Protective effect of ginsenoside Rb1 against aconitine cardiotoxicity studied by myocardial injury, action potential, and calcium signaling.

Aconitine is the main active component of Aconitum plants. Although aconitine has effects that include strengthening the heart, analgesia, anti-tumor, and immune-regulating effects, aconitine has both efficacy and toxicity, especially cardiotoxicity. Severe effects can include arrhythmia and cardiac arrest, which limits the clinical application of aconitine-containing traditional Chinese medicine. Ginsenoside Rb1(Rb1) is mainly found in plants, such as ginseng and Panax notoginseng, and has cardiovascular-protective and anti-arrhythmia effects. This study aimed to investigate the detoxifying effects of Rb1 on aconitine cardiotoxicity and the electrophysiological effect of Rb1 on aconitine-induced arrhythmia in rats. Pathological analysis, myocardial enzymatic indexes, and Western blotting were used to investigate the ameliorating effect of Rb1 on aconitine cardiotoxicity. Optical mapping was used to evaluate the effect of Rb1 on action potential and calcium signaling after aconitine-induced arrhythmia. Rb1 inhibited pathological damage caused by aconitine, decreased myocardial enzyme levels, and restored the balance of apoptotic protein expression by reducing the expression of Bax and cleaved caspase 3 and increasing the expression of Bcl-2, thereby reducing myocardial damage caused by aconitine. Rb1 also reduced the increase in heart rate caused by aconitine, accelerated action potential conduction and calcium signaling, and reduced the dispersion of action potential and calcium signal conduction. Rb1 reduced the cardiotoxicity of aconitine by attenuating aconitine-induced myocardial injury and inhibiting the aconitine-induced retardation of ventricular action potential and calcium signaling in rats.

[Variation Characteristics of Surface Water Quality in China in Recent Years].

Based on data from 839 comparable sections (sites) of the national surface water environmental quality monitoring network from 2012 to 2020, the variation tendency of surface water environmental quality over the past nine years was analyzed. The results showed that the environmental quality of surface water in China has continuously improved, the proportion of Grade Ⅰ-Ⅲ water quality increased steadily, and the proportion of inferior Grade Ⅴ water quality decreased in succession. The annual average concentration of ammonia nitrogen, total phosphorus, and permanganate index all showed a decreasing trend annually; compared with those in 2012, the three indicator concentrations respectively declined 75.9%, 48.2%, and 17.5% by 2020. In Guangxi, Hainan, and Ningxia, the proportion of Grade Ⅰ-Ⅲ water quality sections was maintained at 100%, whereas Hubei and Jiangxi showed a consecutive decreasing trend, and the other provinces showed a consecutive increasing trend. In Guangxi, Hainan, Ningxia, Hunan, and Fujian, the proportion of inferior Grade Ⅴ water quality sections remained at 0, and the other provinces showed a decreasing trend yearly. The annual average concentration of total phosphorus in Guangxi and Jiangxi and the permanganate index in Hubei, Hainan, and Liaoning increased annually, whereas that in the other provinces decreased to varying degrees. The proportion of Grade Ⅰ-Ⅲ water quality sections in Ten Major basins showed a fluctuating upward trend. The proportion of inferior Grade Ⅴ water quality in the Zhejiang and Fujian Slice Rivers was maintained at 0, and the other river basins showed a fluctuating and declining trend. The annual average of the main pollution indicators all decreased to varying degrees. In 2020, 53% of 32 important lakes were eutrophic, which increased 12% compared to that in 2012. On the whole, surface water quality has generally improved in China during the past nine years; especially since the 13th Five-Year Plan period, remarkable achievements have been made in the prevention and control of water pollution. However, there are differences among various provinces and basins, the improvement in water environmental quality is unbalanced and uncoordinated, water resources are distributed unevenly, and the eutrophication trend of lakes and reservoirs is not optimistic. In the future, water resources, water environment, and water ecology should be overall managed, and great attention should be focused on precise pollution control and ecological restoration of surface water.

Combination therapy with B7H3-redirected bispecific antibody and Sorafenib elicits enhanced synergistic antitumor efficacy.

Rationale: Current traditional treatment options are frequently ineffective to fight against ovarian cancer due to late diagnosis and high recurrence. Therefore, there is a vital need for the development of novel therapeutic agents. B7H3, an immune checkpoint protein, is highly expressed in various cancers, representing it a promising target for cancer immunotherapy. Although targeting B7H3 by bispecific T cell-engaging antibodies (BiTE) has achieved successes in hematological malignancies during recent years, attempts to use them for the treatment of solid cancers are less favorable, in part due to the heterogeneity of tumors. Sorafenib is an unselective inhibitor of multiple kinases currently being tested in clinical trials for several tumors, including ovarian cancer which showed limited activity and inevitable side effect for ovarian cancer treatment. However, it is able to enhance antitumor immune response, which indicates sorafenib may improve the efficiency of immunotherapy. Methods: We evaluated the expression of B7H3 in ovarian cancer using online database and validated its expression of tumor tissues by immunohistochemistry staining. Then, B7H3 expression and the effects of sorafenib on ovarian cancer cell lines were determined by flow cytometry. In addition, 2D and 3D ovarian cancer models were established to test the combined therapeutic effect in vitro. Finally, the efficiency of B7H3×CD3 BiTE alone and its combination with sorafenib were evaluated both in vitro and in vivo. Results: Our data showed that B7H3 was highly expressed in ovarian cancer compared with normal samples. Treatment with sorafenib inhibited ovarian cancer cell proliferation and induced a noticeable upregulation of B7H3 expression level. Further study suggested that B7H3×CD3 BiTE was effective in mediating T cell killing to cancer cells. Combined treatment of sorafenib and B7H3×CD3 BiTE had synergistic anti-tumor effects in ovarian cancer models. Conclusions: Overall, our study indicates that combination therapy with sorafenib and B7H3×CD3 BiTE may be a new therapeutic option for the further study of preclinical treatment of OC.