The latest emerging drugs for the treatment of diabetic cardiomyopathy.

INTRODUCTION: Diabetic cardiomyopathy (DCM) is a serious complication of diabetes mellitus involving multiple pathophysiologic mechanisms. In addition to hypoglycemic agents commonly used in diabetes, metabolism-related drugs, natural plant extracts, melatonin, exosomes, and rennin-angiotensin-aldosterone system are cardioprotective in DCM. However, there is a lack of systematic summarization of drugs for DCM. AREAS COVERED: In this review, the authors systematically summarize the most recent drugs used for the treatment of DCM and discusses them from the perspective of DCM pathophysiological mechanisms. EXPERT OPINION: We discuss DCM drugs from the perspective of the pathophysiological mechanisms of DCM, mainly including inflammation and metabolism. As a disease with multiple pathophysiological mechanisms, the combination of drugs may be more advantageous, and we have discussed some of the current studies on the combination of drugs.

Multiple stimulus-response berberine plus baicalin micelles with particle size-charge-release triple variable properties for breast cancer therapy.

OBJECTIVE: The aim was to develop a nanoscale drug delivery system with enzyme responsive and acid sensitive particle size and intelligent degradation aiming to research the inhibitory effect on breast cancer. SIGNIFICANCE: The delivery system addressed the problems of tissue targeting, cellular internalization, and slow drug release at the target site, which could improve the efficiency of drug delivery and provide a feasible therapeutic approach for breast cancer. METHODS: The acid sensitive functional material DSPE-PEG2000-dyn-PEG-R9 was synthesized by Michael addition reaction. Then, the berberine plus baicalin intelligent micelles were prepared by thin-film hydration. Subsequently, we characterized the physical and chemical properties of berberine plus baicalin intelligent micelles, evaluated its anti-tumor effects in vivo and in vitro. RESULTS: The target molecule was successfully synthesized, and the intelligent micelles showed excellent chemical and physical properties, delayed drug release and high encapsulation efficiency. In vitro and in vivo experiments also confirmed that the intelligent micelles could effectively target tumor sites, penetrate tumor tissues, enrich in tumor cells, inhibit tumor cell proliferation, inhibit tumor cell invasion and migration, and induce tumor cell apoptosis. CONCLUSION: Berberine plus baicalin intelligent micelles have excellent anti-tumor effects and no toxicity to normal tissues, which provides a new potential drug delivery strategy for the treatment of breast cancer.

Protein arginine N-methyltransferase 4 (PRMT4) contributes to lymphopenia in experimental sepsis.

BACKGROUND: One hallmark of sepsis is the reduced number of lymphocytes, termed lymphopenia, that occurs from decreased lymphocyte proliferation or increased cell death contributing to immune suppression. Histone modification enzymes regulate immunity by their epigenetic and non-epigenetic functions; however, the role of these enzymes in lymphopenia remains elusive. METHODS: We used molecular biological approaches to investigate the high expression and function of a chromatin modulator protein arginine N-methyltransferase 4 (PRMT4)/coactivator-associated arginine methyltransferase 1 in human samples from septic patients and cellular and animal septic models. RESULTS: We identified that PRMT4 is elevated systemically in septic patients and experimental sepsis. Gram-negative bacteria and their derived endotoxin lipopolysaccharide (LPS) increased PRMT4 in B and T lymphocytes and THP-1 monocytes. Single-cell RNA sequencing results indicate an increase of PRMT4 gene expression in activated T lymphocytes. Augmented PRMT4 is crucial for inducing lymphocyte apoptosis but not monocyte THP-1 cells. Ectopic expression of PRMT4 protein caused substantial lymphocyte death via caspase 3-mediated cell death signalling, and knockout of PRMT4 abolished LPS-mediated lymphocyte death. PRMT4 inhibition with a small molecule compound attenuated lymphocyte death in complementary models of sepsis. CONCLUSIONS: These findings demonstrate a previously uncharacterised role of a key chromatin modulator in lymphocyte survival that may shed light on devising therapeutic modalities to lessen the severity of septic immunosuppression.

Sex differences in patients with COVID-19 after bariatric surgery: a multicenter cross-sectional study.

Objectives: This multicenter, cross-sectional study aimed to investigate whether sex differences persist among patients who have undergone bariatric surgery and tested positive for the coronavirus disease (COVID-19). Methods: We conducted a multicenter cross-sectional study via an online electronic questionnaire to collect data. Categorical data were presented as absolute and relative frequencies. Data for continuous variables were expressed as mean and standard deviation (SD) or median [interquartile range (IQR)]. We employed ordered logistic regression to assess whether females had higher odds of an increased self-reported duration of the most severe symptom compared to males. Using a modified Poisson regression model with robust standard errors to assess the differences in clinical characteristics among COVID-19 cases. Results: Statistical analysis revealed significant differences in the prevalence rates of various comorbidities. Among participants who reported their temperature during COVID-19 infection, more than half engaged in vitamin supplementation and regular exercise, while 4.2% remained asymptomatic. The probability of females experiencing a longer duration of severe symptoms increased compared to males [adjusted Odds Ratio (aOR) = 1.92, 95% confidence interval (CI) 1.73-2.12]. In the multivariate mixed-effects Poisson regression analysis, compared to males, females exhibited a lower prevalence rate of asymptomatic infection [adjusted prevalence ratio (aPR 0.40, 95% CI 0.28-0.58), lower prevalence of infection without therapeutic medication use (aPR 0.76, 95% CI 0.70-0.82), and lower prevalence of multiple infections (aPR 0.39, 95% CI 0.20-0.74)]. Conclusion: This cross-sectional study indicates the persistence of sex differences among patients with COVID-19 who have undergone bariatric surgery. Further research is needed to explore the underlying factors contributing to this disparity.

Synthesis of ginsenoside Re-based carbon dots applied for bioimaging and effective inhibition of cancer cells.

BACKGROUND: Fluorescent carbon-based nanomaterials have promising properties such as biosensing, cell imaging, tracing and drug delivery. However, carbon dots (CDs) with specific inherent biological functions have not been investigated. Ginsenosides are the components with multiple bioactivities found in plants of the genus Panax, which have attracted a lot of attention for their anticancer effect. MATERIALS AND METHODS: In this study, we prepared a kind of novel photoluminescent CDs from ginsenoside Re by one-step hydrothermal synthesis method. The conventional methods including transmission electron microscopy, Fourier transform infrared spectroscopy, HPLC and fluorescence spectrum were used for characterization of CDs. In vitro anticancer effect was investigated by cytotoxicity assay, flow cytometry and Western blot analysis. RESULTS: The as-prepared Re-CDs had an average diameter of 4.6±0.6 nm and excellent luminescent properties. Cellular uptake of Re-CDs was facilitated by their tiny nanosize, with evidence of their bright excitation-dependent fluorescent images. Compared with ginsenoside Re, the Re-CDs showed greater inhibition efficiency of cancer cell proliferation, with lower toxicity to the normal cells. The anticancer activity of Re-CDs was suggested to be associated with the generation of large amount of ROS and the caspase-3 related cell apoptosis. CONCLUSION: Hopefully, the dual functional Re-CDs, which could both exhibit bioimaging and anticancer effect, are expected to have great potential in future clinical applications.

Tetramethylpyrazine suppresses lipid accumulation in macrophages via upregulation of the ATP-binding cassette transporters and downregulation of scavenger receptors.

Tetramethylpyrazine (TMP), a biologically active ingredient first extracted from the Chinese medicinal plant Ligusticum wallichii Franchat., has athero-protective activity, yet the particular mechanisms have not been completely explored. The present study was designed to investigate the effect of TMP and its possible mechanisms in RAW264.7 macrophages and apolipoprotein E-deficient (ApoE-/-) mice. TMP treatment markedly increased the cholesterol efflux and inhibited oxidized low-density lipoprotein (ox-LDL) uptake, thus, ameliorating lipid accumulation in macrophages. In addition, TMP significantly increased the protein and mRNA expression of ATP-binding cassette transporters A1 (ABCA1) and G1 (ABCG1), while suppressing the protein and mRNA expression of class A scavenger receptor (SR-A) and the cluster of differentiation 36 (CD36). Moreover, the effects of TMP on the upregulation of the expression of ABCA1 and ABCG1, the downregulation of the expression of CD36 and SR-A, the increase of cholesterol efflux and the decrease of lipid accumulation as well as the uptake of ox-LDL were mediated by the inactivation of PI3K/Akt and p38 MAPK. Furthermore, TMP upregulated the protein stability of ABCA1 without affecting ABCG1. Accordingly, TMP regulated the expression of SR-A, CD36, ABCA1 and ABCG1 in aortas of ApoE-/- mice, which resembled the findings observed in macrophages. TMP was also capable of delaying the progression of atherosclerosis in ApoE-/- mice. These findings revealed that TMP downregulates scavenger receptors and upregulates ATP-binding cassette transporters via PI3K/Akt and p38 MAPK signaling, thus suppressing lipid accumulation in macrophages.

Antiparasitic efficacy of Gracillin and Zingibernsis newsaponin from Costus speciosus (Koen ex. Retz) Sm. against Ichthyophthirius multifiliis.

The present study aims to evaluate the antiparasitic activity of active components from Costus speciosus against Ichthyophthirius multifiliis. Bioassay-guided fractionation was employed to identify active compounds from C. speciosus yielding 2 bioactive compounds: Gracillin and Zingibernsis newsaponin. In-vitro assays revealed that Gracillin and Zingibernsis newsaponin could be 100% effective against I. multifiliis at concentrations of 0.8 and 4.5 mg L(-1), with median effective concentration (EC50) values of 0.53 and 3.2 mg L(-1), respectively. All protomonts and encysted tomonts were killed when the concentrations of Gracillin and Zingibernsis newsaponin were 1.0 and 5.0 mg L(-1). In-vivo experiments demonstrated that fish treated with Gracillin and Zingibernsis newsaponin at concentrations of 1.0 and 5.0 mg L(-1) carried significantly fewer parasites than the control (P<0.05). Mortality of fish did not occur in the treatment group (Zingibernsis newsaponin at 5.0 mg L(-1)) during the trial, although 100% of untreated fish died. Acute toxicities (LD50) of Gracillin and Zingibernsis newsaponin for grass carp were 1.64 and 20.7 mg L(-1), respectively. These results provided evidence that the 2 compounds can be selected as lead compounds for the development of new drugs against I. multifiliis.

Modulation of drug-resistant membrane and apoptosis proteins of breast cancer stem cells by targeting berberine liposomes.

The recurrence of breast cancer is associated with drug-resistance of cancer stem cells (CSCs), while overexpression of cell membrane ATP-binding cassette (ABC) transporters and resistance of mitochondrial apoptosis-related proteins are responsible for the drug-resistance of CSCs. The targeting berberine liposomes were developed to modulate the resistant membrane and mitochondrial proteins of breast CSCs for the treatment and prevention of breast cancer relapse. Evaluations were performed on human breast CSCs and CSC xenografts in nude mice. The targeting berberine liposomes were shown to cross the CSC membrane, inhibit ABC transporters (ABCC1, ABCC2, ABCC3, ABCG2) and selectively accumulate in the mitochondria. Furthermore, the pro-apoptotic protein Bax was activated while the anti-apoptotic protein Bcl-2 was inhibited resulting in opening of the mitochondrial permeability transition pores, release of cytochrome c, and activation of caspase-9/caspase-3 enzymes. Significant efficacy of the administrations in mice was observed, indicating that the targeting berberine liposomes are a potential therapy for the treatment and prevention of breast cancer relapse arising from CSCs.

A novel synchronous fluorescence spectroscopic approach for the rapid determination of three polycyclic aromatic hydrocarbons in tea with simple microwave-assisted pretreatment of sample.

Many polycyclic aromatic hydrocarbons (PAHs) are carcinogenic, and some have been reported to be present in tea. People can be exposed to PAHs through tea consumption. Therefore, there is real importance for the determination of PAHs in tea. Because of the complex matrix of tea, it is hard to detect PAHs in tea without cleanup and chromatographic separation procedures. In this research, for the first time, a novel synchronous fluorescence spectroscopic approach coupling nonlinear variable-angle synchronous and matrix-isopotential synchronous scanning modes has been developed for the rapid determination of benzo(a)pyrene (BaP), benzo(k)fluoranthene (BkF), and anthracene (AN) in tea with simple microwave-assisted pretreatment of samples. This novel technique is able to resolve the spectra of the three PAHs well, even with interference from other EPA PAHs. The detection limits for BaP, BkF, and AN in tea were 0.18-0.28, 0.55-0.89, and 0.64-3.58 µg/kg, respectively, depending on various teas, with satisfactory recoveries ranging from 77.1 to 116%. The relative standard deviations achieved for BaP, BkF, and AN were 1.5, 6.6, and 8.5% for green tea; 2.9, 7.4, and 2.1% for oolong tea; and 5.6, 5.4, and 5.8% for black tea, respectively. Our results showed good correlation with those of gas chromatography-mass spectrometry. The approach developed is simple, reliable, and cost-efficient, providing an attractive alternative for the rapid selective screening of PAHs in tea.

The effect of tetramethylpyrazine on hydrogen peroxide-induced oxidative damage in human umbilical vein endothelial cells.

Tetramethylpyrazine has been widely used in traditional Chinese medicine to treat cardiovascular diseases such as atherosclerosis and hypertension. The underlying mechanism of cardioprotective effects, however, remains to be elucidated. Here, using human umbilical vein endothelial cells (HUVECs), we have assessed the protective effect of tetramethylpyrazine on H(2)O(2)-induced oxidative damage. After pre-incubation with tetramethylpyrazine (50, 100 and 150 microg/ml) for 24 hr., viability loss in H(2)O(2)-induced HUVECs (76.5% of the control level, p < 0.05, at 400 microM of H(2)O(2) for 12 hr.) was restored in a concentration-dependent manner, and the maximal recovery (88.7% of the control level, p < 0.05) was achieved with tetramethylpyrazine at 150 microg/ml. The production of reactive oxygen species was suppressed by measuring fluorescent intensity of 2',7'-dichorofluorescein (83.1% of the H(2)O(2)-treated group, p < 0.05, at 150 microg/ml of tetramethylpyrazine). Tetramethylpyrazine also increased activities of superoxide dismutase and glutathione peroxidase (144.1% and 118.3% of the H(2)O(2)-treated group, respectively, p < 0.05, at 150 microg/ml of tetramethylpyrazine). In addition, tetramethylpyrazine reduced levels of malonaldehyde, intracellular nitric oxide and nitric oxide synthase (83.8%, 91.2% and 78.7% of the H(2)O(2)-treated group, respectively, p < 0.05, at 150 microg/ml of tetramethylpyrazine). Furthermore, pre-incubation of tetramethylpyrazine with HUVECs for 24 hr. resulted in reduction of apoptosis and removal of cell cycle arrest in the S phase (56.6% and 59.7% of the H(2)O(2)-treated group, respectively, p < 0.01, at 150 microg/ml of tetramethylpyrazine). Altogether, these results suggest that tetramethylpyrazine has a protective effect on H(2)O(2)-induced oxidative damage in HUVECs due to its antioxidant and antiapoptotic properties.

Tetramethylpyrazine suppresses interleukin-8 expression in LPS-stimulated human umbilical vein endothelial cell by blocking ERK, p38 and nulear factor-kappaB signaling pathways.

AIM OF THE STUDY: To determine the anti-inflammatory effects of Tetramethylpyrazine (TMP) and to investigate the inhibitory effect of TMP on IL-8 production in human umbilical vein endothelial cells (HUVECs) induced by LPS might be mediated by inhibiting p38, ERK and NF-kappaB signaling pathways. MATERIALS AND METHODS: HUVECs were treated with or without TMP for 24h before exposure to LPS for 4h. IL-8 gene and protein expressions were determined by RT-PCR and ELISA. Cell viability was determined by methyl thiazoyltetrazolium (MTT) assay. Phosphorylation of ERK1/2 and p38 were examined by western blotting. RESULTS: TMP inhibits LPS-induced IL-8 production in HUVECs at both the protein and mRNA levels, suggesting that TMP has an antiinflammatory effect on endothelial cells. TMP also inhibited U937 monocyte adhesion to HUVECs stimulated by LPS. LPS-induced phosphorylation of ERK1/2 and p38 were inhibited by TMP. The inhibitory effect of TMP on NF-kappaB (p65) activity was mediated by blocking the consequent translocation of p65 into the nucleus. CONCLUSIONS: The inhibitory effect of TMP on the LPS-induced IL-8 production is mediated by the NF-kappaB-dependent pathway, and TMP also separately affects the ERK and p38 MAPK pathway. TMP may be beneficial in the treatment of cardiovascular disorders such as atherosclerosis.

[Clinical observation on effect of compound Shiwei Tablet in treating urinary tract infection].

OBJECTIVE: To evaluate the safety and efficacy of Compound Shiwei Tablet (CST) in treating upper and lower urinary tract infection (UTI, pyretic stranguria of dampness-heat of the Lower-jiao type in 'TCM). METHODS: A multi-center, randomized, and opened clinical trial was conducted in the UTI patients with Sanjin Tablet (ST) as the parallel positive control medicine. The comprehensive efficacy, effect on TCM syndrome score, and change of urinary leukocyte count were observed, and the adverse reaction was recorded. RESULTS: In the 147 upper UTI cases and the 312 lower UTI cases after treatment, the comprehensive effect was higher and urinary leukocyte was less in the CST treated patients than in the ST treated patients (P < 0.05); but significant difference in the improvement of TCM symptoms was found between them only in the lower UTI cases ( P < 0.05); and no adverse reaction was observed during the treatment course. CONCLUSION: CST has definite therapeutic efficacy on UTI and is safe in clinical application.