Dihydroartemisinin inhibits tumor progress via blocking ROR1-induced STAT3-activation in non-small cell lung cancer.

In non-small cell lung cancer (NSCLC), identifying a component with certain molecular targets can aid research on cancer treatment. Dihydroartemisinin (DHA) is a semisynthetic derivative of artemisinin which induced the anti-cancer effects via the STAT3 signaling pathway, but the underlying molecular mechanism is still elusive. In this study, we first proved that DHA prohibits the growth of tumors both in vitro and in vivo. Data from transcriptomics showed that DHA reduced the expression level of the genes involved in cell cycle-promoting and anti-apoptosis, and most importantly, DHA restricted the expression level of receptor tyrosine kinase-like orphan receptor 1 (ROR1) which has been reported to have abnormal expression on tumor cells and had close interaction with STAT3 signaling. Then, we performed comprehensive experiments and found that DHA remarkably decreased the expression of ROR1 at both mRNA and protein levels and it also diminished the phosphorylation level of STAT3 in NSCLC cell lines. In addition, our data showed that exogenously introduced ROR1 could significantly enhance the phosphorylation of STAT3 while blocking ROR1 had the opposite effects indicating that ROR1 plays a critical role in promoting the activity of STAT3 signaling. Finally, we found that ROR1 overexpression could partially reverse the decreased activity of STAT3 induced by DHA which indicates that DHA-induced anti-growth signaling is conferred, at least in part, through blocking ROR1-mediated STAT3 activation. In summary, our study indicates that in NSCLC, ROR1 could be one of the critical molecular targets mediating DHA-induced STAT3 retardation.

Screening anabolic androgenic steroids in human urine: an application of the state-of-the-art gas chromatography-Orbitrap high-resolution mass spectrometry.

Over the past few decades, anabolic androgenic steroids (AASs) have been abused in and out of competition for their performance-enhancing and muscle-building properties. Traditionally, AASs were commonly detected using gas chromatography-mass spectrometry in the initial testing procedure for doping control purposes. Gas chromatography-Orbitrap high-resolution mass spectrometry (GC-Orbitrap-HRMS) is a new technology that has many advantages in comparison with GC-MS (e.g., a maximum resolving power of 240,000 (FWHM at m/z 200), excellent sub-ppm mass accuracy, and retrospective data analysis after data acquisition). Anti-doping practitioners are encouraged to take full advantage of the updated techniques of chromatography-mass spectrometry to develop sensitive, specific, and rapid screening methods for AASs. A new method for screening a wide range of AASs in human urine using GC-Orbitrap-HRMS was developed and validated. The method can qualitatively determine 70 anabolic androgenic steroids according to the minimum required performance limit of the World Anti-Doping Agency. Moreover, the validated method was successfully applied to detect six metabolites in urine after the oral administration of metandienone, and their excretion curves in vivo were studied. Metandienone M6 (17ß-hydroxymethyl-17α-methyl-18-nor-androst-1,4,13-trien-3-one) has been identified as a long-term urinary metabolite which can be detected up to 7 weeks, thus providing a longer detection window compared with previous studies. This study provides a rationale for GC-Orbitrap-HRMS in drug metabolism and non-targeted screening.

Limonin alleviates high-fat diet-induced dyslipidemia by regulating the intestinal barrier via the microbiota-related ILC3-IL22-IL22R pathway.

High-fat diet (HFD)-induced dyslipidemia is frequently accompanied by gut microbiota dysbiosis and a compromised gut barrier. Enhancing the intestinal barrier function emerges as a potential therapeutic approach for dyslipidemia. The ILC3-IL22-IL22R pathway, which responds to dietary and microbial signals, has not only attracted attention for its crucial role in maintaining the intestinal barrier, but recent reports have also suggested its potential in regulating lipid metabolism. Limonin is derived from the Chinese herb Evodiae fructus, which has shown potential in ameliorating dysbiosis of serum lipids. However, its underlying mechanisms remain elusive. Consequently, targeting the ILC3-IL22-IL22R pathway to enhance intestinal barrier function holds promise as a therapeutic approach for dyslipidemia. In this study, male C57BL/6 mice were subjected to a 16-week HFD to induce dyslipidemia and concurrently administered oral limonin. We discovered that limonin supplementation dramatically reduced serum lipid profiles in HFD-fed mice, significantly curbing HFD-induced weight gain and epididymal fat accumulation. Ileal histopathological evaluation indicated limonin's ameliorative effects on HFD-induced intestinal barrier impairment. Limonin also moderated the intestinal microbiota dysbiosis, which is characterized by the elevation of Firmicutes in HFD mice, and notably amplified the abundance of probiotic Lactobacillus. In addition, supported by flow cytometry and other analyses, we observed that limonin upregulated the ILC3-IL22-IL22R pathway, enhancing phosphorylated STAT3 (pSTAT3) in intestinal epithelial cells (IECs), thereby reducing lipid transporter expression. In conclusion, our study revealed that limonin exerted a promising preventive effect against HFD-induced dyslipidemia by the mitigation of the intestinal barrier function and intestinal microbiota, and its mechanism was related to the upregulation of the ILC3-IL22-IL22R pathway.

Controllable Assembly of Cu2+ and Chlorin E6 for H2 S-Activatable Recognition of Bacterial Infection and Enhanced Antibacterial Therapy.

Antibacterial photodynamic therapy (APDT) has emerged as one of the intriguing strategies to combat bacterial resistance. However, the antibacterial efficacy of APDT is found to be severely impacted by the hydrogen sulfide (H2 S)-overproduced bacterial infection microenvironment. Herein, a multifunctional APDT platform is developed by assembling Cu2+ and chlorin e6 (Ce6), which exhibits unique H2 S-activatable fluorescence (FL) and antibacterial features. Noteworthily, the assembly conditions are crucial for achievement of Cu-Ce6 nanoassemblies (NAs) with the on-demand responsive properties. The quenched FL and photosensitization of Cu-Ce6 NAs can be selectively activated by the overexpressed H2 S in infected area, enabling specific recognition of bacterial infection and localized antibacterial therapy with minimized side effects. Significantly, amplified oxidative stress is achieved owning to the effective consumption of H2 S by Cu2+ in the NAs, leading to an enhanced APDT. The antibacterial mechanisms including broad-spectrum APDT activity of released Ce6, inherent sterilization effects of produced copper polysulfides and the accompanying disturbance of bacterial sulphide metabolism are further identified. This study may pave a new avenue for the rational design of intelligent APDT platform using minimalist biological building units and thus facilitating the clinical translation of nano-antibacterial agents.

Use of consecutive transcutaneous oxygen measurement when assessing the need for revascularization and association with the outcomes of ischemic diabetic ulcers.

This study compared the ankle-brachial index (ABI) with transcutaneous oxygen pressure (TcPO2 ) in assessing peripheral vascular disease (PVD) prevalence in 100 diabetic foot ulcer (DFU) patients. Patients were categorized into vascular or nonvascular reconstruction groups and underwent both ABI and TcPO2 measurements four times over 6 months. Predictive validity for PVD diagnosis was analysed using the area under the receiver-operating characteristic curve (AUC). The study found TcPO2 to be a superior predictor of PVD than ABI. Among the DFU patients, 51 with abnormal TcPO2 values underwent vascular reconstruction. Only TcPO2 values showed significant pretreatment differences between the groups and increased post-reconstruction. These values declined over a 6-month follow-up, whereas ABI values rose. For those with end-stage renal disease (ESRD), TcPO2 values saw a sharp decrease within 3 months. Pre-reconstruction TcPO2 was notably lower in amputation patients versus limb salvage surgery patients. In conclusion, TcPO2 is more effective than ABI for evaluating ischemic limb perfusion and revascularization necessity. It should be prioritized as the primary follow-up tool, especially for ESRD patients.

Antitumor activity of a ROR1 × CD3 bispecific antibody in non-small cell lung cancer.

Over the last decade, immuno-oncologic drugs especially CD3-engaging bispecific antibodies (biAbs) are experiencing fast-paced evolution, but big challenges still exist in the clinical development of biAbs in solid tumors, especially non-small cell lung cancer (NSCLC). In this study, we choose a ROR1 × CD3 biAb in scFv-Fc format, named R11 × v9 biAb, to investigate its tumor-inhibiting role in NSCLC. Notably, the ROR1-engaging arm binds both human and mouse ROR1. We found that R11 × v9 biAb specifically binds T cells and tumor cells simultaneously, and dose-dependent cytotoxicity was detected for various ROR1+ NSCLC cell lines. Further, R11 × v9 biAb mediated T-cell derived proinflammatory cytokine secretion, boosted granzyme B and perforin production from CD8+ T cells, and recruited more CD4+ T cells and CD8+ T cells into the tumor tissues. The antitumor activity of R11 × v9 biAb was confirmed in two xenograft mouse models of ROR1+ NSCLC. Importantly, no harmful side effects were observed in these in vivo studies, warranting further preclinical and clinical studies of R11 × v9 biAb in NSCLC.

Recent Advances of Marine Natural Indole Products in Chemical and Biological Aspects.

The ocean has always been one of the important sources of natural products. In recent years, many natural products with different structures and biological activities have been obtained, and their value has been clearly recognized. Researchers have been deeply engaged in the field of separation and extraction, derivative synthesis, structural studies, biological evaluation, and other fields of research for marine natural products. Thus, a series of marine indole natural products which have structural and biological prospect have caught our eyes. In this review, we summarize some of these marine indole natural products with relatively good pharmacological activity and research value, and discuss issues concerning chemistry, pharmacological activity, biological evaluation, and synthesis, including monomeric indoles, indole peptides, bis-indoles, and annelated indoles. Most of the compounds have cytotoxic, antiviral, antifungal, or anti-inflammatory activities.

A Residual Network and FPGA Based Real-Time Depth Map Enhancement System.

Depth maps obtained through sensors are often unsatisfactory because of their low-resolution and noise interference. In this paper, we propose a real-time depth map enhancement system based on a residual network which uses dual channels to process depth maps and intensity maps respectively and cancels the preprocessing process, and the algorithm proposed can achieve real-time processing speed at more than 30 fps. Furthermore, the FPGA design and implementation for depth sensing is also introduced. In this FPGA design, intensity image and depth image are captured by the dual-camera synchronous acquisition system as the input of neural network. Experiments on various depth map restoration shows our algorithms has better performance than existing LRMC, DE-CNN and DDTF algorithms on standard datasets and has a better depth map super-resolution, and our FPGA completed the test of the system to ensure that the data throughput of the USB 3.0 interface of the acquisition system is stable at 226 Mbps, and support dual-camera to work at full speed, that is, 54 fps@ (1280 × 960 + 328 × 248 × 3).

Efficient Synthesis of 2,3'-Spirobi (Indolin)-2'-Ones and Preliminary Evaluation of Their Damage to Mitochondria in HeLa Cells.

A novel formal (4 + 1) annulation between N-(o-chloromethyl)aryl amides and 3-chlorooxindoles through in situ generated aza-ortho-QMs with 3-chlorooxindoles is reported for the synthesis of a series of 2,3'-spirobi (indolin)-2'-ones in high yields. Under structured illumination microscopy, compound 3a is found to change the mitochondrial morphology and induce mitophagy pathway, which might then trigger mitophagy in cancer cells.