Polyphyllin D punctures hypertrophic lysosomes to reverse drug resistance of hepatocellular carcinoma by targeting acid sphingomyelinase.

Hypertrophic lysosomes are critical for tumor progression and drug resistance; however, effective and specific lysosome-targeting compounds for cancer therapy are lacking. Here we conducted a lysosomotropic pharmacophore-based in silico screen in a natural product library (2,212 compounds), and identified polyphyllin D (PD) as a novel lysosome-targeted compound. PD treatment was found to cause lysosomal damage, as evidenced by the blockade of autophagic flux, loss of lysophagy, and the release of lysosomal contents, thus exhibiting anticancer effects on hepatocellular carcinoma (HCC) cell both in vitro and in vivo. Closer mechanistic examination revealed that PD suppressed the activity of acid sphingomyelinase (SMPD1), a lysosomal phosphodieserase that catalyzes the hydrolysis of sphingomyelin to produce ceramide and phosphocholine, by directly occupying its surface groove, with Trp148 in SMPD1 acting as a major binding residue; this suppression of SMPD1 activity irreversibly triggers lysosomal injury and initiates lysosome-dependent cell death. Furthermore, PD-enhanced lysosomal membrane permeabilization to release sorafenib, augmenting the anticancer effect of sorafenib both in vivo and in vitro. Overall, our study suggests that PD can potentially be further developed as a novel autophagy inhibitor, and a combination of PD with classical chemotherapeutic anticancer drugs could represent a novel therapeutic strategy for HCC intervention.

Hsa-miR-335 enhances cell migration and invasion in lung adenocarcinoma through targeting Copine-1.

Lung adenocarcinoma (LAC) is one of the most common pulmonary adenocarcinomas with a high peak of mortality, and metastasis is the main culprit of LAC deaths. microRNAs play important role in cancer metastasis, and thus are regarded as potential diagnostic and prognostic markers for human cancers. However, many miRNAs exhibit dual roles in diverse cellular contexts. Here, we revealed that hsa-miR-335, a previously reported tumor suppressor, exhibited an oncogenic role in LAC. Overexpression of miR-335 enhanced the abilities of A549 and H1299 cells to invade and migrate by regulating epithelial-mesenchymal transition, while inhibition of miR-335 exhibited an opposite effect in vitro and in vivo. Mechanically, miR-335 inhibited the expression of Copine-1 (CPNE1), an NF-κB suppressor, through interacting with its mRNA 3'UTR, while mutating the binding sites abolished this inhibitory effect. This finding not only highlights the suppressive effect of CPNE1 on cell motility, but also provides new insight into miR-335 in promoting LAC metastasis.

[Efficacy and future of endoscopic bariatric surgery in the treatment of obesity and metabolic diseases].

The emerging endoscopic technologies are proved to be effective treatments for obesity in selected patients and to offer the potential advantages of reduced invasiveness, reversibility and repeatability. From the view of operation principle, endoscopic technologies can be classified as restrictive procedure, malabsorption procedure and endoscopic revision of gastric bypass. Restrictive procedures include intragastric balloon, aspiration therapy, endoscopic sleeve gastroplasty (ESG) and transoral gastroplasty. Intragastric balloon employs space occupying, volume restriction and satiety mechanisms, which is superior to drugs and lifestyle change, but shorter than sleeve and bypass surgery. Aspiration therapy is similar to standard percutaneous endoscopic gastrostomy, while there are no available data regarding the obesity and metabolic improvement. Compared with traditional bariatric surgery, ESG does not excise gastric tissue with less complications and without weight regain, but it can not be used as an independent operation still now. Transoral gastroplasty is rarely applied clinically whose efficacy and long-term complications need further studies. Malabsorption surgery includes endoscopic duodenojejunal bypass sleeve (EDJBS) and endoscopic gastroduodenojejunal bypass sleeve(EGDJBS). EDJBS may have the similar mechanism like bypass reducing the blood glucose. Even with obvious effect of weight loss, EDJBS has high morbidity of complications and requirements of the skilled operators. EGDJBS, which imitates bypass anatomy changes and belongs to the mixed operation, should be superior to the above procedures in reducing weight theoretically, but due to the lack of clinical data, its short-term and long-term efficacy still need further clinical observation. As compared to the complexity and risks associated with telescopic surgical revision, endoscopic suturing has been confirmed as less invasive and safer for stomal revisions, while its long-term efficacy of reducing weight and improvement of diabetes are not yet clear. Even if long-term efficacy of reducing weight and morbidity of complication in endoscopic bariatric surgery are still indefinite, and clinical trial researches of large sample and long-term follow-up are absent, with the development of endoscopic skill and the gradual clinical application, endoscopic bariatric surgery will provide a new option for the patients of obesity and metabolic diseases.