ABSTRACT
The uncertainty and unknowability of emerging infectious diseases have caused many major public health and security incidents in recent years. As a new tick-borne disease, Dabieshan tick virus (DBTV) necessitate systematic epidemiological and spatial distribution analysis. In this study, tick samples from Liaoning Province were collected and used to evaluate distribution of DBTV in ticks. Outbreak points of DBTV and the records of the vector Haemaphysalis longicornis in China were collected and used to establish a prediction model using niche model combined with environmental factors. We found that H. longicornis and DBTV were widely distributed in Liaoning Province. The risk analysis results showed that the DBTV in the eastern provinces of China has a high risk, and the risk is greatly influenced by elevation, land cover, and meteorological factors. The risk geographical area predicted by the model is significantly larger than the detected positive areas, indicating that the etiological survey is seriously insufficient. This study provided molecular and important epidemiological evidence for etiological ecology of DBTV. The predicted high-risk areas indicated the insufficient monitoring and risk evaluation and the necessity of future monitoring and control work.
Subject(s)
Tick-Borne Diseases , Ticks , Animals , Humans , Haemaphysalis longicornis , Tick-Borne Diseases/epidemiology , China/epidemiologyABSTRACT
A reactive fluorescent "turn-on" probe (di-PIP) with imine-linked dual phenanthro[9,10-d]imidazole luminophore have been conveniently prepared as an Al3+ and H+ dual functional receptor. di-PIP displayed high selectivity and sensitivity towards Al3+ ion in DMF/HEPES accompanied by fluorescence blue-shift and a good linear relationship as well as a low detection limit of 30.5 nmol·L-1, which can root from the synergetic functions of the decomposition reaction of di-PIP promoted by acidic Al3+ and the coordination effect between decomposition product and Al3+. Intriguingly, it was found that hydrogen ion H+ can be sufficient for simulating the fluorescence enhancing of di-PIP. 1H NMR titration and MS analyses for elucidation of the intermediate structure further revealed that the acid-triggered decomposition reaction resulted in the rapid, and sensitive sensing to Al3+ and H+. In addition, the probe di-PIP could be successfully applied to the detection of Al3+ in real water samples, and also utilized to visualize Al3+ and H+ in the living cells.
Subject(s)
Fluorescent Dyes , Protons , Fluorescent Dyes/chemistry , Aluminum/analysis , Spectrometry, Fluorescence , WaterABSTRACT
Current therapy for acute myeloid leukemia (AML) is largely hindered by the development of drug resistance of commonly used chemotherapy drugs, including cytarabine, daunorubicin, and idarubicin. In this study, we investigated the molecular mechanisms underlying the chemotherapy drug resistance and potential strategy to improve the efficacy of these drugs against AML. By analyzing data from ex vivo drug-response and multi-omics profiling public data for AML, we identified autophagy activation as a potential target in chemotherapy-resistant patients. In THP-1 and MV-4-11 cell lines, knockdown of autophagy-regulated genes ATG5 or MAP1LC3B significantly enhanced AML cell sensitivity to the chemotherapy drugs cytarabine, daunorubicin, and idarubicin. In silico screening, we found that chloroquine phosphate mimicked autophagy inactivation. We showed that chloroquine phosphate dose-dependently down-regulated the autophagy pathway in MV-4-11 cells. Furthermore, chloroquine phosphate exerted a synergistic antitumor effect with the chemotherapy drugs in vitro and in vivo. These results highlight autophagy activation as a drug resistance mechanism and the combination therapy of chloroquine phosphate and chemotherapy drugs can enhance anti-AML efficacy.
Subject(s)
Idarubicin , Leukemia, Myeloid, Acute , Humans , Idarubicin/pharmacology , Idarubicin/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Daunorubicin/pharmacology , Daunorubicin/therapeutic use , Cytarabine/pharmacology , Cytarabine/therapeutic use , Autophagy , Chloroquine/pharmacology , Chloroquine/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic useABSTRACT
PURPOSE: Androgen deprivation therapy (ADT) includes bilateral orchiectomy or long-acting gonadotropin-releasing hormone (GnRH) agonists/antagonists. It remains controversial with respect to ADT associated cardiovascular outcomes. Hereby, we compared the risk of major adverse cardiovascular and cerebrovascular events (MACCEs) in patients with prostate cancer receiving either surgical castration or GnRH therapies. MATERIALS AND METHODS: Using the Taiwan Cancer Registry and Taiwan's National Health Insurance Research Database, we identified 8,413 patients receiving GnRH therapies compared with 694 receiving surgical castration from 2008 to 2017. The median followup duration was 3 years. RESULTS: The crude incidences of 3-year mortality and MACCEs were 19.90% vs 26.51% and 8.23% vs 8.65% in patients receiving GnRH therapies or surgical castration, respectively. After adjusting for age, cancer stage and comorbidities, despite no significant differences in MACCEs between groups there was a slight increase in the incidence of acute myocardial infarction (AMI) in patients receiving surgical castration compared with those receiving GnRH therapies. The mortality adjusted hazard ratios of MACCEs and AMI among patients receiving surgical castration were 1.11- and 1.8-fold higher than those receiving GnRH therapies. Notably, in subgroup analysis regarding cancer stage, patients with cancer stage IV showed the most significantly increasing risk of AMI in those receiving surgical castration compared with GnRH therapies. CONCLUSIONS: Collectively, we indicated an increased risk of AMI in patients with prostate cancer, especially in patients receiving surgical castration rather than those receiving GnRH therapies. Our findings highlight concerns regarding the cardiac safety of surgical castration compared with GnRH therapies.
Subject(s)
Androgen Antagonists/adverse effects , Antineoplastic Agents, Hormonal/adverse effects , Cardiotoxicity/etiology , Cardiovascular Diseases/etiology , Orchiectomy/adverse effects , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/surgery , Cardiotoxicity/epidemiology , Cardiotoxicity/mortality , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/mortality , Humans , Male , Postoperative Complications/etiology , Risk Factors , Taiwan/epidemiologyABSTRACT
Checkpoint kinase 1 inhibitors (CHK1i) have shown impressive single-agent efficacy in treatment of certain tumors, as monotherapy or potentiators of chemotherapy in clinical trials, but the sensitive tumor types and downstream effectors to dictate the therapeutic responses to CHK1i remains unclear. In this study we first analyzed GDSC (Genomics of Drug Sensitivity in Cancer) and DepMap database and disclosed that hematologic malignancies (HMs) were relatively sensitive to CHK1i or CHK1 knockdown. This notion was confirmed by examining PY34, a new and potent in-house selective CHK1i, which exhibited potent anti-HM effect in vitro and in vivo, as single agent. We demonstrated that the downregulation of c-Myc and its signaling pathway was the common transcriptomic profiling response of sensitive HM cell lines to PY34, whereas overexpressing c-Myc could partially rescue the anticancer effect of PY34. Strikingly, we revealed the significant correlations between downregulation of c-Myc and cell sensitivity to PY34 in 17 HM cell lines and 39 patient-derived cell (PDC) samples. Thus, our results demonstrate that HMs are more sensitive to CHK1i than solid tumors, and c-Myc downregulation could represent the CHK1i efficacy in HMs.
Subject(s)
DNA-Binding Proteins/antagonists & inhibitors , Down-Regulation/drug effects , Hematologic Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , Transcription Factors/antagonists & inhibitors , Animals , Cell Proliferation/drug effects , Cells, Cultured , Checkpoint Kinase 1/antagonists & inhibitors , Checkpoint Kinase 1/deficiency , Checkpoint Kinase 1/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Female , Hematologic Neoplasms/metabolism , Hematologic Neoplasms/pathology , Humans , Mice , Mice, Inbred NOD , Mice, Nude , Mice, SCID , Molecular Structure , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/metabolism , Neoplasms, Experimental/pathology , Protein Kinase Inhibitors/chemistry , Structure-Activity Relationship , Transcription Factors/genetics , Transcription Factors/metabolismABSTRACT
Doxorubicin (Dox), an effective therapy in different types of cancer, is known to exhibit cardiotoxic effects. Despite previous studies indicating the benefits of dapagliflozin (DAPA) in patients experiencing heart failure, it remains uncertain whether DAPA exerts a protective effect on Dox-induced cardiac dysfunction. Signal transducer and activator of transcription 3 (STAT3) participates in various mechanisms of cardioprotection. Herein, we aimed to investigate the effects of DAPA on Dox-induced cardiotoxicity and the role of STAT3. Sprague-Dawley rats were pretreated with oral DAPA for 6 weeks followed by Dox for 4 weeks. Sequential echocardiography was applied to assess cardiac function. For in vitro analysis, cardiomyocytes were treated with 10 µM DAPA and subsequently exposed to 1 µM Dox. The expression of reactive oxygen species- and apoptosis-related proteins was measured. Using STAT3 siRNA, we further examined the effects of STAT3 effect on DAPA-associated protection against Dox-induced apoptosis. In rats treated with Dox, DAPA significantly reduced cardiac fibrosis and improved cardiac function and hemodynamics. Additionally, DAPA effectively inhibited Dox-induced apoptosis and reactive oxygen species (ROS) in cardiomyocytes. Mechanistically, we showed that DAPA decreased cardiac expression of Bax and cleaved caspase 3 but increased Bcl-2 expression. DAPA also significantly rescued Dox-suppressed STAT3 expression. Conversely, knocking down STAT3 in cardiomyocytes reversed the DAPA-related protective effects on Dox-induced cell apoptosis and ROS. Collectively, our findings indicate that DAPA could be useful for preventing Dox-induced cardiotoxicity by restoring STAT3.
Subject(s)
Cardiotoxicity , STAT3 Transcription Factor , Animals , Apoptosis , Apoptosis Regulatory Proteins/metabolism , Benzhydryl Compounds , Cardiotoxicity/metabolism , Doxorubicin/toxicity , Glucosides , Humans , Myocytes, Cardiac , Oxidative Stress , Rats , Rats, Sprague-Dawley , Reactive Oxygen Species/metabolism , STAT3 Transcription Factor/metabolismABSTRACT
Although sepsis and acute kidney injury (AKI) have a bidirectional interplay, the pathophysiological mechanisms between AKI and sepsis are not clarified and worthy of a comprehensive and updated review. The primary pathophysiology of sepsis-associated AKI (SA-AKI) includes inflammatory cascade, macrovascular and microvascular dysfunction, cell cycle arrest, and apoptosis. The pathophysiology of sepsis following AKI contains fluid overload, hyperinflammatory state, immunosuppression, and infection associated with kidney replacement therapy and catheter cannulation. The preventive strategies for SA-AKI are non-specific, mainly focusing on infection control and preventing further kidney insults. On the other hand, the preventive strategies for sepsis following AKI might focus on decreasing some metabolites, cytokines, or molecules harmful to our immunity, supplementing vitamin D3 for its immunomodulation effect, and avoiding fluid overload and unnecessary catheter cannulation. To date, several limitations persistently prohibit the understanding of the bidirectional pathophysiologies. Conducting studies, such as the Kidney Precision Medicine Project, to investigate human kidney tissue and establishing parameters or scores better to determine the occurrence timing of sepsis and AKI and the definition of SA-AKI might be the prospects to unveil the mystery and improve the prognoses of AKI patients.
Subject(s)
Acute Kidney Injury , Sepsis , Apoptosis , Humans , Kidney , Renal Replacement Therapy , Sepsis/complicationsABSTRACT
Acute kidney injury (AKI) and gut dysbiosis affect each other bidirectionally. AKI induces microbiota alteration in the gastrointestinal (GI) system, while gut dysbiosis also aggravates AKI. The interplay between AKI and gut dysbiosis is not yet well clarified but worthy of further investigation. The current review focuses on the pathophysiology of this bidirectional interplay and AKI treatment in this base. Both macrophages and neutrophils of the innate immunity and the T helper type 17 cell from the adaptive immunity are the critical players of AKI-induced gut dysbiosis. Conversely, dysbiosis-induced overproduction of gut-derived uremic toxins and insufficient generation of short-chain fatty acids are the main factors deteriorating AKI. Many novel treatments are proposed to deter AKI progression by reforming the GI microbiome and breaking this vicious cycle. Data support the benefits of probiotic treatment in AKI patients, while the results of postbiotics are mainly limited to animals. Prebiotics and synbiotics are primarily discussed in chronic kidney disease patients rather than AKI patients. The effect of adsorbent treatment seems promising, but more studies are required before the treatment can be applied to patients. Immune therapy and some repurposed drugs such as allopurinol are prospects of future treatments and are worth more discussion and survey.
Subject(s)
Acute Kidney Injury , Gastrointestinal Microbiome , Probiotics , Synbiotics , Acute Kidney Injury/etiology , Acute Kidney Injury/therapy , Animals , Dysbiosis/metabolism , Dysbiosis/therapy , Humans , Prebiotics , Probiotics/therapeutic useABSTRACT
Vancomycin is the most frequently used antibiotic, accounting for up to 35% of hospitalized patients with infection, because of its optimal bactericidal effectiveness and relatively low price. Vancomycin-associated AKI (VA-AKI) is a clinically relevant but not yet clearly understood entity in critically ill patients. The current review comprehensively summarizes the pathophysiological mechanisms of, biomarkers for, preventive strategies for, and some crucial issues with VA-AKI. The pathological manifestations of VA-AKI include acute tubular necrosis, acute tubulointerstitial nephritis (ATIN), and intratubular crystal obstruction. The proposed pathological mechanisms of VA-AKI include oxidative stress and allergic reactions induced by vancomycin and vancomycin-associated tubular casts. Concomitant administration with other nephrotoxic antibiotics, such as piperacillin-tazobactam, high vancomycin doses, and intermittent infusion strategies compared to the continuous infusion are associated with a higher risk of VA-AKI. Several biomarkers could be applied to predict and diagnose VA-AKI. To date, no promising therapy is available. Oral steroids could be considered for patients with ATIN, whereas hemodialysis might be applied to remove vancomycin from the patient. In the future, disclosing more promising biomarkers that could precisely identify populations susceptible to VA-AKI and detect VA-AKI occurrence early on, and developing pharmacological agents that could prevent or treat VA-AKI, are the keys to improve the prognoses of patients with severe infection who probably need vancomycin therapy.
Subject(s)
Acute Kidney Injury/diagnosis , Anti-Bacterial Agents/toxicity , Vancomycin/toxicity , Acute Kidney Injury/etiology , Acute Kidney Injury/metabolism , Acute Kidney Injury/therapy , Animals , Anti-Bacterial Agents/pharmacokinetics , Biomarkers/metabolism , Humans , Vancomycin/pharmacokineticsABSTRACT
The effect of warm-water footbath in improving dysmenorrhoea has been rarely investigated. The study aimed to examine whether a warm-water footbath effectively reduces dysmenorrhoea pain and improves the autonomic nervous system (ANS) activity. The randomised controlled trial was registered at ClinicalTrials.gov. (NCT04071028) We enrolled college students with dysmenorrhoea in Northern Taiwan from December 1 2013 to June 30 2014, and randomised them into footbath (n = 35, median age 19 years) and control groups (n = 33, 18 years). Pain visual analogue scale and Short-Form McGill Pain Questionnaire were used for pain assessment, while heart rate variability (HRV) was measured to assess ANS function. After the interventions, the footbath group significantly improved ANS activity and reduced pain severity comparing to the control group. Furthermore, the changes in HRV positively correlated with the improvement of pain severity. In conclusion, a warm-water footbath is beneficial in improving the pain severity among college students with dysmenorrhoea.Impact StatementWhat is already known on this subject? Dysmenorrhoea is the most common gynaecological condition affecting 34-94% of young women. The existing conventional therapeutic strategies for dysmenorrhoea have potential adverse events. Among the complementary therapies for pain, the warm-water footbath is a widely used thermal therapy in improving peripheral neuropathy symptoms and improving patients' quality of life. The subjects with dysmenorrhoea associate with significantly altered autonomic nervous system (ANS) activity. However, the association among warm-water footbath, menstrual pain and ANS was rarely investigated previously.What the results of this study add? The randomised controlled trial enrolling 68 college students with dysmenorrhoea found warm-water footbath improved ANS activity and reduced pain severity. Furthermore, the changes in heart rate variability positively correlated with pain severity improvement.What the implications are of these findings for clinical practice and/or further research? A warm-water footbath for 20 minutes on menstruation days 1 and 2 is beneficial in improving pain among college students with dysmenorrhoea.
Subject(s)
Dysmenorrhea , Quality of Life , Adult , Dysmenorrhea/drug therapy , Female , Heart Rate , Humans , Students , Water , Young AdultABSTRACT
Diffuse large B-cell lymphoma (DLBCL) is the most widespread type of non-Hodgkin lymphoma (NHL). As the most aggressive form of the DLBCL, the activated B-cell-like (ABC) subtype is often resistant to standard chemotherapies. Bruton's tyrosine kinase (BTK) inhibitor ibrutinib provides a potential therapeutic approach for the DLBCL but fails to improve the outcome in the phase III trial. In the current study, we investigated the molecular mechanisms underlying ibrutinib resistance and explored new combination therapy with ibrutinib. We generated an ibrutinib-resistant ABC-DLBCL cell line (OCI-ly10-IR) through continuous exposure to ibrutinib. Transcriptome analysis of the parental and ibrutinib-resistant cell lines revealed that the ibrutinib-resistant cells had significantly lower expression of the unfolded protein response (UPR) marker genes. Overexpression of one UPR branch-XBP1s greatly potentiated ibrutinib-induced apoptosis in both sensitive and resistant cells. The UPR inhibitor tauroursodeoxycholic acid (TUDCA) partially reduced the apoptotic rate induced by the ibrutinib in sensitive cells. The UPR activator 2-deoxy-D-glucose (2-DG) in combination with the ibrutinib triggered even greater cell growth inhibition, apoptosis, and stronger calcium (Ca2+) flux inhibition than either of the agents alone. A combination treatment of ibrutinib (15 mg·kg-1·d-1, po.) and 2-DG (500 mg/kg, po, b.i.d.) synergistically retarded tumor growth in NOD/SCID mice bearing OCI-ly10-IR xenograft. In addition, ibrutinib induced the UPR in the sensitive cell lines but not in the resistant cell lines of the DLBCL. There was also a combined synergistic effect in the primary resistant DLBCL cell lines. Overall, our results suggest that targeting the UPR could be a potential combination strategy to overcome ibrutinib resistance in the DLBCL.
Subject(s)
Adenine/analogs & derivatives , Antineoplastic Agents/therapeutic use , Drug Resistance, Neoplasm/drug effects , Lymphoma, Large B-Cell, Diffuse/drug therapy , Piperidines/therapeutic use , Unfolded Protein Response/drug effects , Adenine/therapeutic use , Animals , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Deoxyglucose/therapeutic use , Drug Resistance, Neoplasm/physiology , Drug Synergism , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Lymphoma, Large B-Cell, Diffuse/genetics , Lymphoma, Large B-Cell, Diffuse/physiopathology , Mice, Inbred NOD , Mice, SCID , Unfolded Protein Response/physiology , X-Box Binding Protein 1/genetics , X-Box Binding Protein 1/metabolism , Xenograft Model Antitumor AssaysABSTRACT
Wnt signaling is initiated by Wnt ligand binding to the extracellular ligand binding domain, called the cysteine-rich domain (CRD), of a Frizzled (Fzd) receptor. Norrin, an atypical Fzd ligand, specifically interacts with Fzd4 to activate ß-catenin-dependent canonical Wnt signaling. Much of the molecular basis that confers Norrin selectivity in binding to Fzd4 was revealed through the structural study of the Fzd4CRD-Norrin complex. However, how the ligand interaction, seemingly localized at the CRD, is transmitted across full-length Fzd4 to the cytoplasm remains largely unknown. Here, we show that a flexible linker domain, which connects the CRD to the transmembrane domain, plays an important role in Norrin signaling. The linker domain directly contributes to the high-affinity interaction between Fzd4 and Norrin as shown by â¼10-fold higher binding affinity of Fzd4CRD to Norrin in the presence of the linker. Swapping the Fzd4 linker with the Fzd5 linker resulted in the loss of Norrin signaling, suggesting the importance of the linker in ligand-specific cellular response. In addition, structural dynamics of Fzd4 associated with Norrin binding investigated by hydrogen/deuterium exchange MS revealed Norrin-induced conformational changes on the linker domain and the intracellular loop 3 (ICL3) region of Fzd4. Cell-based functional assays showed that linker deletion, L430A and L433A mutations at ICL3, and C-terminal tail truncation displayed reduced ß-catenin-dependent signaling activity, indicating the functional significance of these sites. Together, our results provide functional and biochemical dissection of Fzd4 in Norrin signaling.
Subject(s)
Eye Proteins/chemistry , Frizzled Receptors/chemistry , Nerve Tissue Proteins/chemistry , Wnt Signaling Pathway , Animals , Eye Proteins/metabolism , Frizzled Receptors/metabolism , Mice , Nerve Tissue Proteins/metabolism , Protein Binding , Protein Domains , Protein Structure, Quaternary , Protein Structure, Secondary , Structure-Activity RelationshipABSTRACT
Acute kidney injury (AKI) is a common yet complicated clinical entity with high morbidity and mortality. An essential strategy to improve AKI patients' prognoses is finding optimal biomarkers to identify AKI in a timely manner. Procalcitonin (PCT), a well-recognized biomarker for diagnosing infection and guiding antibiotics therapy, has been proposed to predict AKI development and recovery in many clinical settings. The current review provides comprehensive and updated information from relevant studies to evaluate PCT's AKI-predictive ability and the influence of infection on this predictive ability. PCT has demonstrated optimal predictive ability for AKI in various populations irrespective of infection. However, the predictive ability seems to be blunted by infection since infection and inflammation have a more potent influence than AKI on PCT elevation. We furthermore explain the complicated association between elevated PCT levels and AKI in infection and inflammation situations and recommend directions for further investigations to clarify the essential issue. In conclusion, although conflicting data exist, serum PCT level is a potential biomarker for predicting AKI in many clinical settings regardless of infection. Nevertheless, further studies are warranted to clarify the association between PCT, infection, and AKI and to confirm the utilization of PCT for AKI prediction.
Subject(s)
Acute Kidney Injury/blood , Acute Kidney Injury/diagnosis , Biomarkers , Procalcitonin/blood , Acute Kidney Injury/etiology , Disease Susceptibility , Humans , Kidney Function Tests , Prognosis , Sepsis/bloodABSTRACT
Pulmonary fibrosis (PF) is a fatal disease with increasing prevalence. Nonradioactive and noninvasive diagnosis of PF at an early stage can improve the prognosis but represents a daunting challenge. Up-regulation of nitric oxide (NO) is a typical microenvironmental feature of PF. Here, we report a small-molecule probe, PNO1, that can fluorogenically sense this microenvironmental feature for PF diagnosis. We demonstrate that PNO1 fluorescence is 6-fold higher in PF-diseased mice lungs than in normal-control groups. In addition to this in vivo result, PNO1 can also be applied in vitro to detect PF-diseased cells and ex vivo to detect PF-diseased tissues from clinical patients. These results highlight PNO1 as a complement to the traditional immunostaining-based methods for PF detection to facilitate quick screening for anti-PF drug candidates.
Subject(s)
Fluorescent Dyes/chemistry , Pulmonary Fibrosis/diagnosis , Small Molecule Libraries/chemistry , Animals , Cell Line , Fluorescent Dyes/administration & dosage , Fluorescent Dyes/chemical synthesis , Injections, Intravenous , Mice , Molecular Structure , Nitric Oxide/analysis , Nitric Oxide/metabolism , Optical Imaging , Pulmonary Fibrosis/metabolism , Small Molecule Libraries/administration & dosage , Small Molecule Libraries/chemical synthesisABSTRACT
BACKGROUND: The aim of this study was to assess trends in drug resistance and associated clinical and programmatic factors at a national level during the rapid scale up of ART. METHODS: Logistic regression was used to identify the factors associated with HIVDR. Variables associated with drug resistance in multivariable logistic regression were included in the Cochran-Armitage test for trend. RESULTS: A total of 11,976 patients were enrolled in the study. The prevalence of HIVDR among patients who received ART for 9-24 months during 2003-2008, 2009-2012, and 2013-2015 significantly decreased (15.5%, 6.3%, and 2.3%, respectively, P < 0.01). With respect to the class of antiretroviral, there were substantial increases in resistance to both non-nucleoside reverse transcriptase inhibitors (NNRTIs) and nucleoside reverse transcriptase inhibitors (NRTIs) (2003-2008, 2009-2012, and 2013-2015: 49.7%, 58.9%, and 73.0%, respectively, P < 0.01). The prevalence of DR to protease inhibitors (PIs) was low, which supported their continued use as second-line therapy in China. CONCLUSIONS: Our results provide evidence for the effectiveness of China's "Treat All" approach to guide policy makers to improve training for healthcare providers and education on ART adherence among patients.
Subject(s)
Anti-HIV Agents/therapeutic use , Drug Resistance, Viral , HIV Infections/drug therapy , HIV-1/drug effects , Adult , China , Cross-Sectional Studies , Epidemiological Monitoring , Female , Humans , Logistic Models , Male , Prevalence , Time Factors , Treatment Failure , Young AdultABSTRACT
Advanced glycation end products (AGE) and angiotensin II were closely correlated with the progression of diabetic nephopathy (DN). Nitric oxide (NO) is a protective mediator of renal tubular hypertrophy in DN. Here, we examined the molecular mechanisms of angiotensin-converting enzyme inhibitor (ACEI) and NO signaling responsible for diminishing AGE-induced renal tubular hypertrophy. In human renal proximal tubular cells, AGE decreased NO production, inducible NOS activity, guanosine 3',5'-cyclic monophosphate (cGMP) synthesis, and cGMP-dependent protein kinase (PKG) activation. All theses effects of AGE were reversed by treatment with ACEIs (captopril and enalapril), the NO donor S-nitroso-N-acetylpenicillamine (SNAP), and the PKG activator 8-para-chlorophenylthio-cGMPs (8-pCPT-cGMPs). In addition, AGE-enhanced activation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) were clearly reduced by captopril, enalapril, SNAP, and 8-pCPT-cGMPs. The abilities of ACEIs and NO/PKG activation to inhibit AGE-induced hypertrophic growth were verified by the observation that captopril, enalapril, SNAP, and 8-pCPT-cGMPs decreased protein levels of fibronectin, p21 Waf1/Cip1 , and receptor for AGE. The results of the present study suggest that ACEIs significantly reduced AGE-increased ERK/JNK/p38 MAPK activation and renal tubular hypertrophy partly through enhancement of the NO/PKG pathway.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/pharmacology , Glycation End Products, Advanced/metabolism , Kidney Tubules, Proximal/drug effects , Kidney Tubules, Proximal/metabolism , Nitric Oxide/metabolism , Captopril/pharmacology , Cell Enlargement/drug effects , Cell Line , Cyclic GMP/analogs & derivatives , Cyclic GMP/pharmacology , Cyclic GMP-Dependent Protein Kinases/metabolism , Enalapril/pharmacology , Enzyme Activation/drug effects , Glycation End Products, Advanced/toxicity , Humans , Hypertrophy/prevention & control , Kidney Tubules, Proximal/pathology , MAP Kinase Signaling System/drug effects , Nitric Oxide Donors/pharmacology , Nitric Oxide Synthase Type II/metabolism , S-Nitroso-N-Acetylpenicillamine/pharmacology , Signal Transduction/drug effects , Thionucleotides/pharmacologyABSTRACT
Liddle syndrome is an inherited form of human hypertension caused by increasing epithelial Na+ channel (ENaC) expression. Increased Na+ retention through ENaC with subsequent volume expansion causes hypertension. In addition to ENaC, the Na+-K+-Cl- cotransporter (NKCC) and Na+-Cl- symporter (NCC) are responsible for Na+ reabsorption in the kidneys. Several Na+ transporters are evolutionarily regulated by the Ste20 kinase family. Ste20-related proline/alanine-rich kinase and oxidative stress-responsive kinase-1 phosphorylate downstream NKCC2 and NCC to maintain Na+ and blood pressure (BP) homeostasis. Mammalian Ste20 kinase 3 (MST3) is another member of the Ste20 family. We previously reported that reduced MST3 levels were found in the kidneys in spontaneously hypertensive rats and that MST3 was involved in Na+ regulation. To determine whether MST3 is involved in BP stability through Na+ regulation, we generated a MST3 hypomorphic mutation and designated MST3+/- and MST3-/- mice to examine BP and serum Na+ and K+ concentrations. MST3-/- mice exhibited hypernatremia, hypokalemia, and hypertension. The increased ENaC in the kidney played roles in hypernatremia. The reabsorption of more Na+ promoted more K+ secretion in the kidney and caused hypokalemia. The hypernatremia and hypokalemia in MST3-/- mice were significantly reversed by the ENaC inhibitor amiloride, indicating that MST3-/- mice reabsorbed more Na+ through ENaC. Furthermore, Madin-Darby canine kidney cells stably expressing kinase-dead MST3 displayed elevated ENaC currents. Both the in vivo and in vitro results indicated that MST3 maintained Na+ homeostasis through ENaC regulation. We are the first to report that MST3 maintains BP stability through ENaC regulation.
Subject(s)
Epithelial Sodium Channels/physiology , Hypertension/etiology , Hypertension/physiopathology , Protein Serine-Threonine Kinases/physiology , Animals , Blood Pressure/physiology , Electric Conductivity , Epithelial Sodium Channels/analysis , Genotype , Kidney/chemistry , Liddle Syndrome/physiopathology , Mice , Mice, Knockout , Potassium/blood , Potassium/urine , Protein Serine-Threonine Kinases/analysis , Protein Serine-Threonine Kinases/deficiency , Sodium/blood , Sodium/urineABSTRACT
Accurate fabrication of fluorescence probes to efficiently monitor and detect H2S levels in the fields of foodstuffs and physiology is crucial. Herein, we report two isomeric phenanthro[9,10-d]imidazole benzene sulfonamide-derived fluorescence probes (PI-2-SA and PI-4-SA), both of which display remarkable responses toward H2S over other analytes. The spectral characteristics of the two probes were investigated and are discussed in detail. By comparison, PI-2-SA was specific, sensitive (the limit of detection was ca. 12.3 nM), rapid (within ≤3 min) and dynamic (the rate constant was 0.02 s-1). Significantly, PI-2-SA was proved to be effective in monitoring the shelf-time progress of egg samples in real time as well as in the imaging of exogenous and endogenous H2S in HeLa cells.
Subject(s)
Eggs/analysis , Fluorescent Dyes/chemistry , Hydrogen Sulfide/analysis , Imidazoles/chemistry , Phenanthrenes/chemistry , Sulfonamides/chemistry , Animals , Chickens , Ducks , Fluorescent Dyes/chemical synthesis , Fluorescent Dyes/toxicity , Food Preservation/methods , HeLa Cells , Humans , Hydrogen Sulfide/metabolism , Imidazoles/chemical synthesis , Imidazoles/toxicity , Isomerism , Microscopy, Confocal/methods , Microscopy, Fluorescence/methods , Phenanthrenes/chemical synthesis , Phenanthrenes/toxicity , Quail , Sulfonamides/chemical synthesis , Sulfonamides/toxicityABSTRACT
BACKGROUND: Acute kidney injury (AKI) after cardiovascular surgery is a serious complication. Little is known about the ability of novel biomarkers in combination with clinical risk scores for prediction of advanced AKI. METHODS: In this prospectively conducted multicenter study, urine samples were collected from 149 adults at 0, 3, 6, 12 and 24 h after cardiovascular surgery. We measured urinary hemojuvelin (uHJV), kidney injury molecule-1 (uKIM-1), neutrophil gelatinase-associated lipocalin (uNGAL), α-glutathione S-transferase (uα-GST) and π-glutathione S-transferase (uπ-GST). The primary outcome was advanced AKI, under the definition of Kidney Disease: Improving Global Outcomes (KDIGO) stage 2, 3 and composite outcomes were KDIGO stage 2, 3 or 90-day mortality after hospital discharge. RESULTS: Patients with advanced AKI had significantly higher levels of uHJV and uKIM-1 at 3, 6 and 12 h after surgery. When normalized by urinary creatinine level, uKIM-1 in combination with uHJV at 3 h post-surgery had a high predictive ability for advanced AKI and composite outcome (AUC = 0.898 and 0.905, respectively). The combination of this biomarker panel (normalized uKIM-1, uHJV at 3 h post-operation) and Liano's score was superior in predicting advanced AKI (AUC = 0.931, category-free net reclassification improvement of 1.149, and p < 0.001). CONCLUSIONS: When added to Liano's score, normalized uHJV and uKIM-1 levels at 3 h after cardiovascular surgery enhanced the identification of patients at higher risk of progression to advanced AKI and composite outcomes.
Subject(s)
Biomarkers/analysis , Acute Kidney Injury/mortality , Acute Kidney Injury/physiopathology , Adult , Aged , Analysis of Variance , Biomarkers/urine , Cardiac Surgical Procedures , Chi-Square Distribution , Female , GPI-Linked Proteins/analysis , GPI-Linked Proteins/urine , Glutathione S-Transferase pi/analysis , Glutathione S-Transferase pi/urine , Glutathione Transferase/analysis , Glutathione Transferase/urine , Hemochromatosis Protein , Hepatitis A Virus Cellular Receptor 1/analysis , Hospital Mortality , Humans , Intensive Care Units/organization & administration , Intensive Care Units/statistics & numerical data , Isoenzymes/analysis , Isoenzymes/urine , Lipocalin-2/analysis , Lipocalin-2/urine , Male , Middle Aged , Organ Dysfunction Scores , Prospective Studies , ROC Curve , Statistics, Nonparametric , TaiwanABSTRACT
Four coordination polymers, namely, [Zn(HL1)(L2)0.5]·H2O (1), [Cd(HL1)(L2)0.5]·H2O (2), [Zn(L1)(L3)0.5]·H2O (3), and [Cd(L1)(L3)0.5] (4) (H3L1 = (3,5-dicarboxyl-phenyl)-(4-(2'-carboxyl-phenyl)-benzyl)ether, H2L2Cl2 = 1,1'-bis(4-carboxy-benzyl)-4,4'-bipyridinium dichloride, and L3Cl2 = 1,1'-dimethyl-4,4'-bipyridylium dichloride), have been synthesized hydrothermally. The structures of compounds 1-4 have been determined by single-crystal X-ray diffraction analyses, and further characterized by elemental analyses, infrared (IR) spectra, powder X-ray diffraction (PXRD) analyses, and thermogravimetric analyses. Compounds 1 and 2 display three-dimensional 2-fold interpenetrating frameworks, whereas compounds 3 and 4 exhibit two-dimensional layer structures. These compounds display photochromic behaviors from pale yellow to green under UV light, visible light, or sunlight. The photochromic mechanisms of these compounds have been studied by IR spectra, PXRD analyses, UV-vis absorption spectra, electron paramagnetic resonance spectra, density functional theory calculations, and X-ray photoelectron spectroscopy. The capabilities of compounds 1 and 2 as inkless and erasable printing media have also been tested. Moreover, the photomodulated fluorescence of these compounds has also been investigated.