Discovery and therapeutic implications of bioactive dihydroxylated phenolic acids in patients with severe heart disease and conditions associated with inflammation and hypoxia.

Our initial studies detected elevated levels of 3,4-dihydroxyphenyllactic acid (DHPLA) in urine samples of patients with severe heart disease when compared with healthy subjects. Given the reported anti-inflammatory properties of DHPLA and related dihydroxylated phenolic acids (DPAs), we embarked on an exploratory multi-centre investigation in patients with no urinary tract infections to establish the possible pathophysiological significance and therapeutic implications of these findings. Chinese and Caucasian patients being treated for severe heart disease or those conditions associated with inflammation (WBC ≥ 10 ×109/L or hsCRP ≥ 3.0 mg/L) and/or hypoxia (PaO2 ≤ 75 mmHg) were enrolled; their urine samples were analyzed by HPLC, HPLC-MS, GC-MS and biotransformation assays. DHPLA was detected in urine samples of patients, but undetectable in healthy volunteers. Dynamic monitoring of inpatients undergoing treatment showed their DHPLA levels declined in proportion to their clinical improvement. In DHPLA-positive patients' fecal samples, Proteus vulgaris and P. mirabilis were more abundant than healthy volunteers. In culture, these gut bacteria were capable of reversible interconversion between DOPA and DHPLA. Furthermore, porcine and rodent organs were able to metabolize DOPA to DHPLA and related phenolic acids. The elevated levels of DHPLA in these patients suggest bioactive DPAs are generated de novo as part of a human's defense mechanism against disease. Because DHPLA isolated from Radix Salvia miltiorrhizae has a multitude of pharmacological activities, these data underpin the scientific basis of this medicinal plant's ethnopharmacological applications as well as highlighting the therapeutic potential of endogenous, natural or synthetic DPAs and their derivatives in humans.

Associations of exposure to polycyclic aromatic hydrocarbons and kidney stones in U.S. general population: results from the National Health and Nutrition Examination Survey 2007-2016.

PURPOSE: It has been reported that polycyclic aromatic hydrocarbons (PAHs) exposure was associated with the increasing risk of various diseases. Utilizing the data from the general population of the U.S., we tried to assess the association between PAHs exposure and KS. METHODS: The dataset was extracted from National Health and Nutrition Examination Survey (NHANES) 2007-2016. The hydroxylated metabolites of polycyclic aromatic hydrocarbons (OH-PAHs) were detected as representative of urinary PAHs. Ranking-based PAHs score was used to evaluate the total PAHs exposure burden. Multivariable logistic regression analyses were performed to assess the association between PAHs exposure and KS after adjusting a series of confounding factors. RESULTS: 8975 eligible participants were included. In multivariable logistic regression analyses, after adjusting confounding variables, 2-hydroxynaphthalene (OR 1.38, 1.16-1.65; p = 0.038) and 9-hydroxyfluorene (OR 1.39, 1.06-1.84, p = 0.019) were still observed to have significant positive correlations with the prevalence of KS, respectively. The incidence of KS increased significantly with the increase of total PAHs burden (p for trend = 0.011). Significant interaction effects were observed in the subgroup of gender (p for interaction < 0.05). Among female participants, PAHs exposure was more significantly correlated with KS. Higher 2-hydroxynaphthalene (OR 1.94, 1.39-2.70; p < 0.001), 1-hydroxyphenanthrene (OR 1.57, 1.07-2.30; p = 0.022) and 2-hydroxyphenanthrene (OR 1.85, 1.11-3.06; p = 0.018) were significantly associated with the increased incidence of KS in women. CONCLUSIONS: There is a significant association between a high level of PAHs exposure and increased prevalence of KS. In particular, in the female population, the relationship between PAHs exposure and KS is especially significant.

Association between testosterone and serum soluble α-klotho in U.S. males: a cross-sectional study.

PURPOSE: Testosterone plays a crucial role in males, and the deficiency of testosterone leads to multiple adverse health conditions. Klotho is a recently discovered protein encoded by antiaging gene klotho. Both the levels of testosterone and klotho change with aging, so the relationship between them is worth exploring. The purpose of this study was to investigate whether total testosterone is associated with serum klotho levels in U.S. males aged 40-79 years. METHODS: Included in this study were 3750 male participants from the 2011 to 2016 National Health and Nutrition Examination Survey, aged 40-79 years with included information on klotho and sex hormones. The sex steroid hormone levels and klotho concentrations were assayed in laboratories using the recommended methods according to Nutrition Examination Survey guidelines. The association between sex hormones and klotho was calculated using multivariate linear regression models after adjustment for several possible confounding variables. RESULTS: Among the 3750 participants, the total testosterone concentration was 399.048 ± 184.780 ng/dL, and the testosterone deficiency prevalence was 1160 (30.942%). The geometric mean of serum klotho levels was 791.000 pg/mL. In the adjusted models, klotho increased 0.165 pg/mL for every 1 ng/dL increase of total testosterone (p = 0.004). In addition, estradiol (ß 2.232; 95% CI 0.588-3.876; p = 0.032) and sex hormone-binding globulin (ß 2.013; 95% CI 1.173-2.583; p = 0.002) were also positively associated with klotho concentrations. CONCLUSION: This study reported a significant association between klotho and sex hormones in the U.S. male population. The levels of klotho in men increased with total testosterone, estradiol and sex hormone-binding globulin levels, which may have implications for future research and clinical practice.

Correction: Recent development of AAV-based gene therapies for inner ear disorders.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Recent development of AAV-based gene therapies for inner ear disorders.

Gene therapy for auditory diseases is gradually maturing. Recent progress in gene therapy treatments for genetic and acquired hearing loss has demonstrated the feasibility in animal models. However, a number of hurdles, such as lack of safe viral vector with high efficiency and specificity, robust deafness large animal models, translating animal studies to clinic etc., still remain to be solved. It is necessary to overcome these challenges in order to effectively recover auditory function in human patients. Here, we review the progress made in our group, especially our efforts to make more effective and cell type-specific viral vectors for targeting cochlea cells.

Analysis of the clinical characteristics, drug treatments and prognoses of 136 patients with coronavirus disease 2019.

WHAT IS KNOWN AND OBJECTIVE: Since the December 2019 discovery of several cases of coronavirus disease 2019 (COVID-19) in Wuhan, China, the infection has spread worldwide. Our aim is to report on the clinical characteristics, treatments and prognoses of COVID-19. METHODS: This was a retrospective, single-centre, case series of 136 patients who were diagnosed with COVID-19 at Wuhan Third Hospital in Wuhan, China, between 28 January 2020 and 12 February 2020. The clinical characteristics, laboratory tests, treatment features and prognoses were summarized. RESULTS AND DISCUSSION: The 136 patients were divided into a moderate (M) group (n = 103, 75.7%) and a severe and critical (SC) group (n = 33, 24.3%). There were significant differences in the incidences of concomitant chronic medical illnesses (eg, hypertension, diabetes and cardiovascular disease), fever, dry cough and dyspnoea among the two groups (P < .05). Compared with those in the M group, lymphocyte count (LYM) decreased significantly in the SC group, while the serum levels of C-reactive protein (CRP), procalcitonin (PCT), creatinine (Cre), D-dimer, lactic dehydrogenase (LDH), myoglobin (MB) and troponin I (cTnl) increased significantly in the SC group (P < .05). The main therapeutic drugs were antivirals, antibiotics, glucocorticoids, immunomodulators, traditional Chinese medicine preparations and symptomatic support drugs. There were significant differences in the incidences of shock, myocardial injury, acute respiratory distress syndrome (ARDS) and renal injury among the two groups (P < .05). Among the 136 patients, 99 (72.7%) were cured, 14 (10.3%) were transferred to other hospital and 23 (16.9%) died. WHAT IS NEW AND CONCLUSION: Elderly patients with chronic diseases are more likely to develop severe or critical COVID-19 with multiple organ damage or systemic injuries. The improvement of LYM and CRP may be associated with the prognoses of COVID-19. The combined use of three or more antiviral drugs is to be avoided. The combination of broad-spectrum antibacterial drugs is not recommended and the risk of drug-induced liver injury should be monitored. Throughout a patient's hospitalization, their treatment plan should be evaluated and adjusted according to their vital signs, clinical symptoms, laboratory tests and imaging changes. Patients should receive effective psychological counselling.

Enhanced Corrosion Resistance of Layered Double Hydroxide Films on Mg Alloy: The Key Role of Cationic Surfactant.

In this study, dense anticorrosion magnesium-aluminum layered double hydroxide (MgAl-LDH) films were prepared for the first time by introducing a cationic surfactant tetradecyltrimethyl ammonium bromide (TTAB) in the process of in situ hydrothermal synthesis of Mg-Al LDH films on an AZ31 magnesium alloy. Results of XRD, FTIR, and SEM confirmed that TTAB forms the MgAl-LDH-TTAB, although TTAB cannot enter into LDH layers, and MgAl-LDH-TTAB powders are much smaller and more homogenous than MgAl-CO32--LDH powders. Results of SEM, EDS, mapping, and XPS confirmed that TTAB forms the MgAl-LDH-TTAB films and endows LDH films with denser structure, which provides films with better shielding efficiency. Results of potentiodynamic polarization curves (PDP) and electrochemical impedance spectroscopy (EIS) confirmed that MgAl-LDH-TTABx g films have better corrosion resistance than an MgAl-CO32--LDH film. The corrosion current density (icorr) of the MgAl-LDH-TTAB0.35 g film in 3.5 wt.% NaCl solution was reduced to 1.09 × 10-8 A.cm-2 and the |Z|f = 0.05 Hz value was increased to 4.48 × 105 Ω·cm2. Moreover, the increasing concentration of TTAB in MgAl-LDH-TTABx g (x = 0.025, 0.05, 0.1, 0.2 and 0.35) provided denser outer layer LDH films and thereby increased the corrosion resistance of the AZ31 Mg alloy. Additionally, the |Z|f = 0.05 Hz values of the MgAl-LDH-TTAB0.35 g film still remained at 105 Ω·cm2 after being immersed in 3.5 wt.% NaCl solution for 168 h, implying the good long-term corrosion resistance of MgAl-LDH-TTABx g films. Therefore, introducing cationic surfactant in the process of in situ hydrothermal synthesis can be seen as a novel approach to creating efficient anticorrosion LDH films for Mg alloys.

LncRNA MIAT Upregulates NEGR1 by Competing for miR-150-5p as a Competitive Endogenous RNA in SCIRI Rats.

Objective: Spinal cord ischemia-reperfusion injury (SCIRI) can cause a pathological state of irreversible delayed death of neurons in the spinal cord tissue and a range of complications, such as spinal cord dysfunction and motor function impairment. This study aimed to determine whether the long-stranded non-coding ribonucleic acid (lncRNA), myocardial infarction-associated transcript (MIAT), could upregulate neuronal growth regulator 1 (NEGR1) by competing for miR-150-5p as a competitive endogenous RNA in a rat SCIRI model. Methods: The MIAT knockdown vector or the corresponding blank vector was injected into the spinal cord of healthy sprague Dawley (SD) rats. Administration of the MIAT knockdown vector led to the establishment of the SCIRI rat model. Basso, Beattie & Bresnahan locomotor rating scale (BBB) assessment of hind limb motion. Pathological changes in the spinal cord were observed via hematoxylin and eosin staining and eosin staining. Quantitative polymerase chain reaction was performed to determine the expression levels of the candidate microRNAs and predicted candidate genes, and the relationship between them. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay (TUNEL) staining was used to detect apoptosis in the spinal cord tissue of rats in each group. Western blotting was performed to determine the expression of the apoptosis-related proteins, caspase-9, caspase-3, and BCL2-Associated X (Bax)/B-cell lymphoma-2 (Bcl-2). The luciferase reporter gene was used to assess the interaction among the lncRNA, MIAT, and miR-150-5, and the interaction between miR-150-5 and NEGR1. Results: The sh-lncRNA, MIAT, improved exercise status, and pathological changes in the spinal cord of SCIRI rats, inhibited apoptosis, increased the expression of miR-150-5p, and reduced the expression of NEGR1. Compared with mimics-NC, the transfection of miR-150-5p significantly decreased the relative fluorescence activity ratio of MIAT 3'-untranslated region (3'-UTR) wild-type Human embryonic kidney cells 293 (HEK-293 cells). Compared with mimics-negative control (NC), the transfection of miR-150-5p significantly decreased the relative fluorescence activity ratio of NEGR1 3'-UTR wild-type HEK-293 cells. Conclusion: MIAT can affect the symptoms of SCIRI in rats. Furthermore, as a competitive endogenous RNA, MIAT upregulates NEGR1 by competing with miR-150-5p in SCIRI rats.

[The Clinical Characteristics and Influencing Factors of Patients with Severe COVID-19].

OBJECTIVE: To investigate the clinical characteristic of coagulation, possible causes and countermeasures of patients with severe corona virus disease 2019 (COVID-19). METHODS: The clinical data of the 142 patients diagnosed as COVID-19 at Wuhan Third Hospital in Wuhan, China, from February 10 to February 16, 2020 were collected and analyzed retrospective. Among the patients, 17 cases of dead patients were divided into observe group, and 125 cases of cured patients were divided into control group. The clinical characteristics, laboratory tests, influencing factors, anticoagulant therapy, embolization and bleeding events of the two groups were observed. RESULTS: The average hospital stay time in 142 patients was 22 d. For the 17 dead patients in the observe group, the average hospital stay time was 9.9 d, and the D-dimer, prothrombin time, WBC count and Padua score of the patients in the observe group were significantly higher as compared with the patients in the control group. PT(OR=1.064, 95%CI 1.012-1.119) and D-D(OR=1.045, 95%CI 1.027-1.064) were the independent risk factors that causing the death of COVID-19 patients. Among the patients, 36(25.4%) patients received low-molecular-weight heparin for anticoagulant therapy, with the average course of 9.6 d. The cumulative incidence of the embolism of the patients in the observe group was 7（41.2%）, while 2(11.8%) patients developed to deep vein thrombosis (DVT) and pulmonary embolism (PE), 3 (17.6%) patients occurred acute cerebral infarction and 2 (11.8%) patients occurred acute myocardial infarction. 3 (17.6%) dead patients revealed dominant disseminated intravascular coagulation (DIC). CONCLUSION: Most patients with severe COVID-19 shows a variety of risk factors for thrombus, and those with coagulation dysfunction shows a high dead rate and rapid disease progression. Therefore, coagulation indicators should be dynamically monitored, and mechanical and drug prevention should be actively carried out.

microRNA-125b reverses the multidrug resistance of nasopharyngeal carcinoma cells via targeting of Bcl-2.

Multidrug resistance (MDR) is a major clinical obstacle in the successful treatment of patients with metastatic nasopharyngeal carcinoma (NPC). Results from previous studies suggest that microRNAs (miRNA) may be involved in promoting MDR in multiple cancer types. However, the role of miR­125b in modulating the MDR of NPC is elusive. In the present study, miR­125b expression in cisplatin (DDP) ­resistant CNE2 cells (CNE2/DDP) was compared with parental counterparts, using reverse transcription­quantitative polymerase chain reaction. A >3­fold reduction in miR­125b expression levels was observed in CNE2/DDP cells compared with parental CNE2 cells. Ectopic expression of miR­125b by transfecting CNE2/DDP cells with miR-125b mimics, increased DDP­induced cytotoxicity, apoptosis and chemosensitivity. By contrast, suppression of miR-125b by transfecting CNE2 cells with miR­125b inhibitors, reduced DDP­induced cytotoxicity and apoptosis, and facilitated cisplatin resistance. The results suggest that miR­125b may regulate the sensitivity of NPC cells to DDP by modulating the expression levels of antiapoptotic factor B-cell CLL/lymphoma 2. Collectively, the results of the present study highlight miR­125b as a potential therapeutic target for reversing MDR in NPC.

Angelica sinensis polysaccharide regulates glucose and lipid metabolism disorder in prediabetic and streptozotocin-induced diabetic mice through the elevation of glycogen levels and reduction of inflammatory factors.

The present study was designed to evaluate the potential hypoglycemic and hypolipidemic effects of Angelica sinensis polysaccharide (ASP), purified from the fresh roots of Angelica sinensis (AS), in prediabetic and streptozotocin (STZ)-induced diabetic BALB/c mice. It was observed that fasting blood glucose (FBG) levels in both models were reduced after a 4-week oral administration of ASP or metformin, and abnormal fasting serum insulin (FINS) concentrations were ameliorated as well. Moreover, the homeostasis model assessment-insulin resistance (HOMA-IR) index was decreased strikingly and body weight (BW) was reduced significantly in prediabetic mice after treatment with ASP. In addition, ASP also contributed to improving the dyslipidemia conditions. Elevated serum total cholesterol (TC) or triglyceride (TG) concentrations were reduced after treatment with ASP in prediabetic mice or STZ-induced diabetic mice. Meanwhile, hepatic glycogen (HG) and muscle glycogen (MG) concentrations were increased while insulin resistance (IR)-related inflammatory factors IL-6 and TNF-α in serum were reduced in STZ-induced diabetic mice. Histopathological examination indicated that the impaired pancreatic/hepatic tissues or adipose tissues were effectively restored in STZ-induced diabetic mice or prediabetic mice after the ASP treatment. Taken together, these results revealed that ASP efficiently exerted hypoglycemic and hypolipidemic benefits, and its potential effect was associated with the amelioration of IR. ASP can be applied in the prevention and treatment of diabetes.

A metabolite of Danshen formulae attenuates cardiac fibrosis induced by isoprenaline, via a NOX2/ROS/p38 pathway.

BACKGROUND AND PURPOSE: Cardiac fibrosis is a common feature of advanced coronary heart disease and is characteristic of heart disease. However, currently available drugs against cardiac fibrosis are still very limited. Here, we have assessed the role of isopropyl 3-(3,4-dihydroxyphenyl)-2-hydroxylpropanoate (IDHP), a new metabolite of Danshen Dripping Pills, in cardiac fibrosis mediated by the ß-adrenoceptor agonist, isoprenaline, and its underlying mechanisms. EXPERIMENTAL APPROACH: Identification of IDHP was identified by mass spectrometry, and proton and carbon nuclear magnetic resonance spectra. Myocardial collagen was quantitatively assessed with Picrosirius Red staining. Expression of mRNA for collagen was evaluated with real-time PCR. Phosphorylated and total p38 MAPK, NADPH oxidase (NOX) and superoxide dismutase (SOD) were analysed by Western blot. Generation of reactive oxygen species (ROS) generation was evaluated by dihydroethidium (DHE) fluorescent staining. NOX2 was knocked down using specific siRNA. KEY RESULTS: IDHP attenuated ß-adrenoceptor mediated cardiac fibrosis in vivo and inhibited isoprenaline-induced proliferation of neonatal rat cardiac fibroblasts (NRCFs) and collagen I synthesis in vitro. Phosphorylation of p38 MAPK, which is an important mediator in the pathogenesis of isoprenaline-induced cardiac fibrosis, was inhibited by IDHP. This inhibition of phospho-p38 by IDHP was dependent on decreased generation of ROS. These effects of IDHP were abolished in NRCFs treated with siRNA for NOX2. CONCLUSIONS AND IMPLICATIONS: IDHP attenuated the cardiac fibrosis induced by isoprenaline through a NOX2/ROS/p38 pathway. These novel findings suggest that IDHP is a potential pharmacological candidate for the treatment of cardiac fibrosis, induced by ß-adrenoceptor agonists.

A 46-year-old Chinese woman presenting with retroperitoneal follicular dendritic cell sarcoma: a case report.

INTRODUCTION: Follicular dendritic cells are non-phagocytic, non-lymphoid cells of the immune system that are necessary for antigen presentation and the regulation of reactions in the germinal centers of the lymph nodes. Follicular dendritic cell sarcoma is an unusual cancer, particularly in the intra-abdominal region. In the present report we describe an unusual case of retroperitoneal follicular dendritic cell sarcoma that emphasizes the difficulty of diagnosing and treating this tumor. Retroperitoneal follicular dendritic cell sarcoma has only been rarely reported in the literature to date. CASE PRESENTATION: A 46-year-old Chinese woman of Han ethnicity presented with chronic right lower quadrant abdominal pain over the preceding 4 weeks. The tumor was resected and submitted to histopathological examination. The case was verified as retroperitoneal follicular dendritic cell sarcoma by microscopic examination and immunohistochemical analysis. After diagnosis, she received postoperative radiotherapy and chemotherapy. She has survived 3 years postoperatively, although she has a pulmonary metastasis. CONCLUSIONS: Retroperitoneal follicular dendritic cell sarcoma may demonstrate aggressive potential. This study indicated that postoperative adjuvant radiotherapy and chemotherapy could extend the survival of a patient with retroperitoneal follicular dendritic cell sarcoma.