No abstract

Bacterial pathogens have specific virulence factors (e.g., toxins) that contribute significantly to the virulence and infectivity of microorganisms within the human hosts. Virulence factors are molecules expressed by pathogens that enable colonization, immunoevasion, and immunosuppression, obtaining nutrients from the host or gaining entry into host cells. They can cause pathogenesis by inhibiting or stimulating certain host functions. For example, in systemic Staphylococcus aureus infections, virulence factors such as toxic shock syndrome toxin 1 (TSST-1), staphylococcal enterotoxin A (SEA), and staphylococcal enterotoxin B (SEB) cause sepsis or toxic shock by uncontrolled stimulation of T lymphocytes and by triggering a cytokine storm. In vitro, these superantigens stimulate the proliferation of human peripheral blood mononuclear cells (PBMC) and the release of many cytokines. NVC-422 (N,N-dichloro-2,2-dimethyltaurine) is a broad-spectrum, fast-acting topical anti-infective agent against microbial pathogens, including antibiotic-resistant microbes. Using mass spectrometry, we demonstrate here that NVC-422 oxidizes methionine residues of TSST-1, SEA, SEB, and exfoliative toxin A (ETA). Exposure of virulence factors to 0.1% NVC-422 for 1 h prevented TSST-1-, SEA-, SEB-, and ETA-induced cell proliferation and cytokine release. Moreover, NVC-422 also delayed and reduced the protein A-and clumping factor-associated agglutination of S. aureus cultures. These results show that, in addition to its well-described direct microbicidal activity, NVC-422 can inactivate S. aureus virulence factors through rapid oxidation of methionines.

Cardiac hypertrophy can lead to congestive heart failure and is a leading cause of morbidity and mortality worldwide. In recent years, it has been essential to find the treatment and prevention of cardiac hypertrophy. Betulinic acid (BA), the main active ingredient in many natural products, is known to have various physiological effects. However, as the potential effect of BA on cardiac hypertrophy and consequent renal dysfunction is unknown, we investigated the effect of BA on isoprenaline (ISO)-induced cardiac hypertrophy and related signaling. ISO was known to induce left ventricular hypertrophy by stimulating the β2-adrenergic receptor (β2AR). ISO was injected into Sprague Dawley rats (SD rats) by intraperitoneal injection once a day for 28 days to induce cardiac hypertrophy. From the 14th day onwards, the BA (10 or 30 mg/kg/day) and propranolol (10 mg/kg/day) were administered orally. The study was conducted in a total of 5 groups, as follows: C, control; Is, ISO (10 mg/kg/day); Pr, positive-control, ISO + propranolol (10 mg/kg/day); Bl, ISO + BA (10 mg/kg/day); Bh, ISO + BA (30 mg/kg/day). As a result, the total cardiac tissue and left ventricular tissue weights of the ISO group increased compared to the control group and were significantly reduced by BA treatment. In addition, as a result of echocardiography, the effect of BA on improving cardiac function, deteriorated by ISO, was confirmed. Cardiac hypertrophy biomarkers such as β-MHC, ANP, BNP, LDH, and CK-MB, which were increased by ISO, were significantly decreased by BA treatment. Also, the cardiac function improvement effect of BA was confirmed to improve cardiac function by inhibiting calcineurin/NFATc3 signaling. Renal dysfunction is a typical complication caused by cardiac hypertrophy. Therefore, the study of renal function indicators, creatinine clearance (Ccr) and osmolality (BUN) was aggravated by ISO treatment but was significantly restored by BA treatment. Therefore, it is thought that BA in cardiac hypertrophy can be used as valuable data to develop as a functional material effective in improving cardiac-renal dysfunction.

Progressive diabetic nephropathy (DN) in diabetes leads to major morbidity and mortality. The major pathological alterations of DN include mesangial expansion, extracellular matrix alterations, tubulointerstitial fibrosis, and glomerular sclerosis. Polygoni avicularis is widely used in traditional oriental medicine and has long been used as a diuretic, astringent, insecticide and antihypertensive. However, to the best of the authors’ knowledge, the effects of the ethanolic extract from rhizome of Polygoni avicularis (ER-PA) on DN have not yet been assessed. The present study aimed to identify the effect of ER-PA on renal dysfunction, which has been implicated in DN in human renal mesangial cells and db/db mice and investigate its mechanism of action. The in vivo experiment was performed using Polygoni avicularis-ethanol soluble fraction (ER-PA) and was administrated to db/db mice at 10 and 50 mg/kg dose. For the in vitro experiments, the human renal mesangial cells were induced by high glucose (HG, 25 mM). The ER-PA group showed significant amelioration in oral glucose tolerance, and insulin resistance index. ER-PA significantly improved the albumin excretion and markedly reduced plasma creatinine, kidney injury molecule-1 and C-reactive protein. In addition, ER-PA significantly suppressed inflammatory cytokines. Histopathologically, ER-PA attenuated glomerular expansion and tubular fibrosis in db/db mice. Furthermore, ER-PA suppressed the expression of renal fibrosis biomarkers (TGF and Collagen IV). ER-PA also reduced the NLR family pyrin domain containing 3 inflammatory factor level. These results suggest that ER-PA has a protective effect against renal dysfunction through improved insulin resistance as well as the inhibition of nephritis and fibrosis in DN.

YG-1 extract used in this study is a mixture of Lonicera japonica, Arctic Fructus, and Scutellariae Radix. The present study was designed to investigate the effect of YG-1 extract on bronchodilatation (ex vivo) and acute bronchial and pulmonary inflammation relief (in vivo). Ex vivo: The bronchodilation reaction was confirmed by treatment with YG-1 concentration-accumulation (0.01, 0.03, 0.1, 0.3, and 1 mg/mL) in the bronchial tissue ring pre-contracted by acetylcholine (10 μM). As a result, YG-1 extract is considered to affect bronchodilation by increased cyclic adenosine monophosphate, cAMP) levels through the β2-adrenergic receptor. In vivo: experiments were performed in C57BL/6 mice were divided into the following groups: control group; PM2.5 (fine particulate matter)-exposed group (PM2.5, 200 μg/kg/mL saline); and PM2.5-exposed + YG-1 extract (200 mg/kg/day) group. The PM2.5 (200 μg/kg/mL saline) was exposed for 1 h for 5 days using an ultrasonic nebulizer aerosol chamber to instill fine dust in the bronchi and lungs, thereby inducing acute lung and bronchial inflammation. From two days before PM2.5 exposure, YG-1 extract (200 mg/kg/day) was administered orally for 7 days. The PM2.5 exposure was involved in airway remodeling and inflammation, suggesting that YG-1 treatment improves acute bronchial and pulmonary inflammation by inhibiting the inflammatory cytokines (NLRP3/caspase-1 pathway). The application of YG-1 extract with broncho-dilating effect to acute bronchial and pulmonary inflammation animal models has great significance in developing therapeutic agents for respiratory diseases. Therefore, these results can provide essential data for the development of novel respiratory symptom relievers. Our study provides strong evidence that YG-1 extracts reduce the prevalence of respiratory symptoms and the incidence of non-specific lung diseases and improve bronchial and lung function.

Diabetic cardiovascular dysfunction is a representative complication of diabetes. Inflammation associated with the onset and exacerbation of type 2 diabetes mellitus (T2DM) is an essential factor in the pathogenesis of diabetic cardiovascular complications. Diabetes-induced myocardial dysfunction is characterized by myocardial fibrosis, which includes structural heart changes, myocardial cell death, and extracellular matrix protein accumulation. The mice groups in this study were divided as follows: Cont, control (db/m mice); T2DM, type 2 diabetes mellitus mice (db/db mice); Vil.G, db/db + vildagliptin 50 mg/kg/day, positive control, dipeptidyl peptidase-4 (DPP-4) inhibitor; Bla.C, db/db + blackcurrant 200 mg/kg/day. In this study, Bla.C treatment significantly improved the homeostatic model evaluation of glucose, insulin, and insulin resistance (HOMA-IR) indices and diabetic blood markers such as HbA1c in T2DM mice. In addition, Bla.C improved cardiac function markers and cardiac thickening through echocardiography. Bla.C reduced the expression of fibrosis biomarkers, elastin and type IV collagen, in the left ventricle of a diabetic cardiopathy model. Bla.C also inhibited TD2M-induced elevated levels of inflammatory cytokines in cardiac tissue (IL-6, IL-1β, TNF-α, and TGF-β). Thus, Bla.C significantly improved cardiac inflammation and cardiovascular fibrosis and dysfunction by blocking inflammatory cytokine activation signals. This showed that Bla.C treatment could ameliorate diabetes-induced cardiovascular complications in T2DM mice. These results provide evidence that Bla.C extract has a significant effect on the prevention of cardiovascular fibrosis, inflammation, and consequent diabetes-induced cardiovascular complications, directly or indirectly, by improving blood glucose profile.

The diabetes-resistant DR-BB rat, derived from diabetesprone forebears, does not normally develop spontaneous insulitis or diabetes, but when infected with Kilham rat virus (KRV) this animal develops autoimmune diabetes similar to the diabetes-prone DP-BB rat. KRV infects the lymphoid organs, such as the spleen, thymus, and lymph nodes, but this virus does not infect pancreatic f3-cells, indicating that KRV-induced diabetes in DR-BB rats does not result from direct cytolysis of f3-cells after infection with KRV [1,2].Recent experimental data suggest that KRV infection of DR-BB rats leads to the activation of silent autoreactive T-cells [3]. However, the precise mechanisms by which KRV induces autoimmune insulin-dependent diabetes mellitus (IDDM) without the infection of f3-cells are poorly understood. In this study, we attempted to determine whether macrophages and macrophage-derived cytokines play any role in the development of KRV-induced diabetes in DR-BB rats. 78% of DR-BB rats treated with KRV and Poly I:C develop diabetes, whereas depletion of macrophages with liposome-encapsulated dichioromethylene diphosphonate in KRV and Poly I:C-treated DR-BB rats results in the near complete prevention of insulitis and diabetes. Measurement of the macrophage-derived cytokines IL-12, TNF-a, and IL-1f3 revealed a selective increase of their expression, after KRV infection, in the splenic lymphocytes and the pancreatic islets. Measurement of CD4 T-cell-derived cytokines revealed that IL-2 and IFN-y cytokine gene expression closely correlates with an elevation of IL-12, but IL-4 and IL-10 does not change. Depletion of macrophages before the isolation of splenic lymphocytes from DR-BB rats treated with KRV and Poly I:C resulted in the loss of ability to transfer diabetes to young DP-BB rats. On the basis of these observations, we conclude that macrophages and macrophage-derived cytokines play a critical role in the cascade of events leading to the destruction of pancreatic 3-cells, culminating in the development of IDDM.