Diallyl trisulfide alleviates chemotherapy sensitivity of ovarian cancer via the AMPK/SIRT1/PGC1α pathway.

Platinum-based chemotherapy promotes drug resistance in ovarian cancer. We investigated the antichemoresistance characteristics of diallyl trisulfide (DATS) in cisplatin-resistant ovarian cancer cells, in vitro and in vivo. Previous preclinical studies have revealed that DATS regulates distinct hallmark cancer-signaling pathways. The cell cycle pathway is the most investigated signaling pathway in DATS. Additionally, post-DATS treatment has been found to promote proapoptotic capacity through the regulation of intrinsic and extrinsic apoptotic pathway components. In the present study, we found that treating cisplatin-sensitive and cisplatin-resistant ovarian cell lines with DATS inhibited their proliferation and reduced their IC50. It induced cell apoptosis and promoted oxidative phosphorylation through the regulation of the AMPK/SIRT1/PGC1α pathway, OXPHOS, and enhanced chemotherapy sensitivity. DATS treatment alleviated glutamine consumption in cisplatin-resistant cells. Our findings highlight the role of DATS in overcoming drug resistance in ovarian cancer in vitro and in vivo. In addition, we elucidated the role of the AMPK/SIRT1/PGC1α signaling pathway as a potential target for the treatment of drug-resistant ovarian cancer.

Electrochemical Tri- and Difluoromethylation-Triggered Cyclization Accompanied by the Oxidative Cleavage of Indole Derivatives.

Considering their unique roles in organic synthesis, and pharmaceutical and agrochemical applications, the development of fluoroalkylation, cyclization, and indole oxidative cleavage are important topics. Herein, an unprecedented electrochemical tri- and difluoromethylation/cyclization/indole oxidative cleavage process occurring in an undivided cell is presented. The protocol employs a readily prepared Langlois reagent as the fluoroalkyl source, affording a series of tri- or difluoromethylated 2-(2-acetylphenyl)isoquinoline-1,3-diones in good yields with excellent stereoselectivity. It is worth noting that this new methodology merges the fluoroalkylation/cyclization of N-substituted acrylamide alkenes with the oxidative cleavage of an indole C(2)=C(3) bond under external oxidant-free conditions.

Co-Crystals of Resveratrol and Polydatin with L-Proline: Crystal Structures, Dissolution Properties, and In Vitro Cytotoxicities.

Resveratrol (RSV) and polydatin (PD) have been widely used to treat several chronic diseases, such as atherosclerosis, pulmonary fibrosis, and diabetes, among several others. However, their low solubility hinders their further applications. In this work, we show that the solubility of PD can be boosted via its co-crystallization with L-proline (L-Pro). Two different phases of co-crystals, namely the RSV-L-Pro (RSV:L-Pro = 1:2) and PD-L-Pro (PD:L-Pro = 1: 3), have been prepared and characterized. As compared to the pristine RSV and PD, the solubility and dissolution rates of PD-L-Pro in water (pH 7.0) exhibited a 15.8% increase, whereas those of RSV-L-Pro exhibited a 13.8% decrease. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay of pristine RSV, PD, RSV-L-Pro, and PD-L-Pro against lung cancer cell line A549 and human embryonic kidney cell line HEK-293 indicated that both compounds showed obvious cytotoxicity against A549, but significantly reduced cytotoxicity against HEK-293, with PD/PD-L-Pro further exhibiting better biological safety than that of RSV/RSV-L-Pro. This work demonstrated that the readily available and biocompatible L-Pro can be a promising adjuvant to optimize the physical and chemical properties of RSV and PD to improve their pharmacokinetics.

Effects of ocean eddies on the tropical storm Roanu intensity in the Bay of Bengal.

A tropical storm (TS) Roanu occurred in northern Sri Lanka in 2016, which transported northwards along the west coast of the Bay of Bengal (BoB). During the development of the TS, ocean eddies on its track had an important effect on the intensity of Roanu. The dynamic mechanism was investigated with multisource reanalysis and Argo float data in this study. The results show that ocean eddies were the main reason why Roanu first enhanced, weakened, and then enhanced again. Warm eddy W1 supports the initial development of the TS, cold eddy C1 weakens Roanu, and warm eddy W2 continues to support Roanu. On May 19, 2016, the maximum average latent heat flux over W1 was 260.85 w/m2, while that of C1 was only 200.71 w/m2. After the passage of Roanu, the tropical cyclone heat potential (TCHP) of eddies significantly decreased. The TCHP of W1, W2, C1 and C2 decreased by 20.95 kJ/cm2, 11.07 kJ/cm2, 29.82 kJ/cm2, 9.31 kJ/cm2, respectively. The mixed layer of warm eddies deepened much more than that of cold eddies, supporting Roanu development. In addition, changes in potential vorticity (PV) values caused by the disturbance of eddies may also reflect changes in the TS intensity. This study offers new insights on the influence of ocean eddies in regulating the development of tropical cyclone (TC) in the BoB.

Anti-Autophagy Mechanism of Zhi Gan Prescription Based on Network Pharmacology in Nonalcoholic Steatohepatitis Rats.

Background and Aims: Zhi Gan prescription (ZGP) has been clinically proven to exert a favorable therapeutic effect on nonalcoholic steatohepatitis (NASH). This study purpose to reveal the underlying molecular mechanisms of ZGP action in NASH. Methods: Systematic network pharmacology was used to identify bioactive components, potential targets, and the underlying mechanism of ZGP action in NASH. High fat (HF)-induced NASH model rats were used to assess the effect of ZGP against NASH, and to verify the possible molecular mechanisms as predicted by network pharmacology. Results: A total of 138 active components and 366 potential targets were acquired in ZGP. In addition, 823 targets of NASH were also screened. In vivo experiments showed that ZGP significantly improved the symptoms in HF-induced NASH rats. qRT-PCR and western blot analyses showed that ZGP could regulate the hub genes, PTEN, IL-6 and TNF in NASH model rats. In addition, ZGP suppressed mitochondrial autophagy through mitochondrial fusion and fission via the PINK/Parkin pathway. Conclusion: ZGP exerts its effects on NASH through mitochondrial autophagy. These findings provide novel insights into the mechanisms of ZGP in NASH.

Visible-Light Photocatalytic Tri- and Difluoroalkylation Cyclizations: Access to a Series of Indole[2,1-a]isoquinoline Derivatives in Continuous Flow.

A process for achieving photocatalyzed tri- and difluoromethylation/cyclizations for constructing a series of tri- or difluoromethylated indole[2,1-a]isoquinoline derivatives is described. This protocol utilized an inexpensive organic photoredox catalyst and provided good yields. Moreover, the combination of continuous flow and photochemistry, designed to provide researchers with a unique green process, was also shown to be key to allowing the reaction to proceed (product yield of 83% in flow vs 0% in batch).

Photocatalytic radical defluoroalkylation of unactivated alkenes via distal heteroaryl ipso-migration.

Currently, the selective activation of C(sp3)-F bonds and C-C bonds constitute one of the most widely used procedures for the synthesis of high-value products that range from pharmaceuticals to agrochemical applications. While numerous examples of these two methods have been reported in their respective fields, the processes which merge the activation of both single C(sp3)-F bonds and C-C bonds in one step still remain elusive. Here, we demonstrate the controllable defluoroalkylation-distal functionalization of trifluoromethylarenes with unactivated alkenes via distal heteroaryl migration. This is proposed to proceed via tandem C(sp3)-F and C-C bond cleavage using visible-light photoredox catalysis combined with Lewis acid activation. This strategy provides facile and flexible access to multiply functionalized α,α-difluorobenzylic ketones in useful yields (up to 88%) under mild conditions. The products can be further transformed into other valuable compounds, demonstrating the method's utility.

Electrochemical Sulfonylation/Heteroarylation of Alkenes via Distal Heteroaryl ipso-Migration.

A direct electrooxidative sulfonylation/heteroarylation reaction of alkenes with sulfinic acids, which proceeds through distal heteroaryl ipso-migration and C-S and C-C bond formations, is reported. This electro-synthetic method offers an efficient and environmentally friendly entry to prepare various sulfonated functionalized heteroarenes under an undivided cell at room temperature, avoiding the use of any metal catalysts, additives, and oxidants. Preliminary mechanistic studies indicated a radical pathway.