Global trends and partial forecast of adverse effects of medical treatment from 1990 to 2019: an epidemiological analysis based on the global burden of disease study 2019.

BACKGROUND: The possibility of adverse effects of medical treatment (AEMT) is increasing worldwide, but little is known about AEMT in China. This study analyzed the health burden of AEMT in China in recent years through the Global Burden of Disease Study (GBD) 2019 and compared it with the worldwide average level and those in different sociodemographic index (SDI) regions. METHODS: We calculated the age-standardized rate (ASR) of deaths, disability-adjusted life years (DALYs), years of life lost (YLLs), years lived with disability (YLDs), incidence and prevalence attributed to AEMT in China, worldwide and countries with different sociodemographic indices during 1990-2019 using the latest data and methods from the GBD 2019. RESULTS: From 1990 to 2019, the global age-standardized death rate (ASDR), DALYs, and YLLs for AEMT showed a significant downward trend and were negatively associated with the SDI. By 2040, the ASDR is expected to reach approximately 1.58 (95% UI: 1.33-1.80). From 1990 to 2019, there was no significant change in the global incidence of AEMT. The occurrence of AEMT was related to sex, and the incidence of AEMT was greater among females. In addition, the incidence of AEMT-related injuries and burdens, such as ASR of DALYs, ASR of YLLs and ASR of YLDs, was greater among women than among men. Very old and very young people were more likely to be exposed to AEMT. CONCLUSIONS: From 1990 to 2019, progress was made worldwide in reducing the harm caused by AEMT. However, the incidence and prevalence of AEMT did not change significantly overall during this period. Therefore, the health sector should pay more attention to AEMT and take effective measures to reduce AEMT.

Tryptophan metabolite norharman secreted by cultivated Lactobacillus attenuates acute pancreatitis as an antagonist of histone deacetylases.

BACKGROUND: Patients with acute pancreatitis (AP) exhibit specific phenotypes of gut microbiota associated with severity. Gut microbiota and host interact primarily through metabolites; regrettably, little is known about their roles in AP biological networks. This study examines how enterobacterial metabolites modulate the innate immune system in AP aggravation. METHODS: In AP, alterations in gut microbiota were detected via microbiomics, and the Lactobacillus metabolites of tryptophan were identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). By culturing Lactobacillus with tryptophan, differential metabolites were detected by LC-MS/MS. Lipopolysaccharide (LPS)-stimulated RAW264.7 cells and mice with cerulein plus LPS-induced AP were used to evaluate the biological effect of norharman on M1 macrophages activation in AP development. Further, RNA sequencing and lipid metabolomics were used for screening the therapeutic targets and pathways of norharman. Confocal microscopy assay was used to detect the structure of lipid rafts. Molecular docking was applied to predict the interaction between norharman and HDACs. Luciferase reporter assays and chromatin immunoprecipitation (ChIP) were used to explore the direct mechanism of norharman promoting Rftn1 expression. In addition, myeloid-specific Rftn1 knockout mice were used to verify the role of Rftn1 and the reversed effect of norharman. RESULTS: AP induced the dysfunction of gut microbiota and their metabolites, resulting in the suppression of Lactobacillus-mediated tryptophan metabolism pathway. The Lactobacillus metabolites of tryptophan, norharman, inhibited the release of inflammatory factor in vitro and in vivo, as a result of its optimal inhibitory action on M1 macrophages. Moreover, norharman blocked multiple inflammatory responses in AP exacerbation due to its ability to maintain the integrity of lipid rafts and restore the dysfunction of lipid metabolism. The mechanism of norharman's activity involved inhibiting the enzyme activity of histone deacetylase (HDACs) to increase histone H3 at lysine 9/14 (H3K9/14) acetylation, which increased the transcription level of Rftn1 (Raftlin 1) to inhibit M1 macrophages' activation. CONCLUSIONS: The enterobacterial metabolite norharman can decrease HDACs activity to increase H3K9/14 acetylation of Rftn1, which inhibits M1 macrophage activation and restores the balance of lipid metabolism to relieve multiple inflammatory responses. Therefore, norharman may be a promising prodrug to block AP aggravation.

ROS in hepatocellular carcinoma: What we know.

Hepatocellular carcinoma (HCC), which is a primary liver cancer subtype, has a poor prognosis due to its high degree of malignancy. The lack of early diagnosis makes systemic therapy the only hope for HCC patients with advanced disease; however, resistance to drugs is a major obstacle. In recent years, targeted molecular therapy has gained popularity as a potential treatment for HCC. An increase in reactive oxygen species (ROS), which are cancer markers and a potential target for HCC therapy, can both promote and inhibit the disease. At present, many studies have examined targeted regulation of ROS in the treatment of HCC. Here, we reviewed the latest drugs that are still in the experimental stage, including nanocarrier drugs, exosome drugs, antibody drugs, aptamer drugs and polysaccharide drugs, to provide new hope for the clinical treatment of HCC patients.

Naringin against doxorubicin-induced hepatotoxicity in mice through reducing oxidative stress, inflammation, and apoptosis via the up-regulation of SIRT1.

Clinical application of doxorubicin is limited because of its potential side effects. The present study examined whether naringin had protective actions on doxorubicin-induced liver injury. Male BALB/c mice and alpha mouse liver 12 (AML-12) cells were used in this paper. The results showed that AML-12 cells treated with naringin significantly reduced cell injury, reactive oxygen species release and apoptosis level; Moreover, naringin notably alleviated liver injury by decreasing aspartate transaminase, alanine transaminase and malondialdehyde, and increasing superoxide dismutase, glutathione and catalase levels. Mechanism researches indicated that naringin increased the expression levels of sirtuin 1 (SIRT1), and inhibited the downstream inflammatory, apoptotic and oxidative stress signaling pathways. Further validation was obtained by knocking down SIRT1 in vitro, which proved the effects of naringin on doxorubicin-induced liver injury. Therefore, naringin is a valuable lead compound for preventing doxorubicin-induced liver damage by reducing oxidative stress, inflammation, and apoptosis via up-regulation of SIRT1.

Research Methods and New Advances in Drug-Drug Interactions Mediated by Renal Transporters.

The kidney is critical in the human body's excretion of drugs and their metabolites. Renal transporters participate in actively secreting substances from the proximal tubular cells and reabsorbing them in the distal renal tubules. They can affect the clearance rates (CLr) of drugs and their metabolites, eventually influence the clinical efficiency and side effects of drugs, and may produce drug-drug interactions (DDIs) of clinical significance. Renal transporters and renal transporter-mediated DDIs have also been studied by many researchers. In this article, the main types of in vitro research models used for the study of renal transporter-mediated DDIs are membrane-based assays, cell-based assays, and the renal slice uptake model. In vivo research models include animal experiments, gene knockout animal models, positron emission tomography (PET) technology, and studies on human beings. In addition, in vitro-in vivo extrapolation (IVIVE), ex vivo kidney perfusion (EVKP) models, and, more recently, biomarker methods and in silico models are included. This article reviews the traditional research methods of renal transporter-mediated DDIs, updates the recent progress in the development of the methods, and then classifies and summarizes the advantages and disadvantages of each method. Through the sorting work conducted in this paper, it will be convenient for researchers at different learning stages to choose the best method for their own research based on their own subject's situation when they are going to study DDIs mediated by renal transporters.

Machine Learning Techniques Applied to the Study of Drug Transporters.

With the advancement of computer technology, machine learning-based artificial intelligence technology has been increasingly integrated and applied in the fields of medicine, biology, and pharmacy, thereby facilitating their development. Transporters have important roles in influencing drug resistance, drug-drug interactions, and tissue-specific drug targeting. The investigation of drug transporter substrates and inhibitors is a crucial aspect of pharmaceutical development. However, long duration and high expenses pose significant challenges in the investigation of drug transporters. In this review, we discuss the present situation and challenges encountered in applying machine learning techniques to investigate drug transporters. The transporters involved include ABC transporters (P-gp, BCRP, MRPs, and BSEP) and SLC transporters (OAT, OATP, OCT, MATE1,2-K, and NET). The aim is to offer a point of reference for and assistance with the progression of drug transporter research, as well as the advancement of more efficient computer technology. Machine learning methods are valuable and attractive for helping with the study of drug transporter substrates and inhibitors, but continuous efforts are still needed to develop more accurate and reliable predictive models and to apply them in the screening process of drug development to improve efficiency and success rates.

Macrophages: A rising star in immunotherapy for chronic pancreatitis.

Chronic pancreatitis (CP) is a chronic wasting disease with an increasing incidence. As an important factor in the pathogenesis of CP, macrophages play a considerable role in the most typical pathological agents throughout the early to late stages of CP. Macrophage-associated cytokines are biomarkers that bring new possibilities for the early diagnosis of CP and differential diagnosis with pancreatic cancer and pancreatic diseases. In addition, in established CP, macrophage interactions with T lymphocytes leads to immune dysregulation, and macrophage secretion of proinflammatory cytokines is considered a potent driver of acinar-to-ductal metaplasia (ADM). In advanced CP, macrophages interact with pancreatic stellate cells (PSCs) and islet cells in an autocrine or paracrine manner to promote the development of pancreatic fibrosis and islet dysfunction. Here, we review the crosstalk of macrophages with pancreatic acinar cells, PSCs, other immune cells and islet cells at different stages of CP progression, as well as current CP immunotherapies targeting macrophages, which will help explain the decisive role of macrophages in CP and their potential as targets of CP immunotherapy. Furthermore, macrophage-targeted immunotherapy can be advanced, not only in terms of physiology and pathology but also in terms of further optimization of dose, forms and delivery. All these efforts are beneficial to enhancing the targeting of macrophages in the treatment of CP.

Research Progress on the Positive and Negative Regulatory Effects of Rhein on the Kidney: A Review of Its Molecular Targets.

Currently, both acute kidney injury (AKI) and chronic kidney disease (CKD) are considered to be the leading public health problems with gradually increasing incidence rates around the world. Rhein is a monomeric component of anthraquinone isolated from rhubarb, a traditional Chinese medicine. It has anti-inflammation, anti-oxidation, anti-apoptosis, anti-bacterial and other pharmacological activities, as well as a renal protective effects. Rhein exerts its nephroprotective effects mainly through decreasing hypoglycemic and hypolipidemic, playing anti-inflammatory, antioxidant and anti-fibrotic effects and regulating drug-transporters. However, the latest studies show that rhein also has potential kidney toxicity in case of large dosages and long use times. The present review highlights rhein's molecular targets and its different effects on the kidney based on the available literature and clarifies that rhein regulates the function of the kidney in a positive and negative way. It will be helpful to conduct further studies on how to make full use of rhein in the kidney and to avoid kidney damage so as to make it an effective kidney protection drug.

Pancreatitis initiated pancreatic ductal adenocarcinoma: Pathophysiology explaining clinical evidence.

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant lethal disease due to its asymptomatic at its early lesion of the disease and drug resistance. Target therapy associated with molecular pathways so far seems not to produce reasonable outcomes. Understanding of the molecular mechanisms underlying inflammation-initiated tumorigenesis may be helpful for development of an effective therapy of the disease. A line of studies showed that pancreatic tumorigenesis was resulted from pancreatitis, which was caused synergistically by various pancreatic cells. This review focuses on those players and their possible clinic implications, such as exocrine acinar cells, ductal cells, and various stromal cells, including pancreatic stellate cells (PSCs), macrophages, lymphocytes, neutrophils, mast cells, adipocytes and endothelial cells, working together with each other in an inflammation-mediated microenvironment governed by a myriad of cellular signaling networks towards PDAC.

Progress on the role of reactive oxygen species-mediated tumor microenvironment in pancreatic cancer.

Pancreatic cancer (PC) is a devastating malignant tumor with high incidence and mortality rate worldwide. Meanwhile, the surgical approaches and drugs of this disease remain challenging. In recent years, reactive oxygen species (ROSs) study has become a hotspot in the field of PC research. ROSs may regulate tumor mic roenvironment (TME), cancer stem cells (CSCs) renewal and epithelial-mesenchymal transition (EMT), which result in drug-resistance and recurrence of the PC. Currently, TME that includes immune infiltrates, fibroblasts, vascular vessels and extracellular matrix has become a hotspot in the cancer research. Meanwhile, numerous researches have shown that ROSs-mediated TME plays a central role in the occurrence and development of PC. Targeting ROSs may be promising therapeutic treatments for the PC patients. Therefore, the purposes of the review were manifold: (1) to summarize the regulations of ROSs in tumorigenesis and drug-resistance of PC; (2) to investigate the modulation of ROSs in signaling cascades in PC; (3) to study the effects of ROSs in stromal cells in PC; (4) to generalize the potent therapies targeting ROSs in PC. Overall, this review summarized the current status of ROSs in PC research and suggested some potential anti-PC drugs that may target ROSs.

Correction: Zhao, X.W., et al. Dioscin Induces the Apoptosis of Human Cervical Carcinoma HeLa and SiHa Cells Through ROS-mediated DNA Damage, Cell Cycle Arrest and Mitochondrial Signaling Pathways. Molecules 2016, 21, 730.

During the course of a review of our publications, an error in the title paper [...].

Correction: Zhao, L.S., et al. Protective Effect of the Total Flavonoids from Rosa laevigata Michx Fruit on Renal Ischemia-Reperfusion Injury through Suppression of Oxidative Stress and Inflammation. Molecules 2016, 21, 952.

During the course of a review of our publications, an error in the title paper [...].

Dioscin: A diverse acting natural compound with therapeutic potential in metabolic diseases, cancer, inflammation and infections.

Currently, the numbers of patients with cancer, fibrosis, diabetes, chronic kidney disease, stroke and osteoporosis are increasing fast and fast. It's critical necessary to discovery lead compounds for new drug development. Dioscin, one active compound in some medicinal plants, has anti-inflammation, immunoregulation, hypolipidemic, anti-viral, anti-fungal and anti-allergic effects. In recent years, dioscin has reached more and more attention with its potent effects to treat liver, kidney, brain, stomach and intestine damages, and metabolic diseases including diabetes, osteoporosis, obesity, hyperuricemia as well as its anti-cancer activities through adjusting multiple targets and multiple signals. Therefore, dioscin is a promising multi-target candidate to treat various diseases. This review paper summarized the progress on pharmacological activities and mechanisms of dioscin, which may provide useful data for development and exploration of this natural product in the further.

Dioscin alleviates non-alcoholic fatty liver disease through adjusting lipid metabolism via SIRT1/AMPK signaling pathway.

Dioscin, one natural product, has active effect against non-alcoholic fatty liver disease (NAFLD) in our previous work. However, the pharmacological data are insufficient and the mechanisms have not been reported. Thus, this study aims to comprehensively investigate the effects and molecular mechanisms of dioscin against NAFLD. The primary cultured hepatocytes, AML-12 and HepG-2 cells were treated with palmic acid (PA) after dioscin treatment. The mice and rats were induced by high fat diet to establish the in vivo models of NAFLD. Dioscin obviously alleviated liver lipid accumulation symptoms and improved the levels of serum and hepatic biochemical parameters in vitro and in vivo. Further investigations revealed that dioscin significantly attenuated lipid metabolism via adjusting SIRT1/AMPK signal pathway to regulate the expression levels of SREBP-1c, CPT, FAS, SCD, FoxO1 and ATGL. In addition, suppression of SIRT1 by Nicotinamide or abrogation of AMPK by Compound C eliminated the inhibitory effects of dioscin on lipid metabolism. Therefore, our findings further demonstrated that dioscin markedly prevented NAFLD through adjusting lipid metabolism via SIRT1/AMPK signal pathway, which should be developed as a new candidate for NAFLD.

Protective effect of dioscin against intestinal ischemia/reperfusion injury via adjusting miR-351-5p-mediated oxidative stress.

Oxidative stress plays important roles in intestinal ischemia-reperfusion (II/R) injury, and exploration of effective lead compounds against II/R injury via regulating oxidative stress is necessary. In this study, the effects and possible mechanisms of dioscin against hypoxia-reoxygenation (H/R) injury in IEC-6 cells and II/R injury in mice were investigated. The results showed that dioscin markedly increased cell viability, and reduced ROS level caused by H/R injury in IEC-6 cells. in vivo, dioscin significantly reduced the levels of MDA, MPO and chiu' score, increased SOD level, and improved pathological changes caused by II/R injury in mice. Mechanism investigation showed that dioscin markedly up-regulated the expression levels of Sirt6 by decreasing miR-351-5p levels, decreased the expression levels of p-FoxO3α via activating AMPK, and increased the expression levels of MnSOD and CAT. In addition, miR-351-5p mimic in IEC-6 cells and agomir in mice increased ROS levels and aggravated II/R injury. MiR-351-5p inhibitor in IEC-6 cells and antagomir in mice alleviated these actions by adjusting Sirt6 signal pathway. MiR-351-5p interference experiment further confirmed that dioscin increased Sirt6 expression level by down- regulating miR-351-5p level to inhibit oxidative stress and reduce II/R injury. Furthermore, we also demonstrated that dioscin inhibited the expression level of miR-351-5p via reducing TRBP expression level during the generation of miR-351-5p mature body. Dioscin showed protective effect against II/R injury via adjusting miR- 351-5/Sirt6 signal to reduce oxidative stress, which should be considered as one potent candidate to treat II/R injury. In addition, miR-351-5/Sirt6 could be one effective drug target against II/R injury.

Dioscin alleviates BDL- and DMN-induced hepatic fibrosis via Sirt1/Nrf2-mediated inhibition of p38 MAPK pathway.

Oxidative stress is involved in hepatic stellate cells (HSCs) activation and extracellular matrix overproduction. We previously reported the promising effects of dioscin against CCl4-induced liver fibrosis, but its effects and mechanisms on BDL- and DMN-induced liver fibrosis remain unknown. The results in the present study indicated that dioscin significantly inhibited HSCs activation and attenuated hepatic fibrosis in rats. Furthermore, dioscin markedly up-regulated the levels of sirtuin 1 (Sirt1), HO-1, GST, GCLC and GCLM via increasing the nuclear translocation of nuclear erythroid factor 2-related factor 2 (Nrf2), which in turn inhibited mitogen-activated protein kinase 14 (p38 MAPK) phosphorylation and reduced the levels of COL1A1, COL3A1, α-SMA and fibronectin. These results were further validated by knockdown of Sirt1 and Nrf2 using siRNAs silencing, and abrogation of p38 MAPK using SB-203580 (a p38 MAPK inhibitor) in HSC-T6 and LX-2 cells. Collectively, our findings confirmed the potent effects of dioscin against liver fibrosis and also provided novel insights into the mechanisms of this compound as a candidate for the prevention of liver fibrosis in the future.

Dioscin reduces ovariectomy-induced bone loss by enhancing osteoblastogenesis and inhibiting osteoclastogenesis.

Our previous studies showed that dioscin can promote osteoblasts proliferation and differentiation in vitro, but its anti-osteoporosis effect in vivo and the underlying mechanisms remain unclear. In the present work, the results showed that dioscin significantly increased the viability of MC3T3-E1 cells, ALP level and alizarin red S staining area, markedly decreased the numbers of RANKL-induced TRAP-positive multinucleated cells and bone resorption pits formation, enhanced the levels of some osteogenic markers including COL1A2, ALP and OC, which suggested that dioscin clearly promoted osteoblasts proliferation and suppressed osteoclasts formation. In vivo experiments demonstrated that dioscin obviously reduced OVX-induced body weight increase, and improved the biochemical indexes including ALP, StrACP, OC, DPD/Cr, HOP/Cr, BMD, biomechanics and microarchitecture. Moreover, H&E, TB, TRAP staining, and fluorescent double labeling tests indicated that dioscin enhanced osteoblastogenesis and inhibited osteoclastogenesis. Further researches demonstrated that dioscin promoted osteoblastogenesis through up-regulating OPG/RANKL ratio, and inhibited osteoclastogenesis through down-regulating the levels of RANKL induced TRAF6 and the downstream signal molecules including MAPKs, Akt, NF-κB, AP-1, cathepsin K and NFATc1. In addition, dioscin also inhibited TLR4/MyD88 pathway to decrease the levels of TRAF6 and the related proteins. These findings provide new insights to elucidate the effects of dioscin against OVX-induced bone loss, which should be developed as a potential candidate for treating postmenopausal osteoporosis in the future.

Dioscin alleviates lipopolysaccharide-induced inflammatory kidney injury via the microRNA let-7i/TLR4/MyD88 signaling pathway.

We previously reported the potent effect of dioscin against renal ischemia/reperfusion injury, but little is known about the role of dioscin in lipopolysaccharide (LPS)-induced inflammatory kidney injury. The present work aimed to investigate the effects and potential mechanisms of dioscin in preventing LPS-induced kidney injury. In vivo injury was induced in rats and mice with an intraperitoneal injection of LPS (10mg/kg), and in vitro studies were performed on NRK-52E and HK-2 cells challenged with LPS (0.5µg/ml). Our results indicated that dioscin significantly protected against renal damage by decreasing blood urea nitrogen and creatinine levels and reversing oxidative stress. Mechanistic studies demonstrated that dioscin markedly up- regulated the level of the microRNA let-7i, resulting in significant inhibition of TLR4 expression. Dioscin significantly down-regulated the levels of MyD88, NOX1 and cleaved caspase-8/3; inhibited the nuclear translocation of NF-κB; inhibited PI3K and Akt phosphorylation; increased the levels of SOD2; and decreased the mRNA levels of IL-1ß, IL-6, MIP-1α, Fas and FasL. In vitro, transfection of microRNA let-7i inhibitor and TLR4 DNA were applied, and the results further confirmed the nephroprotective effect of dioscin in suppressing TLR4/MyD88 signaling and subsequently inhibiting inflammation, oxidative stress and apoptosis. Furthermore, the abrogation of cellular MyD88 expression by ST2825 eliminated the inhibitory effect of dioscin on the levels of nuclear NF-κB, cleaved caspase-3, SOD2 and ROS. These data indicated that dioscin exerted a nephroprotective effect against LPS-induced inflammatory renal injury by adjusting the microRNA let-7i/TLR4/MyD88 signaling pathway, which provided novel insights into the mechanisms of this therapeutic candidate for the treatment of inflammatory kidney injury.