Qingda granule alleviate angiotensin â ±-induced hypertensive renal injury by suppressing oxidative stress and inflammation through NOX1 and NF-κB pathways.

Hypertension has become one of the important diseases harmful to human health. In China, Qingda granule (QDG) has been used to treat hypertension for decades. Previous studies by our team have shown that oxidative stress may be one of the pathways through which QDG inhibits hypertension-induced organs injury. However, the specific molecular mechanism of its anti-hypotension and renal oxidative stress response were unclearly. This study investigated QDG's potential protective mechanism against hypertension-induced renal injury. Mice were infused with Angiotensin Ⅱ (Ang Ⅱ, 500 ng/kg/min) or equivalent saline solution (Control) and administered oral QDG (1.145 g/kg/day) or saline for four weeks. QDG treatment mitigated the elevated blood pressure and reduced renal pathological changes induced by Ang Ⅱ. As per the RNA sequencing results, QDG affects oxidative stress signaling. In agreement with these findings, QDG significantly attenuated the Ang Ⅱ-induced increase in Nitrogen oxides 1 (NOX1) and reactive oxygen species and the decrease in superoxide dismutase in renal tissue. Additionally, QDG significantly inhibited Interleukin 6 (IL-6), Tumor necrosis factor α (TNF-α), and Interleukin 1ß (IL-1ß) expression in renal tissues and blocked the phosphorylation of P65 (NF-κB subunit) and IκB. These results were confirmed in vitro. Overall, QDG reduced Ang Ⅱ-induced elevated blood pressure and renal injury by inhibiting oxidative stress and inflammation caused by NOX1 and NF-κB pathways. The results of this study provide an experimental basis for the clinical application of QDG, and to open up a new direction for the clinical treatment of hypertension.

Huoxin Pill inhibits isoproterenol-induced transdifferentiation and collagen synthesis in cardiac fibroblasts through the TGF-ß/Smads pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: The abnormal proliferation and differentiation of cardiac fibroblasts (CFs) are universally regarded as the key process for the progressive development of cardiac fibrosis following various cardiovascular diseases. Huoxin Pill (Concentrated pill, HXP) is a Chinese herbal formula for treating coronary heart disease. However, the cellular and molecular mechanisms of HXP in the treatment of myocardial fibrosis are still unclear. AIM OF THE STUDY: To investigate the effects of HXP on CFs transdifferentiation and collagen synthesis under isoproterenol (ISO) conditions, as well as the potential mechanism of action. MATERIALS AND METHODS: In vivo, we established a rat model of cardiac fibrosis induced by ISO, and administered with low or high dose of HXP (10 mg/kg/day or 30 mg/kg/day). The level of α-SMA was detected by immunohistochemistry examination, and combined with RNA-sequencing analysis to determine the protective effect of HXP on myocardial fibrosis rats. In vitro, by culturing primary rat CFs, we examined the effects of HXP on the proliferation and transdifferentiation of CFs using CCK8, scratch wound healing and immunofluorescence assays. Western blot was used to determine protein expression. RESULTS: The findings revealed that HXP protects against ISO-induced cardiac fibrosis and CFs transdifferentiation in rats. RNA-sequencing and pathway analyses demonstrated 238 or 295 differentially expressed genes (DEGs) and multiple enriched signal pathways, including transforming growth factor-beta (TGF-ß) receptor signaling activates Smads, downregulation of TGF-ß receptor signaling, signaling by TGF-ß receptor complex, and collagen formation under treatment with low or high-dose of HXP. Moreover, HXP also markedly inhibited ISO-induced primary rat CFs proliferation, transdifferentiation, collagen synthesis and the upregulation of TGF-ß1 and phosphorylated Smad2/3 protein expression. CONCLUSION: HXP suppresses ISO-induced CFs transdifferentiation and collagen synthesis, and it may exert these effects in part by inhibiting the activation of the TGF-ß/Smads pathway. This may be a new therapeutic tool for cardiac fibrosis.

Huoxin Pill Attenuates Cardiac Inflammation by Suppression of TLR4/NF-κB in Acute Myocardial Ischemia Injury Rats.

Huoxin Pill (HXP), a traditional Chinese medicine, has been prescribed widely in the treatment of coronary heart disease, angina pectoris, and other diseases. However, the possible protective mechanisms of HXP on myocardial ischemia remain unclear. In the current study, we investigated the effects and potential mechanism of HXP on myocardial ischemia and cardiac inflammation and the activation of TLR4/NF-κB pathway. Determination of electrocardiogram, echocardiography, and heart weight index (HWI) indicated that HXP treatment obviously attenuated the elevation of ST-segment, end-diastolic volume, and HWI in the AMI rat model. Enzyme-linked immunosorbent assay (ELISA) demonstrated that Huoxin Pill treatment significantly decreased the levels of CTnT, CK-MB, MDA, IL-6, and TNF-α, while it increased SOD content in serum of the AMI rat model. Moreover, hematoxylin and eosin (HE) and immunohistochemistry (IHC) staining revealed that HXP treatment alleviated pathological change, infiltration of inflammatory cells, levels of IL-6 and TNF-α, and expression of TLR4 and p-NF-κB in cardiac tissues of the AMI rat model. In conclusion, HXP treatment significantly improves cardiac function and attenuates cardiac inflammation by suppressing the activation of TLR4/NF-κB pathway in the ISO-induced AMI rat model. This study provides insights into the potential of HXP on prevention and treatment of AMI.

A new class of synthetic retinoid antibiotics effective against bacterial persisters.

A challenge in the treatment of Staphylococcus aureus infections is the high prevalence of methicillin-resistant S. aureus (MRSA) strains and the formation of non-growing, dormant 'persister' subpopulations that exhibit high levels of tolerance to antibiotics and have a role in chronic or recurrent infections. As conventional antibiotics are not effective in the treatment of infections caused by such bacteria, novel antibacterial therapeutics are urgently required. Here we used a Caenorhabditis elegans-MRSA infection screen to identify two synthetic retinoids, CD437 and CD1530, which kill both growing and persister MRSA cells by disrupting lipid bilayers. CD437 and CD1530 exhibit high killing rates, synergism with gentamicin, and a low probability of resistance selection. All-atom molecular dynamics simulations demonstrated that the ability of retinoids to penetrate and embed in lipid bilayers correlates with their bactericidal ability. An analogue of CD437 was found to retain anti-persister activity and show an improved cytotoxicity profile. Both CD437 and this analogue, alone or in combination with gentamicin, exhibit considerable efficacy in a mouse model of chronic MRSA infection. With further development and optimization, synthetic retinoids have the potential to become a new class of antimicrobials for the treatment of Gram-positive bacterial infections that are currently difficult to cure.