysis

Lin Sheng,1– 4,* Yumeng Wei,1,3,* Chao Pi,1,3,* Ju Cheng,3,4 Zhilian Su,1– 4 Yuanyuan Wang,1,5 Tao Chen,1– 4 Jie Wen,1– 4 Yuxun Wei,1– 4 Jingwen Ma,1– 4 Jia Tang,1– 4 Huiyang Liu,1– 4 Zerong Liu,6,7 Hongping Shen,8 Ying Zuo,9 Wenwu Zheng,10 Ling Zhao2– 4 1Key Laboratory of Medical Electrophysiology, Ministry of Education, School of Pharmacy of Southwest Medical University, Luzhou, People’s Republic of China; 2Luzhou Key Laboratory of Traditional Chinese Medicine for Chronic Diseases Jointly Built by Sichuan and Chongqing, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 3Key Laboratory of Medical Electrophysiology, Ministry of Education, Development Planning Department of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 4Central Nervous System Drug Key Laboratory of Sichuan Province, School of Pharmacy of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 5Department of Clinical Pharmacy, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 6Central Nervous System Drug Key Laboratory of Sichuan Province, Sichuan Credit Pharmaceutical CO., Ltd. Luxian County, Luzhou City, People’s Republic of China; 7Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400030, People’s Republic of China; 8Clinical Trial Center, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 9Department of Comprehensive Medicine, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 10Department of cardiology, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wenwu Zheng, Department of Cardiology, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China, Tel/Fax +86 830 3165311, Email zhengwenwu888@163.com Ling Zhao, Luzhou Key Laboratory of Traditional Chinese Medicine for Chronic Diseases Jointly Built by Sichuan and Chongqing, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, No. 182, Chunhui Road, Longmatan District, Luzhou, Sichuan, 646000, People’s Republic of China, Tel/Fax +86 830 3160093, Email zhaoling@swmu.edu.cnPurpose: The early stage of this study verified that a turmeric extract (TUR) including 59% curcumin (CU), 22% demethoxycurcumin (DMC), and 18% bisdemethoxycurcumin (BDMC), could enhance the stability of CU and had greater antidepressant potential in vitro. The objective of the study was to develop a nano-delivery system containing TUR (TUR-NE) to improve the pharmacokinetic behavior of TUR and enhance its antidepressant effect.Methods: The antidepressant potential of TUR was explored using ABTS, oxidative stress-induced cell injury, and a high-throughput screening model. TUR-NE was fabricated, optimized and characterized. The pharmacokinetic behaviors of TUR-NE were evaluated following oral administration to normal rats. The antidepressant effect of TUR-NE was assessed within chronic unpredictable mild stress model (CUMS) mice. The behavioral and biochemical indexes of mice were conducted.Results: The results depicted that TUR had 3.18 and 1.62 times higher antioxidant capacity than ascorbic acid and CU, respectively. The inhibition effect of TUR on ASP+ transport was significantly enhanced compared with fluoxetine and CU. TUR-NE displayed a particle size of 116.0 ± 0.31 nm, polydispersity index value of 0.121 ± 0.007, an encapsulation rate of 98.45%, and good release and stability in cold storage. The results of pharmacokinetics indicated the AUC(0-t) of TUR-NE was 8.436 and 4.495 times higher than that of CU and TUR, while the Cmax was 9.012 and 5.452 times higher than that of CU and TUR, respectively. The pharmacodynamic study confirmed that the superior antidepressant effect of TUR-NE by significantly improving the depressant-like behaviors and elevating the content of 5-hydroxytryptamine in plasma and brain in CUMS mice. TUR-NE showed good safety with repeated administration.Conclusion: TUR-NE, which had small and uniform particle size, enhanced the bioavailability and antidepressant effect of TUR. It could be a promising novel oral preparation against depression.Keywords: turmeric extract, curcuminoids, nanoemulsion, stability, antidepressant effect, 5-hydroxytryptamine

Feihong Huang,1,2,* Zhiping Su,3,* Chaojie Yu1 1Department of Bone and Soft Tissue Surgery, Guangxi Medical University Cancer Hospital, Nanning, People’s Republic of China; 2Spine and Osteopathy Ward, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China; 3Department of Radiation Oncology, Guangxi Medical University Cancer Hospital, Nanning, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chaojie Yu, Guangxi Medical University Cancer Hospital, Department of Bone and Soft Tissue Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China, Email h2021020@sr.gxmu.edu.cnObjective: The mechanism of ankylosing spondylitis (AS) remains unclear, and clinical diagnosis still pose challenges. This study aims to explore potential regulatory mechanisms underlying AS and develop a novel diagnostic model.Methods: Interspinous ligament (ISL) tissues were collected from control samples and ankylosing spondylitis with kyphotic deformity (AS-KD) samples during surgery, followed by high-throughput sequencing. By integrating gene expression profiles from publicly available AS peripheral blood (PB) samples, differentially expressed immune genes (DEIRGs) were identified. Through gene set enrichment analysis(GSEA), gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, the regulatory mechanisms of the immune gene family in AS were explored. A diagnostic model for AS were constructed and validated it externally. Additionally, a competing endogenous RNA(ceRNA)-protein regulatory network was built for key immune genes.Results: Adrenergic receptor beta 2 (ADRB2) was downregulated in both ISL and PB samples. It was enriched in common pathways, including natural killer cell-mediated cytotoxicity, B cell receptor signaling pathway, Th1 and Th2 cell differentiation. Using the LASSO algorithm, 12 DEIRGs were identified, including the downregulated ADRB2. Based on the DEIRGs family, a novel diagnostic model was constructed with an AUC of 0.87 for the validation set and 0.7 for the test set. The AUC for ADRB2 alone was 0.75. Subgrouping AS based on these immune genes revealed a close association with neutrophils. GSEA and KEGG analysis of ISL, PB, and subgrouping of AS showed that ADRB2 may be involved in regulating the T cell receptor signaling pathway. Immune infiltration analysis indicated a decrease in CD8+ T cell infiltration, which was positively correlated with ADRB2. ADRB2 in AS-KD was regulated by multiple ceRNA-protein (lncRNA-[hsa-miR-513a-5p]-mRNA-protein).Conclusion: The immune gene family, especially ADRB2, participates in the mechanism and contributes to the diagnosis of AS.Keywords: ankylosing spondylitis, immune genes, adrenergic receptor beta-2, ADRB2, diagnostic model, competing endogenous RNA network, ceRNA network

Zitian Liang,1,* Ding Chen,2,* Ye Jiang,1 Zhikang Su,2 Yixing Pi,2 Tao Luo,2 Qianzhou Jiang,1 Li Yang,1 Lvhua Guo2 1Department of Endodontics, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, Guangdong, 510182, People’s Republic of China; 2Department of Prosthodontics, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, Guangdong, 510182, People’s Republic of China*These authors contributed equally to this workCorrespondence: Li Yang; Lvhua Guo, Affiliated Stomatology Hospital of Guangzhou Medical University, No. 195 West Dongfeng Road, Guangzhou, 510182, People’s Republic of China, Tel +86-020-81299942, Email 2019686001@gzhmu.edu.cn; 2010686002@gzhmu.edu.cnIntroduction: Effective infection control without irritating the pulp tissue is the key to successful vital pulp therapy. Developing a novel antibacterial biomaterial that promotes dentin regeneration for pulp capping is thus a promising strategy for enhancing vital pulp therapy.Methods: Lithium-doped mesoporous nanoparticles (Li-MNPs) were synthesized using an alkali-catalyzed sol-gel method. The particle size, elemental distribution, surface morphology, pore structure, and ion release from Li-MNPs were measured. Human dental pulp stem cells (hDPSCs) and Streptococcus mutans (S. mutans) were used to evaluate the biological effects of Li-MNPs. In addition, a dental pulp exposure mouse model was used to evaluate the regenerative effects of Li-MNPs.Results: Li-MNPs had a larger surface area (221.18 m2/g), a larger pore volume (0.25 cm3/g), and a smaller particle size (520.92 ± 35.21 nm) than MNPs. The in vitro investigation demonstrated that Li-MNPs greatly enhanced the biomineralization and odontogenic differentiation of hDPSCs through the Wnt/β-catenin signaling pathway. Li-MNPs showed a strong antibacterial effect on S. mutans. As expected, Li-MNPs significantly promoted dentin regeneration in situ and in vivo.Conclusion: Li-MNPs promoted dentin regeneration and inhibited S. mutans growth, implying a possible application as a pulp capping agent in vital pulp therapy.Graphical Abstract: Keywords: lithium, mesoporous nanoparticles, dental pulp stem cells, dentin regeneration, Wnt/β-catenin signaling pathway, antibacterial properties

Reinforcement allows organisms to learn which stimuli predict subsequent biological relevance. Hebbian mechanisms of synaptic plasticity are insufficient to account for reinforced learning because neuromodulators signaling biological relevance are delayed with respect to the neural activity associated with the stimulus. A theoretical solution is the concept of eligibility traces (eTraces), silent synaptic processes elicited by activity which upon arrival of a neuromodulator are converted into a lasting change in synaptic strength. Previously we demonstrated in visual cortical slices the Hebbian induction of eTraces and their conversion into LTP and LTD by the retroactive action of norepinephrine and serotonin Here we show in vivo in mouse V1 that the induction of eTraces and their conversion to LTP/D by norepinephrine and serotonin respectively potentiates and depresses visual responses. We also show that the integrity of this process is crucial for ocular dominance plasticity, a canonical model of experience-dependent plasticity.

Zehui Qin,1 Minhua Li,1,2 Juanjuan Cheng,1,2 Ziwei Huang,1,2 Gaoxiang Ai,1,2 Chang Qu,3 Youliang Xie,1 Yucui Li,1 Huijun Liao,4 Jianhui Xie,5– 7 Ziren Su1,2 1School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, People’s Republic of China; 2Dongguan Institute of Guangzhou University of Chinese Medicine, Dongguan, 523808, People’s Republic of China; 3College of Forestry and Landscape Architecture, South China Agricultural University, Guangzhou, 510006, People’s Republic of China; 4Department of Clinical Pharmacy and Pharmaceutical Services, Huazhong University of Science and Technology Union Shenzhen Hospital (the 6th affiliated Hospital of Shenzhen University), Shenzhen, People’s Republic of China; 5The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 6State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 7Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou, People’s Republic of ChinaCorrespondence: Ziren Su, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China, Dongguan Institute of Guangzhou University of Chinese Medicine, Dongguan, 523808, People’s Republic of China, Email suziren@gzucm.edu.cn Huijun Liao, Department of Clinical Pharmacy and Pharmaceutical Services, Huazhong University of Science and Technology Union Shenzhen Hospital (the 6th affiliated hospital of Shenzhen University), Shenzhen, People’s Republic of China, Email liaohuijun1016@163.comPropose: Berberine (BBR) is extensively studied as an outstanding anti-hyperuricemia drug. However, the clinical application of BBR was limited due to its poor absorption and low bioavailability. Therefore, there is an urgent necessity to find a novel drug formulation to address the issues of BBR in clinical application.Methods: Herein, we conducted the solubility, characterization experiments to verify whether BBR and sodium taurocholate (STC) self-assembled nanoparticles (STC@BBR-SANPs) could form. Furthermore, we proceeded the release experiment in vitro and in vivo to investigate the drug release effect. Finally, we explored the therapeutic effect of STC@BBR-SANPs on hyperuricemia (HUA) through morphological observation of organs and measurement of related indicators.Results: The solubility, particle size, scanning electron microscopy (SEM), and stability studies showed that the stable STC@BBR-SANPs could be formed in the BBR-STC system at ratio of 1:4. Meanwhile, the tissue distribution experiments revealed that the STC@BBR-SANPs could accelerate the absorption and distribution of BBR. In addition, the pharmacology study demonstrated that both BBR and STC@BBR-SANPs exhibited favorable anti-HUA effects and nephroprotective effects, while STC@BBR-SANPs showed better therapeutic action than that of BBR.Conclusion: This work indicated that STC@BBR-SANPs can be self-assembly formed, and exerts excellent uric acid-lowering effect. STC@BBR-SANPs can help to solve the problems of poor solubility and low absorption rate of BBR in clinical use, and provide a new perspective for the future development of BBR.Graphical Abstract: Keywords: berberine, sodium taurocholate, intermolecular interactions, self-assembled, nanoparticles, hyperuricemia

Xinghua Guo,1,2,* Pan Song,1,2,* Feng Li,1,2,* Qihao Yan,1,2,* Yan Bai,3 Jincan He,3 Qishi Che,4 Hua Cao,5 Jiao Guo,2 Zhengquan Su1 1Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou, 510006, People’s Republic of China; 2Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou, 510006, People’s Republic of China; 3School of Public Health, Guangdong Pharmaceutical University, Guangzhou, 510310, People’s Republic of China; 4Guangzhou Rainhome Pharm & Tech Co., Ltd, Science City, Guangzhou, 510663, People’s Republic of China; 5School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Zhongshan, 528458, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhengquan Su, Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Pharmaceutical University, Guangzhou, 510006, People’s Republic of China, Tel +86-20-3935-2067, Fax +86-20-3935-2067, Email suzhq@scnu.edu.cnAbstract: Bone, like most organs, has the ability to heal naturally and can be repaired slowly when it is slightly injured. However, in the case of bone defects caused by diseases or large shocks, surgical intervention and treatment of bone substitutes are needed, and drugs are actively matched to promote osteogenesis or prevent infection. Oral administration or injection for systemic therapy is a common way of administration in clinic, although it is not suitable for the long treatment cycle of bone tissue, and the drugs cannot exert the greatest effect or even produce toxic and side effects. In order to solve this problem, the structure or carrier simulating natural bone tissue is constructed to control the loading or release of the preparation with osteogenic potential, thus accelerating the repair of bone defect. Bioactive materials provide potential advantages for bone tissue regeneration, such as physical support, cell coverage and growth factors. In this review, we discuss the application of bone scaffolds with different structural characteristics made of polymers, ceramics and other composite materials in bone regeneration engineering and drug release, and look forward to its prospect.Graphical Abstract: Keywords: bone scaffold, drug loading, slow release, osteogenesis, biomaterial

Zhaohua Yang,1,* Jinying Wei,1,* Yashu Wang,1 Yunxia Du,1 Shan Song,1 Jiawei Li,2 Ziyuan Su,2 Yonghong Shi,1 Haijiang Wu1 1Department of Pathology, Hebei Medical University, Shijiazhuang, 050017, People’s Republic of China; 2Basic Medical College, Hebei Medical University, Shijiazhuang, 050017, People’s Republic of China*These authors contributed equally to this workCorrespondence: Haijiang Wu, Email haijianglaoqi@163.comBackground: The primary pathophysiology of diabetic kidney disease (DKD) is tubulointerstitial fibrosis (TIF), and an essential contributing element is excessive extracellular matrix deposition. Irisin is a polypeptide formed by splitting fibronectin type III domain containing 5 (FNDC5), which participates in a number of physiological and pathological processes.Methods: The purpose of this article is to examine irisin’s function in DKD and analyze both its in vitro and in vivo effects. The Gene Expression Omnibus (GEO) database was used to download GSE30122, GSE104954, and GSE99325. Analysis of renal tubule samples from nondiabetic and diabetic mice identified 94 differentially expressed genes (DEGs). The transforming growth factor beta receptor 2 (TGFBR2), irisin, and TGF-β 1 were utilized as DEGs to examine the impact of irisin on TIF in diabetic kidney tissue, according to the datasets retrieved from the GEO database and Nephroseq database. Additionally, the therapeutic impact of irisin was also examined using Western blot, RT-qPCR, immunofluorescence, immunohistochemistry, and kits for detecting mouse biochemical indices.Results: In vitro, the findings demonstrated that irisin not only down-regulated the expression of Smad4 and β-catenin but also reduced the expression of proteins linked to fibrosis, the epithelial-mesenchymal transition (EMT), and mitochondrial dysfunction in HK-2 cells maintained in high glucose (HG) environment. In vivo, overexpressed FNDC5 plasmid was injected into diabetic mice to enhance its expression. Our studies found that overexpressed FNDC5 plasmid not only reversed the biochemical parameters and renal morphological characteristics of diabetic mice but also alleviated EMT and TIF by inhibiting Smad4/β-catenin signaling pathway.Conclusion: The above experimental results revealed that irisin could reduce TIF in diabetic mice via regulating the Smad4/β-catenin pathway.Keywords: irisin, diabetic kidney disease, tubulointerstitial fibrosis, Smad4, β-catenin

Yuxun Wei,1– 4,* Yumeng Wei,1– 4,* Lin Sheng,1– 4 Jingwen Ma,1– 4 Zhilian Su,1– 4 Jie Wen,1– 4 Lanmei Li,5 Qiang Jia,2,6 Huiyang Liu,1– 4 Hui Si,2,4 Linjin Xiong,1– 4 Jinglin Chen,1– 4 Ju Cheng,3,4 Ying Zuo,2,7 Hongru Yang,8 Ling Zhao2– 4 1Key Laboratory of Medical Electrophysiology, Ministry of Education, School of Pharmacy of Southwest Medical University, Luzhou, People’s Republic of China; 2Key Laboratory of Medical Electrophysiology, Ministry of Education, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University; Luzhou, Sichuan, People’s Republic of China; 3Central Nervous System Drug Key Laboratory of Sichuan Province, School of Pharmacy of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 4Luzhou Key Laboratory of Traditional Chinese Medicine for Chronic Diseases Jointly Built by Sichuan and Chongqing, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 5Nanchong Key Laboratory of Individualized Drug Therapy, Department of Pharmacy, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, Sichuan, People’s Republic of China; 6Ethics Committee Office, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 7Department of Comprehensive Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 8Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ling Zhao, Key Laboratory of Medical Electrophysiology, Ministry of Education, Luzhou Key Laboratory of Traditional Chinese Medicine for Chronic Diseases Jointly Built by Sichuan and Chongqing, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China, Tel/Fax +86 830 3160093, Email zhaoling-998@163.com Hongru Yang, Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China, Tel/Fax +86 830 8585668, Email yanghongru801@126.comPurpose: The present study aimed to construct a co-loading platform encapsulating curcumin and paclitaxel at ratios of 2:1– 80:1 (w/w) designated “CU-PTX-LNP” and explored the synergistic effects of CU-PTX at different composite proportions on liver cancer cells using the combination index (CI) method.Methods: The CU lipid nanoplatform (CU-LNP) formulation was optimized via single-factor and orthogonal experiments. Various concentrations of PTX were added to the optimal formulation of CU-LNP to generate CU-PTX-LNP and the nanoplatform characterized via differential scanning calorimetry (DSC), transmission electron microscope (TEM), X-ray diffraction (XRD), zeta potential, polydispersity index (PDI), and size analyses. The cumulative release, stability, and cytotoxicity of CU-PTX-LNP in LO2, HepG2, and SMMC-7221 cells were assessed in vitro, followed by safety investigation and pharmacokinetic studies in vivo. The anti-tumor activity of CU-PTX-LNP was also evaluated using nude mice.Results: CU-PTX-LNP formulations containing CU:PTX at a range of proportions (2:1– 80:1; w/w) appeared as uniformly dispersed nanosized spherical particles with high entrapment efficiency (EE> 90%), sustained release and long-lasting stability. Data from in vitro cytotoxicity assays showed a decrease in the IC50 value of PTX of CU-PTX-LNP (by 5.47– 332.7 times in HepG2 and 4.29– 143.21 times in SMMC-7221 cells) compared to free PTX. In vivo, CU-PTX-LNP displayed excellent biosafety, significant anti-tumor benefits and enhanced pharmacokinetic behavior with longer mean residence time (MRT(0-t); CU: 4.31-fold, PTX: 4.61-fold) and half-life (t1/2z; CU: 1.83-fold, PTX: 2.28-fold) relative to free drugs.Conclusion: The newly designed CU-PTX-LNP platform may serve as a viable technological support system for the successful production of CU-PTX composite preparations.Keywords: curcumin, paclitaxel, lipid nano platform, synergistic effect

Qiang Xiao,1,&ast; Shukun Tan,1,2,&ast; Changzhi Liu,3,&ast; Bin Liu,1 Yingxiong Li,1 Yehui Guo,1 Peiyan Hu,1 Zhuoying Su,1 Siqin Chen,1 Wei Lei,1 Xi Li,1 Minhong Su,4 Fu Rong1 1Pulmonary and Critical Care Medicine, Shunde Hospital, Southern Medical University (the First People’s Hospital of Shunde Foshan), Foshan, 528300, People’s Republic of China; 2Respiratory Medicine of the Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan, 528222, People’s Republic of China; 3Critical Care Medicine, Shunde Hospital, Southern Medical University (the First People’s Hospital of Shunde Foshan), Foshan, 528300, People’s Republic of China; 4Pulmonary and Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fu Rong, Pulmonary and Critical Care Medicine, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde Foshan), No. 1, Jiazi Road, Lunjiao Street, Shunde District, Foshan, 528300, People’s Republic of China, Tel +86-757-22318689, Email rongfu828@sina.com Minhong Su, Pulmonary and Critical Care Medicine, Zhujiang Hospital, Southern Medical University, 253 Gongye Middle Avenue, Haizhu District, Guangzhou, 510280, People’s Republic of China, Tel +86-20-62782290, Email 878697159@qq.comPurpose: Community-acquired pneumonia (CAP) is one of the most frequently encountered infectious diseases worldwide. Few studies have explored the microbial composition of the lower respiratory tract (LRT) and host metabolites of CAP. We analyzed the microbial composition of the LRT and levels of host metabolites to explore new biomarkers for CAP.Patients and Methods: Bronchoalveolar lavage fluid (BALF) was collected from 28 CAP patients and 20 healthy individuals. Following centrifugation, BALF pellets were used for amplicon sequencing of a variable region of the bacterial 16S rDNA gene to characterize the microbial composition. Non-targeted metabolomics was used to detect host’s metabolites in the supernatant.Results: Compared with healthy individuals, the bacterial alpha diversity in the LRT of CAP patients was significantly lower in CAP patients (p< 0.05). On the bacterial genus level, over 20 genera were detected with lower relative abundance (p< 0.05), while the relative abundance of Ruminiclostridium-6 was significantly higher in CAP patients. The levels of the host metabolites dimethyldisulfide, choline, pyrimidine, oleic acid and N-acetyl-neuraminic acid were all increased in BALF of CAP patients (p< 0.05), while concentrations of lysophosphatidylcholines (LPC (12:0/0:0)) and phosphatidic acid (PA (20:4/2:0)) were decreased (p< 0.05). Furthermore, the relative abundance of Parvimonas, Treponema-2, Moraxella, Aggregatibacter, Filifactor, Fusobacterium, Lautropia and Neisseria negatively correlated with concentrations of oleic acid (p< 0.05). A negative correlation between the relative abundance of Treponema-2, Moraxella, Filifactor, Fusobacterium and dimethyldisulfide concentrations was also observed (p< 0.05). In contrast, the relative abundance of Treponema-2, Moraxella, Filifactor, and Fusobacterium was found to be positively associated with concentrations of LPC (12:0/0:0) and PA (20:4/2:0) (p< 0.05).Conclusion: The composition of the LRT microbiome differed between healthy individuals and CAP patients. We propose that some respiratory microbial components and host metabolites are potentially novel diagnostic markers of CAP.Keywords: community-acquired pneumonia, microbiome, metabolites, biomarker, diagnosis

Minhua Li,1,&ast; Zehui Qin,1,&ast; Qiuxia Yu,2 Ziwei Huang,3 Juanjuan Cheng,1 Linjiang Zhong,1 Yuhong Liu,1 Jianhui Xie,4– 6 Yucui Li,1 Jiannan Chen,1 Ruoting Zhan,1 Ziren Su1 1School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, People’s Republic of China; 2The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, 510120, People’s Republic of China; 3The First Affiliated Hospital of Chinese Medicine Guangzhou University of Chinese Medicine, Guangzhou, 510120, People’s Republic of China; 4The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510120, People’s Republic of China; 5State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510120, People’s Republic of China; 6Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou, 510120, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ruoting Zhan; Ziren Su, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, no. 232, Waihuandong Road, Guangzhou Higher Education Mega Center, Guangzhou, 510006, People’s Republic of China, Email zhanrt@gzucm.edu.cn; suziren@gzucm.edu.cnBackground: Berberine (BBR) is the primary active component of Phellodendri Chinensis Cortex (PCC), which has been traditionally used to treat inflammatory diseases. However, the discrepancy between its low bioavailability and significant therapeutic effect remains obscure. The purpose of this study was to explore the previously unsolved enigma of the low bioavailability of BBR and its appreciable anti-inflammatory effect to reveal the action mechanism of BBR and PCC.Methods: The quantitative analysis of BBR and its metabolite oxyberberine (OBB) in blood and tissues was performed using high-performance liquid chromatography to investigate the conversion and distribution of BBR/OBB mediated by erythrocytes. Routine blood tests and immunohistochemical staining were used to explore the potential relationship between the amounts of monocyte/macrophage and the drug concentration in erythrocytes and tissues (liver, heart, spleen, lung, kidney, intestine, muscle, brain and pancreas). To comparatively explore the anti-inflammatory effects of BBR and OBB, the acetic acid-induced vascular permeability mice model and lipopolysaccharide-induced RAW 264.7 macrophages were employed.Results: Nearly 92% of BBR existed in the erythrocytes in rats. The partition coefficient of BBR between plasma and erythrocytes (Kp/b) decreased with time. OBB was found to be the oxidative metabolite of BBR in erythrocytes. Proportion of BBR/OBB in erythrocytes changed from 9.38% to 16.30% and from 13.50% to 46.24%, respectively. There was a significant relationship between the BBR/OBB concentration in blood and monocyte depletion after a single administration of BBR. BBR/OBB was transported via erythrocytes to various tissues (liver, kidney, spleen, lung, and heart, etc), with the liver achieving the highest concentration. OBB exhibited similar anti-inflammatory effect in vitro and in vivo as BBR with much smaller dosage.Conclusion: BBR was prodominantly found in erythrocytes, which was critically participated in the biodistribution, pharmacokinetics, metabolism and target delivery of BBR and its metabolite. The anti-inflammatory activity of BBR and PCC was intimately associated with the metabolism into the active congener OBB and the targeted delivery to monocytes/macrophages mediated by the erythrocytes.Graphical Abstract: Keywords: erythrocytes, Phellodendri Chinensis Cortex, transformation, berberine, anti-inflammation

Hai-Ying Chen,1,&ast; Ming-Chao Li,2,&ast; Dan Liao,1 Chi Li,1 Qiu-Ming Ji,1 Ping Guo,1 Zou Su,1 Yu-Hong Yang,1 Wen-Hao Xiao,1 Wen-Hui Zhai1 1Department of Psychiatry, Wuhan Wudong Hospital, Wuhan, People’s Republic of China; 2Department of Psychiatry, Wuhan Mental Health Center, Wuhan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dan Liao; Chi Li, Department of Psychiatry, Wuhan Wudong Hospital, No. 46 of Wudong Street, Qingshan District, Wuhan, 430084, People’s Republic of China, Tel +86 27 5052 8367, Fax +86 27 8643 8247, Email danliaodr@21cn.comObjective: Our study aimed to investigate the effects of computer-assisted cognitive remediation therapy (CCRT) on cognitive function, social function and quality of life in patients with vascular dementia (VD).Methods: Ninety-eight patients with VD were treated with CCRT in four 45-minute sessions per week over a course of 40 sessions to exercise four cognitive functions, including flexibility, working memory, plan execution and social cognition. The Mini-Mental State Examination (MMSE), Social Disability Screening Schedule (SDSS), Personal and Social Performance Scale (PSP), and Generic Quality of Life Inventory-74 (GQOL-74) were used to assess before and after treatment.Results: (1) The scores of orientation (5.60 ± 1.35), calculation (2.20 ± 0.79), verbal ability (7.10 ± 0.36), spatial ability (0.78 ± 0.42), immediate memory (2.42 ± 0.53), short-term memory (1.17 ± 0.78) and MMSE (23.36 ± 2.98) were all improved after treatment (P < 0.05) compared with those before treatment; (2) The scores of SDSS, PSP and Activities of Daily Living (ADL) after treatment were 8.23 ± 0.94, 81.36 ± 14.23, and 32.7 ± 12.1, and all of which improved (P < 0.05); (3) The scores of physical health were 68.24 ± 7.44, mental health were 69.75 ± 7.15, social function were 69.08 ± 7.43, material life were 37.46 ± 4.85 and the total score were 230.79 ± 9.56, all of which improved (P < 0.05).Conclusion: For patients with VD, CCRT can improve their cognitive function, social function, daily life ability and quality of life.Keywords: computer-assisted cognitive remediation, vascular dementia, cognitive function, social function, daily life ability

AbstractThe Third Pole (TP) is experiencing rapid warming and is currently in its warmest period in the past 2,000 years. This paper reviews the latest development in multidisciplinary TP research associated with this warming. The rapid warming facilitates intense and broad glacier melt over most of the TP, although some glaciers in the northwest are advancing. By heating the atmosphere and reducing snow/ice albedo, aerosols also contribute to the glaciers melting. Glacier melt is accompanied by lake expansion and intensification of the water cycle over the TP. Precipitation has increased over the eastern and northwestern TP. Meanwhile, the TP is greening and most regions are experiencing advancing phenological trends, although over the southwest there is a spring phenological delay mainly in response to the recent decline in spring precipitation. Atmospheric and terrestrial thermal and dynamical processes over the TP affect the Asian monsoon at different scales. Recent evidence indicates substantial roles that mesoscale convective systems play in the TP’s precipitation as well as an association between soil moisture anomalies in the TP and the Indian monsoon. Moreover, an increase in geohazard events has been associated with recent environmental changes, some of which have had catastrophic consequences caused by glacial lake outbursts and landslides. Active debris flows are growing in both frequency of occurrences and spatial scale. Meanwhile, new types of disasters, such as the twin ice avalanches in Ali in 2016, are now appearing in the region. Adaptation and mitigation measures should be taken to help societies’ preparation for future environmental challenges. Some key issues for future TP studies are also discussed.

Previous work has identified synaptic eligibility traces in slice preparations. Here the authors provide demonstration of eligibility traces in vivo during reinforcement learning.

Under the influence of climate warming, the frequency and intensity of extreme weather events are increasing, posing a greater risk of exposing the ecological environment to extreme climatic conditions. Ecological land, as a land use type of paramount importance to both the natural environment and humanity, has not been examined regarding its exposure under extreme climatic conditions. Therefore, this study focuses on the ecologically significant Southwest China, characterized by frequent extreme temperature events. Based on CMIP6 climate data and land use data, and utilizing ArcGIS software, the exposure of ecological land to extreme temperature conditions is analyzed. The results indicate that, compared to historical periods, the area of ecological land exposed to extreme high temperatures is rapidly increasing, while the area exposed to extreme low temperatures is decreasing. Various types of ecological land show differences in area changes under extreme temperature exposure, and there is significant spatial heterogeneity in the changes in ecological land exposure, primarily due to the different spatial distributions of ecological land and extreme temperature indicators. The changes in exposure area of ecological land under extreme temperatures exhibit prominent topographical gradients. The findings of this study can provide crucial and clear information for the formulation of disaster prevention mitigation policies and land planning. [ABSTRACT FROM AUTHOR]

Metagenomics, the study of all microbial species cohabitants in an environment, often produces large amount of sequence data varying from several GBs to a few TBs. Analyzing metagenomics data includes both data-intensive and compute-intensive steps, making the entire process hard to scale. Here we aim to optimize a metagenomics application that partitions the shortgun metagenomics sequences based on their species of origin. Our solution combines MapReduce-based BioPig analytic toolkit with MPI to provide scalability in respective to both data and compute. We also made some improvements to the existing BioPig toolkit by using simplified data types and compressed k-mer storage. These optimizations leads up to 193× speedup for the computing-intensive step and 9.6× speedup over the entire pipeline. Our optimized application is also capable of processing datasets that are 16 times larger on the same hardware platform. These results suggest integrating heterogeneous technologies such as Hadoop and MPI is quite efficient to solve large genomics problems that are both data-intensive and compute-intensive.

Nonlinear features extracted from Lamb wave signals (e.g., second harmonic generation) are demonstrably sensitive to microscopic damage, such as fatigue and material thermal degradation. While a majority of the existing studies in this context is focused on detecting undersized damage in metallic materials, the present study is aimed at expanding such a detection philosophy to the domain of composites, by linking the relative acoustic nonlinearity parameter (RANP) – a prominent nonlinear signal feature of Lamb waves – to barely visible impact damage (BVID) in composites. Nevertheless, considering immense uncertainties inevitably embedded in acquired signals (due to instrumentation, environment, operation, computation/estimation, etc.) which can adversely obfuscate nonlinear features, it is necessary to quantify the uncertainty of the RANP (i.e., its statistics) in order to enhance decision-making associated with its use as a detection feature. A probabilistic model is established to numerically evaluate the statistical distribution of the RANP. Using piezoelectric wafers, Lamb waves are acquired and processed to produce histograms of RANP estimates in both the healthy and damaged conditions of a CF/EP laminate, to which the model is compared, with good agreement observed between the model-predicted and experimentally-obtained statistic distributions of the RANP. With the model, BVID in the laminate is predicted. The model is further made use of to quantify the level of confidence in damage prediction results based on the concept of a receiver operating characteristic, enabling the practitioners to better understand the obtained results in the presence of uncertainties.