A Multifunctional Liposome for Synergistic Chemotherapy with Ferroptosis Activation of Triple-Negative Breast Cancer.

There is an urgent need to develop efficient treatments for highly invasive triple-negative breast cancer (TNBC) with a high rate of postoperative. Baicalin (BA) has shown inhibitory effects on several tumor cells and could activate ferroptosis in some tumor cells by producing reactive oxygen species (ROS). For overcoming the shortcomings of BA in clinical applications and enhancing the effect of ferroptosis in TNBC, herein, a multifunctional liposome (BA-Fe(III) coordination-polymer-loaded liposome, BA-Fe(III) Lipo) was developed for synergistic chemotherapy of TNBC with ferroptosis activation. Fe(III) released from BA-Fe(III) Lipo could be efficiently reduced to Fe(II) in the presence of high glutathione in tumor microenvironment, which in turn catalyzed the oxidation of unsaturated fats through lipid peroxidation for more ROS production. In addition, BA-Fe(III) Lipo activated tumor cell ferroptosis by down-regulating the enzymatic activity of ferritin heavy chain 1 protein and glutathione peroxidase. This study provided a novel therapeutic strategy for the treatment of TNBC by ingeniously combining chemotherapy with the activation of ferroptosis, which presented potential clinical applications.

Cost-effectiveness of sacituzumab govitecan versus single-agent chemotherapy for metastatic triple-negative breast cancer: a trial-based analysis.

BACKGROUND: Sacituzumab govitecan (SG) has recently been approved in China for the post-line treatment of metastatic triple-negative breast cancer (mTNBC). SG substantially improves progression-free survival and overall survival compared with single-agent chemotherapy for pretreated mTNBC. However, in view of the high price of SG, it is necessary to consider its value in terms of costs and outcomes. This study aimed to estimate the cost-effectiveness of SG versus single-agent treatment of physician's choice (TPC) in the post-line setting for patients with mTNBC from a Chinese healthcare system perspective. METHODS: The cohort characteristics were sourced from the ASCENT randomized clinical trial, which enrolled 468 heavily pretreated patients with mTNBC between November 2017 and September 2019. A partitioned survival model was constructed to assess the long-term costs and effectiveness of SG versus TPC in the post-line treatment of mTNBC. Quality-adjusted life-months (QALMs) and total costs in 2022 US dollars were used to derive incremental cost effectiveness ratio (ICER). QALMs and costs were discounted at 5% annually. The willingness-to-pay (WTP) threshold was defined as $3188 per QALM, three times China's average monthly per capita gross domestic product in 2022. One-way sensitivity analysis, probabilistic sensitivity analysis, and scenario analyses were performed to estimate the robustness of the results. RESULTS: Treatment with SG yielded an incremental 5.17 QALMs at a cost of $44,792 per QALM, much above the WTP threshold of $3188/QALM in China. One-way sensitivity analysis showed that SG price was a crucial factor in the ICER. Probabilistic sensitivity analysis revealed that the cost-effective acceptability of SG was 0% in the current setting. Scenario analyses indicated that the result was robust in all subgroups in ASCENT or under different time horizons. Furthermore, SG must reduce the price to enter the Chinese mainland market. When the monthly cost of SG reduce to $2298, SG has about 50% probability to be a preferred choice than TPC. CONCLUSIONS: SG was estimated to be not cost-effective compared with TPC for post-line treatment for mTNBC in China by the current price in HK under a WTP threshold of $3188 per QALM. A drastic price reduction is necessary to improve its cost-effectiveness.

The role of the CD39-CD73-adenosine pathway in liver disease.

Extracellular adenosine triphosphate (ATP) is a danger signal released by dying and damaged cells, and it functions as an immunostimulatory signal that promotes inflammation. The ectonucleotidases CD39/ectonucleoside triphosphate diphosphohydrolase-1 and CD73/ecto-5'-nucleotidase are cell-surface enzymes that breakdown extracellular ATP into adenosine. This drives a shift from an ATP-driven proinflammatory environment to an anti-inflammatory milieu induced by adenosine. The CD39-CD73-adenosine pathway changes dynamically with the pathophysiological context in which it is embedded. Accumulating evidence suggests that CD39 and CD73 play important roles in liver disease as critical components of the extracellular adenosinergic pathway. Recent studies have shown that the modification of the CD39-CD73-adenosine pathway alters the liver's response to injury. Moreover, adenosine exerts different effects on the pathophysiology of the liver through different receptors. In this review, we aim to describe the role of the CD39-CD73-adenosine pathway and adenosine receptors in liver disease, highlighting potential therapeutic targets in this pathway, which will facilitate the development of therapeutic strategies for the treatment of liver disease.

Inhibition of Endoplasmic Reticulum Stress Attenuated Ethanol-Induced Exosomal miR-122 and Acute Liver Injury in Mice.

AIMS: In acute alcoholic liver injury, alcohol can directly or indirectly induce endoplasmic reticulum stress (ERS) to participate in liver injury, and it is found that the expression of serum exosomal miR-122 is significantly affected. Therefore, the present study investigated the effects of endoplasmic reticulum stress inhibition on the expression of serum exosomal miR-122 and acute liver injury. METHODS: The acute alcoholic liver injury models were established by the intragastric administration of ethanol (5 g/kg) in ICR mice. Intervention group received 4-phenylbutyric acid (PBA, endoplasmic reticulum stress inhibitor; 75 mg/kg and 150 mg/kg, intraperitoneal) 12 and 24 hours before intragastric administration. Mice treated with saline were used as controls. RESULTS: The ethanol treated mice exhibited significantly elevated hepatosomatic index (liver weight/body weight) and alanine aminotransferase (ALT), compared with those in the control group (P < 0.05). The ERS inhibitor 4-phenylbutyric acid protected against ethanol induced acute liver injury and hepatocyte necrosis, and PBA 150 mg/kg significantly attenuated ethanol induced hepatic ER stress-related proteins (GRP78, pIRE1α and pIF2α) (P < 0.05). Moreover, PBA 150 mg/kg markedly alleviated ethanol induced elevation of hepatic and serum exosomal miR-122 and pri-miR-122 (P < 0.05). CONCLUSIONS: These findings suggest that ER stress inhibitor PBA attenuated ethanol induced acute liver injury and serum exosomal miR-122, and provides a potential therapy strategy for acute alcoholic liver injury.

Macrophage polarization and function: new prospects for fibrotic disease.

Fibrosis is commonly regarded as a pathological and dynamic process with the hallmarks of chronic inflammation and wound healing. Emerging evidence indicates that heterogeneous monocyte-macrophage lineage cells are indispensable for mounting either pro-fibrotic or anti-fibrotic responses in different stages during fibrotic pathogenesis. This review highlights the evolving roles of macrophage polarization and functions linked to fibrosis in multiple organs. In the future, identifying the molecular and cellular factors that influence the macrophage phenotypic balance may provide novel therapeutic approaches for fibrotic diseases.

[Neuroprotective effect of Nogo-66 receptor silencing in preterm rats with brain injury caused by intrauterine infection].

OBJECTIVE: To investigate the effect of Nogo-66 receptor (NgR) silencing with specific small interfering RNA (siRNA) on brain injury repair in preterm rats with brain injury caused by intrauterine infection and related mechanism of action. METHODS: The pregnant Sprague-Dawley rats (with a gestational age of 15 days) were selected, and premature delivery was induced by RU486 or lipopolysaccharide (LPS). The preterm rats delivered by those treated with RU486 were selected as the control group. The preterm rats with brain injury caused by intrauterine infection induced by LPS were divided into model, empty vector, and NgR-siRNA groups, with 36 rats in each group. The rats in the control and model groups were given routine feeding only, and those in the empty vector and NgR-siRNA groups were given an injection of lentiviral empty vector or NgR-siRNA lentivirus via the lateral ventricle on postnatal day 1 (P1) and then fed routinely. On P3, P7, and P14, 8 rats in each group were randomly selected and sacrificed to harvest the brain tissue. RT-PCR was used to measure the mRNA expression of NgR. Western blot was used to to measure the protein expression of active RhoA. The immunofluorescence histochemistry was used to determine the degree of activation of microglial cells and the morphology of oligodendrocyte precursor cells (OPCs). Hematoxylin and eosin staining was used to observe the pathological changes in brain tissue. The behavioral score was evaluated on P30. RESULTS: On P3, the NgR-siRNA group had significantly lower mRNA expression of NgR and protein expression of active RhoA in brain tissue than the model and empty vector groups (P<0.05). In each group, the mRNA expression of NgR was positively correlated with the protein expression of active RhoA (P<0.05). The results of immunofluorescence histochemistry showed that on P3, the NgR-siRNA group had a significantly reduced fluorescence intensity of the microglial cells labeled with CD11b compared with the model and empty vector groups (P<0.05). The OPCs labeled with O4 antibody in the four groups were mainly presented with tripolar cell morphology. The results of pathological examination showed a normal structure of white matter with clear staining in the periventriclar area in the control group, a loose structure of white matter with disorganized fibers and softening lesions in the model and empty vector groups, and a loose structure of white matter with slightly disorganized fibers, slight gliocyte proliferation, and no significant necrotic lesions in the NgR-siRNA group. As for the behavioral score, compared with the model and empty vector groups, the NgR-siRNA group had a higher score in the suspension test, a longer total activity distance, and greater mean velocity and number of squares crossed, as well as a shorter time of slope test and a shorter time and distance of activity in the central area (P<0.05), while there were no significant differences in these parameters between the NgR-siRNA and control groups (P>0.05). CONCLUSIONS: NgR silencing with specific siRNA can effectively silence the expression of NgR in pertem rats with brain injury caused by interauterine infection and has a significant neuroprotective effect in brain injury repair.

Glycemic Control, Weight Management, Cardiovascular Safety, and Cost-Effectiveness of Semaglutide for Patients with Type 2 Diabetes Mellitus: A Rapid Review and Meta-analysis of Real-World Studies.

INTRODUCTION: Semaglutide is a high-profile glucose-lowering drug that medical decision-makers have acknowledged in recent years. This rapid review aims to provide evidence-based clinical recommendations for the treatment of type 2 diabetes mellitus (T2DM) with semaglutide. METHODS: We conducted a rapid review of randomized controlled trial (RCT)-based meta-analyses (MAs) and systematic reviews (SRs) of cost-effectiveness analyses (CEAs) compared to other glucagon-like peptide-1 receptor agonists (GLP-1 RAs) or placebo in patients with T2DM. Prospective cohort real-world studies (RWS) were also retrieved and subjected to MA. Four databases, including PubMed, the Cochrane Library, Embase, and ISPOR, were searched from inception to 5 March 2023. The outcomes of interest were hemoglobin A1c (HbA1c), body weight, major adverse cardiovascular events (MACE), and economic outcomes such as quality-adjusted life-years and total cost. RESULTS: We identified 33 publications: 22 RCT-based MAs, 1 SR of CEAs, and 10 RWS. Evidence showed that semaglutide at usual doses was associated with superior reductions in HbA1c and weight compared to most GLP-1 RAs in patients with T2DM who were drug naive, receiving basal insulin, or using oral hypoglycemic agents, and it was also associated with a lower number of MACE and was more cost-effective. Further, once-weekly semaglutide resulted in a significant reduction in HbA1c levels (-1.1%) and body weight (-4.88 kg) in routine clinical practice. CONCLUSIONS: This review consolidates the positive current evidence base for prescribing semaglutide to patients with T2DM, but further rigorous studies are still urgently required to develop practice guidelines as innovative drugs become commercially available.

Association between GSTP1 I105V polymorphisms and responses to GSTP1 inhibitor treatment: in silico and in vitro insights.

Glutathione S-transferase P1 (GSTP1) has gradually become a promising target for cancer prevention and treatment. However, subtle variations in GSTP1 can lead to the occurrence of single nucleotide polymorphisms (SNPs). The correlation between specific genotypes of GSTP1 and the clinical outcome of the disease has been extensively investigated, demonstrating a significant area of research in this field. However, their impact on the responses to GSTP1 inhibitor treatment remains to be elucidated. Among the various SNPs of GSTP1, I105V polymorphisms is the most widely studied. In this study, a silico model of GSTP1 I105V polymorphism was successfully established to predict the changes of binding model and binding affinity between GSTP1 I105(WT) or GSTP1 V105 and ethacrynic acid via molecular docking and molecular dynamics, and ultimately further evaluated for its anticancer effects. The result demonstrated that the binding capacity of ethacrynic acid decreases with the I105V mutation of GSTP1, indicating the changes in its anticancer activities. Cancer cells expressing GSTP1 V105 may exhibit greater tolerance to ethacrynic acid-induced toxicity compared to other genotypes. In summary, this study provides the first evidence that the GSTP1 I105V polymorphism may impact cancer cell sensitivity to its inhibitor through theoretical prediction. Furthermore, a comprehensive understanding of the correlation between GSTP1 I105V polymorphisms and responses to GSTP1 inhibitor treatment would offer valuable insights for future drug development targeting GSTP1 in cancer-related diseases.Communicated by Ramaswamy H. Sarma.

Carbon monoxide therapy: a promising strategy for cancer.

Cancer is one of the acute life-threatening diseases endangering the whole of humanity. The treatment modalities for cancer are various. However, in most cases, a single treatment choice provides multiple side effects, poor targeting, and ineffective treatment. In recent years, the physiological regulatory function of carbon monoxide (CO) in the cancer process has been reported gradually, and CO-related nano-drugs have been explored. It shows better application prospects in cancer treatment and provides new ideas for treatment. The present review introduces the pathophysiological role of CO. The recent advances in cancer therapy, such as CO-mediated gas therapy, combined application of CO chemotherapy, photodynamic therapy (PDT), photothermal therapy (PTT), and immunotherapy, are described. Current challenges and future developments in CO-based treatment are also discussed. This review provides comprehensive information on recent advances in CO therapy and also some valuable guidance for promoting the progress of gas therapy nanomedicine.

The emerging importance role of m6A modification in liver disease.

N6-methyladenosine (m6A) modification, as one of the most common types of inner RNA modification in eukaryotes, plays a multifunctional role in normal and abnormal biological processes. This type of modification is modulated by m6A writer, eraser and reader, which in turn impact various processes of RNA metabolism, such as RNA processing, translation, nuclear export, localization and decay. The current academic view holds that m6A modification exerts a crucial role in the post-transcriptional modulation of gene expression, and is involved in multiple cellular functions, developmental and disease processes. However, the potential molecular mechanism and specific role of m6A modification in the development of liver disease have not been fully elucidated. In our review, we summarized the latest research progress on m6A modification in liver disease, and explored how these novel findings reshape our knowledge of m6A modulation of RNA metabolism. In addition, we also illustrated the effect of m6A on liver development and regeneration to prompt further exploration of the mechanism and role of m6A modification in liver physiology and pathology, providing new insights and references for the search of potential therapeutic targets for liver disease.

Comprehensive genomic signature of pyroptosis-related genes and relevant characterization in hepatocellular carcinoma.

Background: Currently, the most predominant type of liver cancer is hepatocellular carcinoma (HCC), which is also the fourth leading cause of cancer-related death in the global population. Pyroptosis is an emerging form of cell death that affects the prognosis of cancer patients by modulating tumor cell migration, proliferation and invasion. However, the evaluation of pyroptosis in the prognosis of HCC is still insufficient. Methods: A total of 365 HCC patients from the TCGA-LIHC cohort were classified into two distinct subtypes using consensus clustering of pyroptosis-related genes (PRGs). Following univariate Cox analysis of differentially expressed genes between subtypes, we established a prognostic model (PRGs-score, PRGS) by LASSO Cox analysis. We further tested the predictive power of the prognostic model in the ICGC (LIRI-JP) and GEO (GSE14520) cohorts. The tumor microenvironment (TME) was studied using the CIBERSORT. The enrichment scores for immune cells and immune functions in low- and high-PRGS groups were assessed using ssGSEA. The IMvigor210 cohort was used to investigate the immunotherapy efficacy. Furthermore, we validated the expression of prognostic genes in PRGS by RT-qPCR in vitro. Results: The subtyping of HCC based on PRGs exhibited distinct clinical characteristics. We developed a prognostic model PRGS by differentially expressed genes between different subtypes. The results showed that PRGS could well forecast the survival of HCC patients in different cohorts and was associated with the immune microenvironment. Moreover, PRGS was considered to be an independent prognostic risk factor and superior to other pyroptosis-related signatures. Low-PRGS implied greater immune cell infiltration and better overall survival with immunotherapy. The results of RT-qPCR also showed that prognostic genes were significantly dysregulated in HCC. Conclusions: PRGS has promising application in forecasting the prognosis of HCC patients, and its relationship with the immune microenvironment provides a basis for the subsequent treatment and research of HCC.

Application of exosomes as nanocarriers in cancer therapy.

Cancer remains the most common lethal disease in the world. Although the treatment choices for cancer are still limited, significant progress has been made over the past few years. By improving targeted drug therapy, drug delivery systems promoted the therapeutic effects of anti-cancer medications. Exosome is a kind of natural nanoscale delivery system with natural substance transport properties, good biocompatibility, and high tumor targeting, which shows great potential in drug carriers, thereby providing novel strategies for cancer therapy. In this review, we present the formation, distribution, and characteristics of exosomes. Besides, extraction and isolation techniques are discussed. We focus on the recent progress and application of exosomes in cancer therapy in four aspects: exosome-mediated gene therapy, chemotherapy, photothermal therapy, and combination therapy. The current challenges and future developments of exosome-mediated cancer therapy are also discussed. Finally, the latest advances in the application of exosomes as drug delivery carriers in cancer therapy are summarized, which provide practical value and guidance for the development of cancer therapy.

Cost-utility analysis of trastuzumab deruxtecan versus trastuzumab emtansine in HER2-positive metastatic breast cancer in Chinese setting.

PURPOSE: Trastuzumab deruxtecan (T-DXd) expressed substantial improvement in the progression-free survival and overall survival contrasted with trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer (mBC), becoming the second-line standard of care, promisingly. We aim to estimate the cost-utility of T-DXd versus T-DM1 in HER2-positive mBC from the Chinese healthcare perspective. METHODS: A partitioned survival model was applied to examine the cost-utility of T-DXd versus T-DM1. Clinical patients and outcome data were sourced from the DESTINY-Breast 03 trial. Costs and utilities were sourced in Chinese setting. Total costs, quality-adjusted life months (QALMs), and an incremental cost-utility ratios (ICUR) were calculated for cost-utility analysis. The willingness-to-pay threshold was set at $3188/QALM. Univariate, scenario, and probabilistic sensitivity analyses were performed. RESULTS: T-DXd group gained ∆QALM of 7.09 months and ∆Cost of $304,503 compared with T-DM1 therapy, which caused an ICUR of $42,936/QALM. The results of sensitivity analyses confirmed the base-case findings. Furthermore, T-DXd must reduce the price to enter the Chinese mainland market. At least when the cycle cost of T-DXd is reduced to $2975, T-DXd has an 83.3% chance of becoming a better choice. CONCLUSIONS: T-DXd appears to be not cost effective compared with T-DM1 for HER2-positive mBC patients previously treated with trastuzumab and a taxane.

Emerging role of m6A modification in fibrotic diseases and its potential therapeutic effect.

Fibrosis can occur in a variety of organs such as the heart, lung, liver and kidney, and its pathological changes are mainly manifested by an increase in fibrous connective tissue and a decrease in parenchymal cells in organ tissues, and continuous progression can lead to structural damage and organ hypofunction, or even failure, seriously threatening human health and life. N6-methyladenosine (m6A) modification, as one of the most common types of internal modifications of RNA in eukaryotes, exerts a multifunctional role in physiological and pathological processes by regulating the metabolism of RNA. With the in-depth understanding and research of fibrosis, we found that m6A modification plays an important role in fibrosis, and m6A regulators can further participate in the pathophysiological process of fibrosis by regulating the function of specific cells. In our review, we summarized the latest research advances in m6A modification in fibrosis, as well as the specific functions of different m6A regulators. In addition, we focused on the mechanisms and roles of m6A modification in cardiac fibrosis, liver fibrosis, pulmonary fibrosis, renal fibrosis, retinal fibrosis and oral submucosal fibrosis, with the aim of providing new insights and references for finding potential therapeutic targets for fibrosis. Finally, we discussed the prospects and challenges of targeted m6A modification in the treatment of fibrotic diseases.

TREM2: Potential therapeutic targeting of microglia for Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease, resulting in the loss of cognitive ability and memory. However, there is no specific treatment to mechanistically inhibit the progression of Alzheimer's disease, and most drugs only provide symptom relief and do not fundamentally reverse AD. Current studies show that triggering receptor expressed on myeloid cells 2 (TREM2) is predominantly expressed in microglia of the central nervous system (CNS) and is involved in microglia proliferation, survival, migration and phagocytosis. The current academic view suggests that TREM2 and its ligands have CNS protective effects in AD. Specifically, TREM2 acts by regulating the function of microglia and promoting the clearance of neuronal toxic substances and abnormal proteins by microglia. In addition, TREM2 is also involved in regulating inflammatory response and cell signaling pathways, affecting the immune response and regulatory role of microglia. Although the relationship between TREM2 and Alzheimer's disease has been extensively studied, its specific mechanism of action is not fully understood. The purpose of this review is to provide a comprehensive analysis of the research of TREM2, including its regulation of the inflammatory response, lipid metabolism and phagocytosis in microglia of CNS in AD, and to explore the potential application prospects as well as limitations of targeting TREM2 for the treatment of AD.

Pers reverse angiotensin II -induced vascular smooth muscle cell proliferation by targeting cyclin E expression via inhibition of the MAPK signaling pathway.

The circadian rhythm of blood pressure (BP) is believed to be regulated by the clock system, which is closely linked to levels of angiotensin II (Ang II). This study aimed to investigate whether Ang II mediates the proliferation of vascular smooth muscle cells (VSMCs) through the interaction between the clock system and the mitogen-activated protein kinase (MAPK) signaling pathway. Primary rat aortic VSMCs were treated with Ang II, with or without MAPK inhibitors. VSMC proliferation, expression of clock genes, CYCLIN E, and MAPK pathways were assessed. Ang II treatment resulted in increased VSMC proliferation and rapid upregulation of clock gene Periods (Pers) expression. Compared to the non-diseased control (NC) group, VSMCs incubated with Ang II displayed a noticeable delay in the G1/S phase transition and downregulation of CYCLIN E upon silencing of Per1 and Per2 genes. Importantly, silencing Per1 or Per2 in VSMCs led to decreased expression of key MAPK pathway proteins, including RAS, phosphorylated mitogen-activated protein kinase (P-MEK), and phosphorylated extracellular signal-regulated protein kinase (P-ERK). Moreover, the MEK and ERK inhibitors, U0126 and SCH772986, significantly attenuated the Ang II-induced proliferation of VSMCs, as evidenced by an increased G1/S phase transition and decreased CYCLIN E expression. The MAPK pathway plays a critical role in regulating VSMC proliferation in response to Ang II stimulation. This regulation is controlled by the expression of circadian clock genes involved in the cell cycle. These findings provide novel insights for further research on diseases associated with abnormal VSMC proliferation.

Problems and challenges encountered by Chinese medical institutions in implementing the national centralized drug procurement.

Objective: The problems and challenges encountered by Chinese medical institutions in implementing the national centralized drug procurement was investigated and analyzed in order to provide reference for the regulatory agencies to formulate policies. Methods: A questionnaire survey was conducted to collect the problems encountered by 329 Chinese medical institutions in implementing the national centralized drug procurement and the corresponding suggestions provided by relevant experts. Statistical analysis was performed to identify differences in the themes and the number of collected problems, further revealing the relevance to the region in which the medical institutions is located. Result: 1360 problems and suggestions were collected from 329 Chinese medical institutions that located in North (19.15%), Northeast (5.78%), East (33.43%), Central (10.03%), South (9.73%), Southwest (14.89%), and Northwest China (6.99%). There was statistically significant difference in the number of collected problems and suggestions between regions (p < 0.001). Furthermore, the content of gathered problems and suggestions involves in 15 themes including system construction, organizational system and work responsibilities, reasonable measurement and reporting of procurement volume et al. These themes that these medical institutions are focusing on are mainly centered on the supply guarantee (15%), reasonable measurement and reporting of procurement volume (11.40%) and guarantee measures for clinical priority use (9.48%) of drugs with national centralized procurement. Meanwhile, we found that problems regarding the supply guarantee of drugs with national centralized procurement displayed significant difference between regions (p = 0.0096). Conclusion: Chinese medical institutions are facing great challenges in implementing the national centralized drug procurement. The scientific study and judgment of the current situation and the construction of corresponding solution require a precise classification of the problems encountered by medical institutions in the process of implementing the national centralized drug procurement policy, which is of great practical significance for deepening the reform of the medical and health system.

Renal protection of in vivo administration of tempol in streptozotocin-induced diabetic rats.

The present study was carried out to investigate the protective effects of tempol on renal function and the underlying mechanism in streptozotocin-induced diabetic rats. The diabetic rats were randomly divided into the model group (without tempol) and tempol group (1 mM tempol in drinking water for 6 weeks). Nondiabetic rats were served as the Control group. The mRNA expression of canonical transient receptor potential 6 (TRPC6), transforming growth factor (TGF)-ß1, and type IV collagen (Col IV) were examined. The malondialdehyde (MDA) level, activities of superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) in renal tissues were measured to assess redox status in kidneys. We found that tempol significantly reduced 24-h urine output and urine albuminuria excretion in the diabetic rats. Compared with the model group, the concentration of MDA was significantly lower in the tempol group. In addition, diabetes decreased activities of SOD and GSH-Px and these responses were prevented by tempol treatment. Moreover, in diabetic rats, the mRNA expression levels of TGF-ß1 and Col IV were upregulated. TRPC6 mRNA expression level was down-regulated in diabetic kidneys. However, all of these diabetic effects were significantly suppressed by tempol treatment. These results suggest that chronic treatment of diabetic rats with tempol can protect kidneys, possibly by reducing expression of TGF-ß1, Col IV, and upregulating TRPC6 expression level.

Valsartan-mediated chronotherapy in spontaneously hypertensive rats via targeting clock gene expression in vascular smooth muscle cells.

OBJECTIVE: This study was to investigate the underlying mechanisms of valsartan chronotherapy in regulating blood pressure variability. METHODS: RT-PCR was used to assay clock genes expression rhythm in the hypothalamus, aortic vessels, and target organs after valsartan chronotherapy. WB was used to measure Period 1 (Per1), Period 2 (Per2) protein expression in aortic vessels, as well as to measure phosphorylation of 20-kDa regulatory myosin light chain (MLC20) in VSMCs. RESULTS: Specific clock genes in the hypothalamus, and Per1 and Per2 in aorta abdominalis, exhibited disordered circadian expression in vivo. Valsartan asleep time administration (VSA) restored circadian clock gene expression in a tissue- and gene-specific manner. In vitro, VSA was more efficient in blocking angiotensin II relative to VWA, which led to differential circadian rhythms of Per1 and Per2, ultimately corrected MLC20 phosphorylation. CONCLUSION: VSA may be efficacious in regulating circadian clock genes rhythm, then concomitantly correct circadian blood pressure rhythms.