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Yan Wang,1– 4,* He Zhao,2– 4,* Kun Zhao,1– 4,* Huhuifen He,1– 4,* Xinyu Li,5 Jingjing Qiu,2– 4 Limei Cui,2– 4 Liang Chen,2– 4 Wenjing Shang,6,7 Yan Sun2– 4 1The Second Medical College, Binzhou Medical University, Yantai, Shandong, People’s Republic of China; 2Department of Otolaryngology and Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, Shandong, People’s Republic of China; 3Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai, Shandong, People’s Republic of China; 4Yantai Key Laboratory of Otorhinolaryngologic Diseases, Yantai, Shandong, People’s Republic of China; 5The First Medical College, Binzhou Medical University, Yantai, Shandong, People’s Republic of China; 6Key Laboratory for Genetic Hearing Disorders in Shandong, Binzhou Medical University, Yantai, Shandong, 264003, People’s Republic of China; 7Department of Biochemistry and Molecular Biology, Binzhou Medical University, Yantai, Shandong, 264003, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yan Sun; Wenjing Shang, Email entsunyan@126.com; wenjshang@bzmc.edu.cnIntroduction: Age-related hearing loss (ARHL) is a degenerative condition that involves both peripheral and central auditory system pathologies. There is a close relationship between chronic inflammation and ARHL, but there is currently a lack of in-depth exploration of this relationship, particularly regarding causality.Methods: Using age-appropriate mice for basic experiments to examine changes in central auditory nervous system inflammation, a cohort study was conducted to select relevant clinical data and observe inflammation changes in the elderly population with ARHL. Mendelian randomization was employed to investigate the causal relationship between chronic inflammation and ARHL.Results: Clinical results indicate that CRP levels in the ARHL group are significantly higher than those in the normal group. Chronic inflammation also occurs in the auditory centers. Mendelian randomization studies provide causal evidence that genetic chronic inflammation factors do not increase the risk of ARHL.Discussion: This article provides reliable causal evidence of the relationship between chronic inflammation and ARHL, confirming the accumulation of inflammatory factors in the auditory center, which provides a basis for the prevention and treatment of ARHL and has a good prevention prospect. However, due to the differences of research objects, this study has limitations and needs further research.Keywords: CRP, TNF-α, chronic inflammation, age-related hearing loss, Mendelian randomization

Mengyang Li,1,* Yuting Wang,2,* He Liu,2 Xiaonan Huang,2 Huagang Peng,2 Yi Yang,2 Zhen Hu,2 Jianxiong Dou,2 Chuan Xiao,2 Juan Chen,3 Weilong Shang,2 Xiancai Rao1,2 1Department of Microbiology, School of Medicine, Chongqing University, Chongqing, 400044, People’s Republic of China; 2Department of Microbiology, College of Basic Medical Sciences, Army Medical University, Key Laboratory of Microbial Engineering Under the Educational Committee in Chongqing, Chongqing, 400038, People’s Republic of China; 3Department of Pharmacy, The Second Affiliated Hospital, Army Medical University, Chongqing, 400037, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiancai Rao; Weilong Shang, Department of Microbiology, College of Basic Medical Sciences, Army Medical University, Key Laboratory of Microbial Engineering under the Educational Committee in Chongqing, Chongqing, 400038, People’s Republic of China, Email raoxiancai@126.com; shangwl0414@163.comIntroduction: Nanosized outer membrane vesicles (OMVs) from Gram-negative bacteria have attracted increasing interest because of their antitumor activity. However, the antitumor effects of MVs isolated from Gram-positive bacteria have rarely been investigated.Methods: MVs of Staphylococcus aureus USA300 were prepared and their antitumor efficacy was evaluated using tumor-bearing mouse models. A gene knock-in assay was performed to generate luciferase Antares2–MVs for bioluminescent detection. Cell counting kit-8 and lactic dehydrogenase release assays were used to detect the toxicity of the MVs against tumor cells in vitro. Active caspase-1 and gasdermin D (GSDMD) levels were determined using Western blot, and the tumor inhibition ability of MVs was determined in B16F10 cells treated with a caspase-1 inhibitor.Results: The vesicular particles of S. aureus USA300 MVs were 55.23 ± 8.17 nm in diameter, and 5 μg of MVs remarkably inhibited the growth of B16F10 melanoma in C57BL/6 mice and CT26 colon adenocarcinoma in BALB/c mice. The bioluminescent signals correlated well with the concentrations of the engineered Antares2–MVs (R2 = 0.999), and the sensitivity for bioluminescence imaging was 4 × 10− 3 μg. Antares2–MVs can directly target tumor tissues in vivo, and 20 μg/mL Antares2–MVs considerably reduced the growth of B16F10 and CT26 tumor cells, but not non-carcinomatous bEnd.3 cells. MV treatment substantially increased the level of active caspase-1, which processes GSDMD to trigger pyroptosis in tumor cells. Blocking caspase-1 activation with VX-765 significantly protected tumor cells from MV killing in vitro and in vivo.Conclusion: S. aureus MVs can kill tumor cells by activating the pyroptosis pathway, and the induction of pyroptosis in tumor cells is a promising strategy for cancer treatment. Keywords: Staphylococcus aureus, membrane vesicles, Antares2, cancer therapy, pyroptosis, caspase-1, GSDMD

Chenglin Miao,1,* Yali Cui,1– 3,* Yingying Li,1 Qianqian Qi,1 Wenling Shang,1 Huilian Chen,2,3 Yujie Gao,2,3 Ruomei Yuan,2,3 Qichen Long,4 Wenjing Wu,1 Xia Wang,1 Ziyi Yan,1 Yongmei Jiang1,5 1Department of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, Sichuan Province, People’s Republic of China; 2Department of Laboratory Medicine, Meishan Women and Children’s Hospital, Alliance Hospital of West China Second University Hospital, Sichuan University, Meishan, Sichuan Province, People’s Republic of China; 3Department of Laboratory Medicine, West China Second University Hospital (Tianfu), Sichuan University/Sichuan Provincial Children’s Hospital, Meishan, Sichuan Province, People’s Republic of China; 4Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, People’s Republic of China; 5Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ziyi Yan; Yongmei Jiang, Department of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, Sichuan Province, People’s Republic of China, Tel +86 28 8857050 ; +86 28 85501543, Email yan_z_y2@qq.com; jiangyongmeiwst@163.comPurpose: This study was designed to evaluate the immune protective efficacy of the novel Streptococcus pneumoniae (S. pneumoniae) protein vaccine PiuA-PlyD4 through immunoinformatics prediction and in vitro and in vivo experiments.Methods: In this study, we conducted immunoinformatics prediction and protection analysis on the fusion protein PiuA-PlyD4. The epitope composition of the vaccine was analyzed based on the prediction of B-cell and helper T-cell epitopes. Meanwhile, the molecular docking of PiuA and TLR2/4 was simulated. After immunizing C57BL/6 mice with the prepared vaccine, the biological safety, immunogenicity and conservation were evaluated. By constructing different infection models and from the aspects of adhesion inhibition and cytokines, the protective effect of the fusion protein vaccine PiuA-PlyD4 on S. pneumoniae infection was explored.Results: PiuA-PlyD4 has abundant B-cell and helper T-cell epitopes and shows a high antigenicity score and structural stability. Molecular docking analysis suggested the potential interaction between PiuA and TLR2/4. The specific antibody titer of fusion protein antiserum was as high as (7.81± 2.32) × 105. The protective effect of the immunized mice on nasal and lung colonization was significantly better than that of the control group, and the survival rate against S. pneumoniae infection of serotype 3 reached 50%. Cytokine detection showed that the humoral immune response, Th1, Th2 and Th17 cellular immune pathways were all involved in the process.Conclusion: The study indicates that PiuA-PlyD4, whether the results are predicted by immunoinformatics or experimentally validated in vivo and in vitro, has good immunogenicity and immunoreactivity and can provide effective protection against S. pneumoniae infection. Therefore, it can be considered a promising prophylactic vaccine candidate for S. pneumoniae.Keywords: Streptococcus pneumoniae, fusion protein vaccine, PiuA-PlyD4, immunoinformatics prediction, protective efficacy

Rongzhi Wen,&ast; Xinhua Cheng,&ast; Hong Cao, Lei Zhang, Fangcheng Luo, Wei Shang Department of Orthopaedics, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, 442000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fangcheng Luo; Wei Shang, Email fangreng79418583@163.com; weiqiaoshi959193@126.comBackground: The treatment of diabetes-related foot complications is a clinical challenge. The underlying complicating factors of peripheral vascular disease render most diabetic foot ulcers asymptomatic until the ulcer fails to heal and becomes clinically distinct, constituting a significant cause of disability and even death in diabetic patients.Objective: To evaluate the clinical efficacy of tibial transverse transport (TTT) in the treatment of patients with diabetic foot ulcers.Methods: A total of 35 patients who met the inclusion criteria were selected as the study group from patients with diabetic foot ulcers diagnosed and treated at our hospital between August 2019 and March 2021 and were treated with TTT, and 35 patients who also met the inclusion criteria were included in the routine group and were given conventional wound debridement. The primary endpoint of this study was clinical efficacy, including pain condition, trauma condition, ankle-brachial index, and peripheral nerve recovery.Results: Patients receiving TTT showed significantly reduced visual analogue scale (VAS) scores than those with conventional treatment (P< 0.05). TTT resulted in a significant reduction of trabecular area and better trabecular healing versus conventional treatment (P< 0.05). TTT was associated with significantly higher ankle-brachial index (ABI) and lower Michigan neuropathy screening instrument (MNSI) scores in patients versus conventional debridement (P< 0.05).Conclusion: TTT effectively alleviates the pain of diabetic foot ulcer patients, promotes wound healing, and improves ankle-brachial index and peripheral nerve recovery. In the context of the high amputation rate of diabetic foot ulcers treated by internal medicine, TTT contributes positively to the enhancement of patient prognosis and merits clinical promotion.Keywords: tibial transverse transport, diabetic foot ulcer, clinical efficacy

Wei Shang, Xin Zhao, Fan Yang, Dongyi Wang, Le Lu, Zihan Xu, Zhiming zhao, Hui Cai, Junyi Shen Department of Integrated Traditional and Western Medicine, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, 210002, People’s Republic of ChinaCorrespondence: Junyi Shen, Email sauron84@163.comBackground: Compared with traditional drugs, nanomaterial drugs have the benefits of improving the solubility, bioavailability, and absorption rate of insoluble drugs. Nanoporous complexes can increase the efficiency with which drugs can penetrate the blood-brain barrier and reach target organs. Ginsenoside Rg1 is an effective drug that promotes angiogenesis. Ginsenoside Rg1 composite nanoparticles were employed to induce the expression of several key epigenetic enzymes and then activate the VEGF and Notch pathways after the onset of ischemic brain lesions.Methods: We constructed nanoparticles to fully encapsulate the therapeutic drug (ginsenoside Rg1), which can be transferred into brain tissue via the receptor-mediated transfer of drug-encapsulated nanoparticles. Evaluation of the therapeutic effect of ginsenoside Rg1 complex nanovesicles (CNV) was performed by in vitro and in vivo experiments. Real-time polymerase chain reaction (RT- PCR), Western blot, immunohistochemistry staining (IHC), and Co-immunoprecipitation (co-IP) were employed to screen for epigenetic enzymes with an up-regulated expression post ginsenoside Rg1-CNV intervention. RNA sequencing, shRNA knockdown, and chromatin Immunoprecipitation (ChIP) sequencing were performed to detect the target genes of ginsenoside Rg1-CNV that regulate angiogenesis. Then, bioinformatic analysis was performed to investigate the mechanism of action of epigenetic modifying enzymes in regulating target genes.Results: The average of the synthesized ginsenoside Rg1-CNV was 203.78± 6.83 nm, the polydispersion index was 0.135± 0.007, and the Zeta potential was 23.13± 1.65 mV. Through in vivo and in vitro experiments, we found that it promotes the proliferation, migration, and tubular formation of brain microvascular endothelial cells (BMECs). Meanwhile, the intervention of ginsenoside Rg1-CNV promoted the demethylation of H3K27me3 within the promoter region of VEGF-A and Jagged1 genes and reduced the H3K27me3 modification within this region.Conclusion: The ginsenoside Rg1 nanoparticles may be an available blood-brain barrier penetrating agent for ischemic stroke.Keywords: ginsenoside Rg1, nanoparticles, angiogenesis, blood-brain barrier, epigenetic, ischemic stroke

Wenqian Shang,1 Jing Zhang,2 Haibo Song,2 Shunfei Zhu,3 Aimin Zhang,1 Yushuang Hua,1 Shujun Han,4 Yan Fu5 1Department of Traditional Chinese Medicine, Zibo Maternal and Child Health Hospital, Zibo, Shandong, 255000, People’s Republic of China; 2Translational Medicine Center, Zibo Maternal and Child Health Hospital, Zibo, Shandong, 255000, People’s Republic of China; 3Clinical Laboratory, Zibo Maternal and Child Health Hospital, Zibo, Shandong, 255000, People’s Republic of China; 4Surgical Department, Zhangdian District Hospital of Traditional Chinese Medicine, Zibo, 255000, Shandong, People’s Republic of China; 5Shandong University of Technology, Zibo, 255000, Shandong, People’s Republic of ChinaCorrespondence: Aimin Zhang; Wenqian ShangDepartment of Traditional Chinese Medicine, Zibo Maternal and Child Health Hospital, No. 66 North Tianjin Road, Zhangdian District, Zibo, Shandong, People’s Republic of ChinaTel +86 18505330408; +86 15053358995Email purplesunk@163.com; shanzhongyiwanyi@126.comBackground: Endometrial cancer (EC) is one of the most common gynaecological malignancies, and its incidence has been rising over the past decade. Tetrandrine, a bisbenzylisoquinoline alkaloid, has been isolated from a vine used in traditional Chinese medicine, Stephania tetrandra. However, the key mechanism of tetrandrine in EC is still unclear.Purpose: This research was designed to predict the molecular mechanisms of tetrandrine against EC based on network pharmacology and to further verify these predictions by in vitro experiments.Methods: The potential therapeutic targets of tetrandrine against EC were predicted by using public databases. Afterwards, the protein–protein interaction (PPI) network of the common targets was constructed, and the key gene targets were obtained. Biological function and pathway enrichment analyses were performed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Furthermore, molecular docking and in vitro experiments were carried out to verify the predictions. The cell counting kit‑8 (CCK‑8) assay, Hoechst 33258 staining, flow cytometry analysis, qRT-PCR, Western blot analysis and an immunofluorescence assay were performed.Results: Our findings identified 111 potential therapeutic targets of tetrandrine against EC. We obtained 7 key gene targets from the PPI network analysis. Furthermore, GO enrichment analysis indicated that these targets were mainly associated with metabolic processes, responses to stimulus, and biological regulation. The KEGG pathway analysis showed that the common targets were mainly distributed in the PI3K/Akt signalling pathway. A potential interaction of tetrandrine with Akt1 was revealed by molecular docking. In addition, in vitro experiments showed that tetrandrine significantly inhibited cell proliferation and induced apoptosis in Ishikawa and HEC-1-B cells in dose- and time-dependent manners. The results also revealed that tetrandrine can downregulate the expression of Bcl-2 and upregulate the expression of Bax at the mRNA level. The mRNA levels of Akt were not significantly different in the various tetrandrine (0, 10 and 20μM) groups. However, Western blot analysis demonstrated that the protein expression ratios of p-Akt/Akt decreased at the protein level. The results were further confirmed by immunofluorescence assays.Conclusion: Based on bioinformatic analysis and experimental verification, our findings demonstrated that tetrandrine exerted tumour-suppressive effects on EC by regulating the PI3K/Akt signalling pathway.Keywords: endometrial carcinoma, mechanism, network pharmacology, tetrandrine

Wen Shang, Qing-Bian Ma Department of Emergency, Perking University Third Hospital, Beijing 100191, People’s Republic of ChinaCorrespondence: Qing-Bian MaDepartment of Emergency, Perking University Third Hospital, 49 Huayuan North Road, Beijing 100191, People’s Republic of ChinaTel +86-10-82264047Fax +86-10-82264040Email maqingbian@medmail.com.cnAbstract: Thyroid storm is usually due to a severe exacerbation of a preexisting thyrotoxicosis, which later leads to decompensation in different organ systems. Thyroid storm with malignant arrhythmia is rare, but the mortality rate is high. Malignant arrhythmia has usually occurred in some patients with hypokalemia or ischemic heart disease. The presentation of these arrhythmias in the initial phase of the disease is much less common, and only a few isolated cases are described in the scientific literature. This paper analyzes and summarizes the clinical characteristics of this disease through literature reviews, for clinicians early detection and diagnosis of this disease. We report a 51-year-old woman with diarrhoea, fever, thyroid storm, ventricular fibrillation and no potential heart disease. The case report is discussed using relevant data from literature. A total of 9 patients were reported in the literature, totalling 10 cases with ours, including 7 cases of ventricular fibrillation and 3 cases of ventricular tachycardia. Most of the treatments were antithyroid drugs, hormones and beta-receptor blockers, and 3 death cases. Patients with thyroid crisis need to be closely monitored for malignant arrhythmias. Early diagnosis and treatment may save lives.Keywords: thyroid storm, malignant arrhythmia, ventricular tachycardia

Haoran Wang,1 Yue Li,2 Xiaoliang Zhang,2 Zhonglin Xu,2 Jianzhong Zhou,3 Wei Shang2 1Department of Endocrinology, The Ninth People’s Hospital of Chongqing, Chongqing 400700, People’s Republic of China; 2Department of Cardiology, The Ninth People’s Hospital of Chongqing, Chongqing 400700, People’s Republic of China; 3Department of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400700, People’s Republic of ChinaCorrespondence: Wei ShangDepartment of Cardiology, The Ninth People’s Hospital of Chongqing, No. 69, Jia Ling Road, Bei Bei District, Chongqing 400700, People’s Republic of ChinaTel +86-15823409229Email wshang355@163.comIntroduction: Atherosclerosis is one of the major causes of cardiovascular diseases. Lipid uptake and accumulation in macrophages play a major role in atherosclerotic plaque formation from its initiation to advanced atheroma formation. The dipeptidyl peptidase-4 (DPP-4) inhibitor Linagliptin is commonly used to lower blood glucose in type 2 diabetes patients. Recent studies report that Linagliptin has cardiovascular protective and anti-inflammatory effects.Methods: THP-1 macrophage cells were treated with 100 nM PMA for 72 hour to induce foam cell formation. The differentiated cells were exposed to 100 μg/mL ox-LDL in the presence or absence of the DPP-4 inhibitor Linagliptin. The expression levels of DPP-4 and inflammatory cytokines were detected by RT-PCR, ELISA, and Western blot experiments. The cellular ROS level was measured by staining the cells with the fluorescent probe DCFH-DA. The separation of lipoprotein fractions was achieved by high-performance liquid chromatography (HPLC). The cells were labeled with fluorescent-labeled cholesterol to measure cholesterol efflux, and lipid droplets were revealed by Nile red staining.Results: The presence of Linagliptin significantly reduced ox-LDL-induced cytokine production (IL-1β and IL-6) and ROS production. Linagliptin ameliorated ox-LDL-induced lipid accumulation and impaired cholesterol efflux in macrophages. Mechanistically, this study showed that Linagliptin mitigated ox-LDL-induced expression of the scavenger receptors CD36 and LOX-1, but not SRA. Furthermore, Linagliptin increased the expression of the cholesterol transporter ABCG1, but not ABCA1.Conclusion: Linagliptin possesses a potent inhibitory effect on THP-1 macrophage-derived foam cell formation in response to ox-LDL. This effect could be mediated through a decrease in the expression of CD36 and LOX-1 on macrophages and an increase in the expression of the cholesterol transporter ABCG1. This study indicates that the DPP-4 inhibitor Linagliptin plays a critical role in preventing foam cell formation in vitro. However, future research using an atherosclerotic animal model is necessary to determine its effectiveness and to prove its potential implication in the prevention and treatment of atherosclerosis.Keywords: atherosclerosis, foam cells, Linagliptin, CD36, LOX-1, ABCG-1, ATP binding cassette transporter G1

Yaqin Wang,1,2,* Wenting Shang,2,* Meng Niu,1 Jie Tian,2,3 Ke Xu11Department of Interventional Radiology, The First Affiliated Hospital of China Medical University, Shenyang, People’s Republic of China; 2Chinese Academy of Sciences Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, People’s Republic of China; 3Institute of Medical Interdisciplinary Innovation, Beihang University, Beijing, 100080, People’s Republic of China*These authors contributed equally to this workAbstract: Hypoxia is a hallmark of malignant tumors and often correlates with increasing tumor aggressiveness and poor treatment outcomes. Therefore, early diagnosis and effective killing of hypoxic tumor cells are crucial for successful tumor control. There has been a surge of interdisciplinary research aimed at developing functional molecules and nanomaterials that can be used to noninvasively image and efficiently treat hypoxic tumors. These mainly include hypoxia-active nanoparticles, anti-hypoxia agents, and agents that target biomarkers of tumor hypoxia. Hypoxia-active nanoparticles have been intensively investigated and have demonstrated advanced effects on targeting tumor hypoxia. In this review, we present an overview of the reports published to date on hypoxia-activated prodrugs and their nanoparticle forms used in tumor-targeted therapy. Hypoxia-responsive nanoparticles are inactive during blood circulation and normal physiological conditions but are activated by hypoxia once they extravasate into the hypoxic tumor microenvironment. Their use can enhance the efficiency of tumor chemotherapy, radiotherapy, fluorescence and photoacoustic intensity, and other imaging and therapeutic strategies. By targeting the broad habitats of tumors, rather than tumor-specific receptors, this strategy has the potential to overcome the problem of tumor heterogeneity and could be used to design diagnostic and therapeutic nanoparticles for a broad range of solid tumors.Keywords: prodrug, tumor microenvironment, metal complex, bioreductive

Bo Gou, Hong Cao, Xinghua Cheng, Wei Shang, Mingqing Xu, Wei Qian Department of Orthopedics, Renmin Hospital, Hubei University of Medicine, Shiyan 442000, Hubei, China Objective: The objective of this study was to investigate the prognostic value of preoperative mean platelet volume to plateletcrit (MPV/PCT) ratio in patients with osteosarcoma. Materials and methods: The retrospective study included 188 consecutive osteosarcoma patients who experienced neoadjuvant chemotherapy and surgical resection of tumor. The relationships between MPV/PCT and clinicopathological characteristics were analyzed. The Kaplan–Meier analysis and Cox regression proportional hazard model were applied to assess the prognostic value of MPV/PCT ratio.Results: MPV/PCT ratio was found to be significantly associated with platelet count, platelet distribution width, and PCT (all P

Jia Li,1–3,* Wenting Shang,2,3,* Yong Li,1,* Sirui Fu,1–3 Jie Tian,2,3 Ligong Lu1 1Zhuhai Precision Medical Center, Zhuhai People’s Hospital, Jinan University, Zhuhai, China; 2CAS Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, Beijing, China; 3Beijing Key Laboratory of Molecular Imaging, Beijing, China *These authors contributed equally to this work Abstract: Hypoxia within solid tumors is often responsible for the failure of radiotherapy. The development of hypoxia-targeting nanomaterials – aimed at enhancing the effect of radiotherapy by electrical or heat effects and at modulating hypoxia in the tumor microenvironment – is a promising strategy to address this issue. We provide an overview of recently developed advanced materials that potentiate radiotherapy. First, we summarize novel materials for oxygen delivery or production to modify the tumor microenvironment, thus improving the effects of ionizing radiation. Second, we present new approaches for the design of high-Z element–based multifunctional nanoplatforms to enhance radiotherapy. Third, novel drug delivery systems for hypoxic regions and hypoxia-inducible factor-1–targeted therapies are discussed. Fourth, we establish the effectiveness of X-ray- or near-infrared–responsive nanoparticles for selectively triggering therapeutic effects under hypoxic conditions. Finally, this review emphasizes the importance of research in the field of nanomedicine focused on tumor hypoxia to improve clinical outcomes. Keywords: radiotherapy, hypoxia, nanomaterials, hypoxia-inducible factor 1

Andi Bai, Chao Wu, Xuan Liu, Huiling Lv, Xiaoyan Xu, Yue Cao, Wenjing Shang, Lili Hu, Ying Liu Department of Pharmaceutics, School of Pharmacy, Jinzhou Medical University, Jinzhou 121000, Liaoning, People’s Republic of China Background: Biopharmaceutics classification system class II drugs have low solubility, which limits their extent and speed of absorption after oral administration. Over the years, mesoporous materials have been widely used to increase the dissolution rate and oral relative bioavailability of poorly water-soluble drugs. Objectives: In order to improve the dissolution rate and increase oral relative bioavailability of the poorly water-soluble drugs, a tin oxide carrier (MSn) with a mesoporous structure was successfully synthesized. Methods: In this study, MSn was synthesized using mesoporous silica material (SBA-15) as the template. Fenofibrate (FNB) was adsorbed into the channels of MSn by an adsorption method. Characterizations of the pure FNB, MSn, physical mixture of the drug and MSn (PM; 1:1) and FNB-loaded MSn (FNB-MSn) samples were carried out by the scanning electron microscopy (SEM), transmission electron microscopy (TEM), N2 adsorption/desorption, powder X-ray diffractometer (PXRD), differential scanning calorimetry (DSC) and Fourier transform infrared (FT-IR) spectroscopy. Cytotoxicity assay (MTT) was used to evaluate the cytotoxicity of MSn. In vitro dissolution studies were performed to investigate the dissolution rate of FNB-MSn. In vivo pharmacokinetic studies were used to investigate the changes of plasma drug concentrations of FNB-MSn tablets and commercial FNB tablets in rabbits. Results: Detailed characterization showed that FNB in the channels of MSn was present in an amorphous state. The in vitro release tests demonstrated that MSn with a good biocompatibility could effectively enhance the dissolution rate of FNB. Pharmacokinetic results indicated that MSn significantly increased the oral relative bioavailability of FNB. Conclusion: MSn can be regarded as a promising carrier for an oral drug delivery system. Keywords: tin oxide, mesoporous material, fenofibrate, dissolution rate, oral relative bioavailability

Junyi Shen, Zhiming Zhao, Wei Shang, Chunli Liu, Beibei Zhang, Lingjie Zhao, Hui Cai Department of Integrated Traditional and Western Medicine, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China Abstract: Diabetic cerebral infarction is with poorer prognosis and high rates of mortality. Ginsenoside Rg1 (Rg1) has a wide variety of therapeutic values for central nervous system (CNS) diseases for the neuron protective effects. However, the blood–brain barrier (BBB) restricts Rg1 in reaching the CNS. In this study, we investigated the therapeutic effects of Rg1 nanoparticle (PHRO, fabricated with γ-PGA, L-PAE (H), Rg1, and OX26 antibody), targeting transferrin receptor, on the diabetes rats complicated with diabetic cerebral infarction in vitro and in vivo. Dynamic light scattering analysis shows the average particle size of PHRO was 79±18 nm and the polydispersity index =0.18. The transmission electron microscope images showed that all NPs were spherical in shape with diameters of 89±23 nm. PHRO released Rg1 with sustained release manner and could promote the migration of cerebrovascular endothelial cells and tube formation and even penetrated the BBB in vitro. PHRO could penetrate the BBB with high concentration in brain tissue to reduce the cerebral infarction volume and promote neuronal recovery in vivo. PHRO was promising to be a clinical treatment of diabetes mellitus with cerebral infarction. Keywords: poly-γ-glutamic acid, ginsenoside Rg1, OX26, blood–brain barrier

Abstract The incidence of patients diagnosed with either breast cancer (BC) or inflammatory bowel disease (IBD) is increasing each year. IBD has been shown to be strongly associated with the development of a variety of solid tumors, but the relationship with breast cancer is not yet definitive. We explored the causative relationship between IBD and BC using a Mendelian randomization (MR) strategy. MR-Egger regression, weighted median (WM), simple median (SM), maximum likelihood (ML), and inverse variance weighting (IVW) methods were among the analytical techniques used in this work. The examination of heterogeneity was conducted by the use of Cochran's Q test and Rucker's Q test. The sensitivity analysis in this study used the IVW and MR-Egger methodologies. The results of our investigation suggested that IBD had a beneficial impact on estrogen receptor-negative (ER-) breast cancer (odds ratio (OR) = 0.92, P = 0.02). The study did not find a significant association between IBD and the risk of developing overall breast cancer (OR = 0.99, P = 0.60), as well as estrogen receptor-positive (ER+) breast cancer (OR = 1.02, P = 0.60) specifically. In addition, our study findings indicated that there was a detrimental association between ER+ breast cancer and IBD as determined using reverse MR analysis (OR = 1.07, P = 0.04). Furthermore, this analysis failed to observe any significant association between overall breast cancer (OR = 1.07, P = 0.07) or ER- breast cancer (OR = 0.99, P = 0.89) and IBD. Our bidirectional MR study yielded a correlation between IBD and some specific hormone receptor status of BC.

Abstract Microbial communities exhibit intricate interactions underpinned by metabolic dependencies. To elucidate these dependencies, we present a workflow utilizing random matrix theory on metagenome-assembled genomes to construct co-occurrence and metabolic complementarity networks. We apply this approach to a temperature gradient hot spring, unraveling the interplay between thermal stress and metabolic cooperation. Our analysis reveals an increase in the frequency of metabolic interactions with rising temperatures. Amino acids, coenzyme A derivatives, and carbohydrates emerge as key exchange metabolites, forming the foundation for syntrophic dependencies, in which commensalistic interactions take a greater proportion than mutualistic ones. These metabolic exchanges are most prevalent between phylogenetically distant species, especially archaea-bacteria collaborations, as a crucial adaptation to harsh environments. Furthermore, we identify a significant positive correlation between basal metabolite exchange and genome size disparity, potentially signifying a means for streamlined genomes to leverage cooperation with metabolically richer partners. This phenomenon is also confirmed by another composting system which has a similar wide range of temperature fluctuations. Our workflow provides a feasible way to decipher the metabolic complementarity mechanisms underlying microbial interactions, and our findings suggested environmental stress regulates the cooperative strategies of thermophiles, while these dependencies have been potentially hardwired into their genomes during co-evolutions.

Abstract Background Microbial anaerobic metabolism is a key driver of biogeochemical cycles, influencing ecosystem function and health of both natural and engineered environments. However, the temporal dynamics of the intricate interactions between microorganisms and the organic metabolites are still poorly understood. Leveraging metagenomic and metabolomic approaches, we unveiled the principles governing microbial metabolism during a 96-day anaerobic bioreactor experiment. Results During the turnover and assembly of metabolites, homogeneous selection was predominant, peaking at 84.05% on day 12. Consistent dynamic coordination between microbes and metabolites was observed regarding their composition and assembly processes. Our findings suggested that microbes drove deterministic metabolite turnover, leading to consistent molecular conversions across parallel reactors. Moreover, due to the more favorable thermodynamics of N-containing organic biotransformations, microbes preferentially carried out sequential degradations from N-containing to S-containing compounds. Similarly, the metabolic strategy of C18 lipid-like molecules could switch from synthesis to degradation due to nutrient exhaustion and thermodynamical disadvantage. This indicated that community biotransformation thermodynamics emerged as a key regulator of both catabolic and synthetic metabolisms, shaping metabolic strategy shifts at the community level. Furthermore, the co-occurrence network of microbes-metabolites was structured around microbial metabolic functions centered on methanogenesis, with CH4 as a network hub, connecting with 62.15% of total nodes as 1st and 2nd neighbors. Microbes aggregate molecules with different molecular traits and are modularized depending on their metabolic abilities. They established increasingly positive relationships with high-molecular-weight molecules, facilitating resource acquisition and energy utilization. This metabolic complementarity and substance exchange further underscored the cooperative nature of microbial interactions. Conclusions All results revealed three key rules governing microbial anaerobic degradation. These rules indicate that microbes adapt to environmental conditions according to their community-level metabolic trade-offs and synergistic metabolic functions, further driving the deterministic dynamics of molecular composition. This research offers valuable insights for enhancing the prediction and regulation of microbial activities and carbon flow in anaerobic environments. Video Abstract

Cu pillar bump (CPB) technology as the representative advanced packaging technology possesses the characteristics of miniaturization and high density, thus playing an important role in the reliability of electronic devices. However, the brittle intermetallic compound (IMC) layer in the joints evidently affects the service performance and reliability of CPB joints. Thus, the influence of IMC layer thickness and microstructure needs to be carefully evaluated. In this study, the reliability of CPB joints with different IMC layer thickness under the condition of isothermal storage and room-temperature electromigration was tested, and the effect of initial IMC thickness of joints on the reliability was revealed. The full-IMC joints have the best isothermal storage reliability while the half-IMC joints perform the worst. Meanwhile, the thin-IMC joints own the best electromigration reliability but the full-IMC joints show the worst because that the initial voids in full-IMC joints accelerate the failure caused by electromigration.

Abstract Infectious diseases usually originate from a specific location within a city. Due to the heterogenous distribution of population and public facilities, and the structural heterogeneity of human mobility network embedded in space, infectious diseases break out at different locations would cause different transmission risk and control difficulty. This study aims to investigate the impact of initial outbreak locations on the risk of spatiotemporal transmission and reveal the driving force behind high-risk outbreak locations. First, we built a SLIR (susceptible-latent-infectious-removed)-based age-stratified meta-population model, integrating mobile phone location data, to simulate the spreading process of an infectious disease across fine-grained intra-urban regions (i.e., 649 communities of Shenzhen City, China). Based on the simulation model, we evaluated the transmission risk caused by different initial outbreak locations by proposing three indexes including the number of infected cases (CaseNum), the number of affected regions (RegionNum), and the spatial diffusion range (SpatialRange). Finally, we investigated the contribution of different influential factors to the transmission risk via machine learning models. Results indicate that different initial outbreak locations would cause similar CaseNum but different RegionNum and SpatialRange. To avoid the epidemic spread quickly to more regions, it is necessary to prevent epidemic breaking out in locations with high population-mobility flow density. While to avoid epidemic spread to larger spatial range, remote regions with long daily trip distance of residents need attention. Those findings can help understand the transmission risk and driving force of initial outbreak locations within cities and make precise prevention and control strategies in advance.

Abstract. Background:. Endometriosis (EM) is a complex benign gynecological disease, but it has malignant biological behavior and can invade any part of the body. Clinical manifestations include pelvic pain, dysmenorrhea, infertility, pelvic nodules, and masses. Our previous study successfully detected circulating endometrial cells (CECs) in the peripheral blood of patients with EM. The purpose of this study is to overcome the limitation of cell size in the previous microfluidic chip method, to further accurately capture CECs, understand the characteristics of these cells, and explore the relationship between CECs and the clinical course characteristics of patients with EM. Methods:. Human peripheral venous blood used to detect CECs and circulating vascular endothelial cells (CVECs) was taken from EM patients (n = 34) hospitalized in the Peking University People's Hospital. We used the subtraction enrichment and immunostaining fluorescence in situ hybridization (SE-iFISH) method to exclude the interference of red blood cells, white blood cells, and CVECs, so as to accurately capture the CECs in the peripheral blood of patients with EM. Then we clarified the size and ploidy number of chromosome 8 of CECs, and a second grouping of patients was performed based on clinical characteristics to determine the relationship between CECs and clinical course characteristics. Results:. The peripheral blood of 34 EM patients and 12 non-EM patients was evaluated by SE-iFISH. Overall, 34 eligible EM patients were enrolled. The results showed that the detection rates of CECs were 58.8% in EM patients and 16.7% in the control group. However, after classification according to clinical characteristics, more CECs could be detected in the peripheral blood of patients with rapidly progressive EM, with a detection rate of 94.4% (17/18). In total, 63.5% (40/63) of these cells were small cells with diameters below 5 μm, and 44.4% (28/63) were aneuploid cells. No significant association was found between the number of CECs and EM stage. Conclusion:. The number and characteristics of CECs are related to the clinical course characteristics of patients with EM, such as pain and changes in lesion size, and may be used as biomarkers for personalized treatment and management of EM in the future.

Abstract The senescence of nucleus pulposus (NP) cells (NPCs), which is induced by the anomalous accumulation of reactive oxygen species (ROS), is a major cause of intervertebral disc degeneration (IVDD). In this research, glutathione-doped carbon dots (GSH-CDs), which are novel carbon dot antioxidant nanozymes, were successfully constructed to remove large amounts of ROS for the maintenance of NP tissue at the physical redox level. After significantly scavenging endogenous ROS via exerting antioxidant activities, such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and total antioxidant capacity, GSH-CDs with good biocompatibility have been demonstrated to effectively improve mitochondrial dysfunction and rescue NPCs from senescence, catabolism, and inflammatory factors in vivo and in vitro. In vivo imaging data and histomorphological indicators, such as the disc height index (DHI) and Pfirrmann grade, demonstrated prominent improvements in the progression of IVDD after the topical application of GSH-CDs. In summary, this study investigated the GSH-CDs nanozyme, which possesses excellent potential to inhibit the senescence of NPCs with mitochondrial lesions induced by the excessive accumulation of ROS and improve the progression of IVDD, providing potential therapeutic options for clinical treatment. Graphical Abstract

Metal oxides are often used as electrode materials for supercapacitors because of their high capacity， low cost， suitability for commercialization， and environmental friendliness. In this study， Mn-MOF was used as a precursor and placed in ethanol for ion exchange and etching reaction with Co（NO3）2， followed by heat treatment in air， and finally highly crystalline CoMn2O4 two-dimensional nanorod structures were obtained on a carbon cloth（CC） substrate. SEM and XRD analyses of CoMn2O4/CC prepared with different Co（NO3）2 additions and Mn2O3/CC obtained by direct heat treatment were performed， and electrochemical properties were measured by cyclic voltammetry test， constant current charge/discharge test and AC impedance test. The results show that the parent structure of CoMn2O4/CC is relatively well preserved after 0.3 g Co（NO3）2 etching， forming a nano-hollow structure， and the vertical nanorod structures grow in situ on carbon cloth after heat treatment wrapping carbon fibers uniformly and densely， ensuring high mechanical stability and electrical conductivity due to the absence of any binder addition. The electrode material has an area specific capacitance of 809.8 mF·cm-2 at the current density of 1.2 mA·cm-2 and the capacitance retention is 79.1% after 5000 cycles at the current density of 5 mA·cm-2，showing potential application prospects.

Abstract Background Circular RNAs (circRNAs) have been recognized as significant regulators of pulmonary hypertension (PH); however, the differential expression and function of circRNAs in different vascular cells under hypoxia remain unknown. Here, we identified co‐differentially expressed circRNAs and determined their putative roles in the proliferation of pulmonary artery smooth muscle cells (PASMCs), pulmonary microvascular endothelial cells (PMECs), and pericytes (PCs) under hypoxia. Methods Whole transcriptome sequencing was performed to analyze the differential expression of circRNAs in three different vascular cell types. Bioinformatic analysis was used to predict their putative biological function. Quantitative real‐time polymerase chain reaction, Cell Counting Kit‐8, and EdU Cell Proliferation assays were carried out to determine the role of circular postmeiotic segregation 1 (circPMS1) as well as its potential sponge mechanism in PASMCs, PMECs, and PCs. Results PASMCs, PMECs, and PCs exhibited 16, 99, and 31 differentially expressed circRNAs under hypoxia, respectively. CircPMS1 was upregulated in PASMCs, PMECs, and PCs under hypoxia and enhanced the proliferation of vascular cells. CircPMS1 may upregulate DEP domain containing 1 (DEPDC1) and RNA polymerase II subunit D expression by targeting microRNA‐432‐5p (miR‐432‐5p) in PASMCs, upregulate MAX interactor 1 (MXI1) expression by targeting miR‐433‐3p in PMECs, and upregulate zinc finger AN1‐type containing 5 (ZFAND5) expression by targeting miR‐3613‐5p in PCs. Conclusions Our results suggest that circPMS1 promotes cell proliferation through the miR‐432‐5p/DEPDC1 or miR‐432‐5p/POL2D axis in PASMCs, through the miR‐433‐3p/MXI1 axis in PMECs, and through the miR‐3613‐5p/ZFAND5 axis in PCs, which provides putative targets for the early diagnosis and treatment of PH.

Background: To delve into the precise mechanisms by which 6-gingerol ameliorates lipid metabolism disorders in skeletal muscle. Methods: The level of triglycerides (TG) was used to evaluate lipid deposition. In skeletal muscle, transmission electron microscopy (TEM) was employed to observe mitochondrial morphology. Additionally, PCR was applied to detect mitochondrial biogenesis, and levels of malondialdehyde (MDA), catalase (CAT), glutathione, r-glutamyl cysteingl+glycine (GSH) and nicotinamide adenine dinucleotide (NADH) were measured to assess mitochondrial oxidative stress levels. In vivo, flow cytometry and immunofluorescence assays were conducted to quantify reactive oxygen species (ROS) and mitochondrial membrane potential (MMP). Furthermore, the Seahorse XF assays was utilized to assess mitochondrial respiratory capacity. Fluorescence confocal microscopy and molecular docking were applied to analyze the binding of 6-gingerol and adiponectin receptor 1 (AdipoR1). The expression of AdipoR1, AMPK, PGC-1α and SIRT1 were detected by Western Blot. Results: In vivo, 6-gingerol could reduce body weight in mice induced by a high-fat diet, enhance metabolic profiles in plasma, decrease lipid accumulation in skeletal muscle and liver, and elevate adiponectin levels. In skeletal muscle, it could restore mitochondrial morphology, boost mitochondrial copy number and biogenesis, and mitigate oxidative stress. In vitro, 6-gingerol may directly interact with AdipoR1 to upregulate the expression of downstream proteins p-AMPK, SIRT1, and PGC-1α, leading to a reduction in lipid deposition, a decrease in ROS production, an increase in mitochondrial membrane potential, and an enhancement of mitochondrial respiratory capacity in C2C12 myotubes. Conclusion: 6-Gingerol ameliorated lipid metabolism in skeletal muscle by regulating the AdipoR1/AMPK signaling pathway.

Abstract With the widespread adoption of metagenomic sequencing, new perspectives have emerged for studying microbial ecological networks, yielding metabolic evidence of interspecies interactions that traditional co‐occurrence networks cannot infer. This protocol introduces the integrated Network Analysis Pipeline 2.0 (iNAP 2.0), which features an innovative metabolic complementarity network for microbial studies from metagenomics sequencing data. iNAP 2.0 sets up a four‐module process for metabolic interaction analysis, namely: (I) Prepare genome‐scale metabolic models; (II) Infer pairwise interactions of genome‐scale metabolic models; (III) Construct metabolic interaction networks; and (IV) Analyze metabolic interaction networks. Starting from metagenome‐assembled or complete genomes, iNAP 2.0 offers a variety of methods to quantify the potential and trends of metabolic complementarity between models, including the PhyloMint pipeline based on phylogenetic distance‐adjusted metabolic complementarity, the SMETANA (species metabolic interaction analysis) approach based on cross‐feeding substrate exchange prediction, and metabolic distance calculation based on parsimonious flux balance analysis (pFBA). Notably, iNAP 2.0 integrates the random matrix theory (RMT) approach to find the suitable threshold for metabolic interaction network construction. Finally, the metabolic interaction networks can proceed to analysis using topological feature analysis such as hub node determination. In addition, a key feature of iNAP 2.0 is the identification of potentially transferable metabolites between species, presented as intermediate nodes that connect microbial nodes in the metabolic complementarity network. To illustrate these new features, we use a set of metagenome‐assembled genomes as an example to comprehensively document the usage of the tools. iNAP 2.0 is available at https://inap.denglab.org.cn for all users to register and use for free.

Abstract The influence of entrainment, a key process characterized by the entrainment rate in cumulus parameterization, on aerosol‐cloud interactions has been widely recognized. However, despite qualitative links established between entrainment and aerosol loading, a quantitative relationship based on observational evidence remains elusive. This study utilizes aircraft observations of cumulus clouds during two field campaigns to determine the quantitative relationship between entrainment rate and aerosol loading. In both campaigns, the entrainment rate is negatively correlated with aerosol loading. It is speculated that increased aerosol loading enhances cloud edge droplet evaporation, which leads to increased buoyancy and vertical velocity within the cloud, thereby reducing the entrainment rate. Further analysis shows that the response of entrainment rate to aerosol perturbations is more significant in smaller cumulus clouds with weak buoyancy and less pronounced under opposite conditions. These findings shed new light on improving the description of aerosol‐cloud interactions in cumulus parameterizations.

Abstract Stretchable electrodes based on liquid metals (LM) are widely used in human‐machine interfacing, wearable bioelectronics, and other emerging technologies. However, realizing the high‐precision patterning and mechanical stability remains challenging due to the poor wettability of LM. Herein, a method is reported to fabricate LM‐based multilayer solid–liquid electrodes (m‐SLE) utilizing electrohydrodynamic (EHD) printed confinement template. In these electrodes, LM self‐assembled onto these high‐resolution templates, assisted by selective wetting on the electrodeposited Cu layer. This study shows that a m‐SLE composed of PDMS/Ag/Cu/EGaIn exhibits line width of ≈20 µm, stretchability of ≈100%, mechanical stability ≈10 000 times (stretch/relaxation cycles), and recyclability. The multi‐layer structure of m‐SLE enables the adjustability of strain sensing, in which the strain‐sensitive Ag part can be used for non‐distributed detection in human health monitoring and the strain‐insensitive EGaIn part can be used as interconnects. In addition, this study demonstrates that near field communication (NFC) devices and multilayer displays integrated by m‐SLEs exhibit stable wireless signal transmission capability and stretchability, suggesting its applicability in creating highly‐integrated, large‐scale commercial, and recyclable wearable electronics.