Transcriptomics analysis of LINC02202/XBP1 axis in melanoma: Implications for drug targeting and PD-1 monoclonal antibody efficacy.

Malignant melanoma (MM) is a highly aggressive and deadly form of skin cancer, primarily caused by recurrence and metastasis. Therefore, it is crucial to investigate the regulatory mechanisms underlying melanoma recurrence and metastasis. Our study has identified a potential targeted regulatory relationship between LINC02202, miR-526b-3p and XBP1 in malignant melanoma. Through the regulation of the miR-526b-3p/XBP1 signalling pathway, LINC02202 may play a role in tumour progression and immune infiltration and inhibiting the expression of LINC02202 can increase the efficacy of immunotherapy for melanoma. Our findings shed light on the impact of LINC02202/XBP1 on the phenotype and function of malignant melanoma cells. Furthermore, this study provides a theoretical foundation for the development of novel immunotherapy strategies for malignant melanoma.

[Effects of elevated CO2 concentration, warming, and winter wheat planting on soil enzyme activities.] / CO2æµ“åº¦å‡é«˜ã€å¢žæ¸©å’Œå†¬å°éº¦ç§æ¤å¯¹åœŸå£¤é ¶æ´»æ€§çš„å½±å“.

Understanding the responses of soil enzyme activities to elevated CO2 concentration and warming can provide a scientific basis for nutrient management of croplands under global climate change. We conducted a pot expe-riment with climate chamber to examine the effects of elevated CO2 concentration and warming and winter wheat growth on soil enzyme activities. There were four climate scenarios: control (CK, 400 µmol·mol-1 CO2 concentration+normal ambient temperature), and CO2 concentration elevation (ECO2, 800 µmol·mol-1 CO2 concentration+normal ambient temperature), elevated temperature (ET, 400 µmol·mol-1 + temperature increased 4 ℃), and elevated CO2 concentration and temperature (ECO2+T, 800 µmol·mol-1 CO2 concentration + temperature increased 4 ℃). We measured the activities of soil ß-glucosidase (ßG), ß-N-acetyl glucosidase (NAG), alkaline phosphate (ALP) and polyphenol oxidase (PPO) at four growth stages (JS, jointing stage; AS, anthesis stage; FS, filling stage and MS, maturity stage), with and without winter wheat planting. Without winter wheat planting, there was no significant difference in four kinds of soil enzyme activities between ECO2 and CK, while ET and ECO2+T treatments had significant negative effect on soil enzyme activities. With winter wheat planting, compared with CK, ECO2 and ECO2+T treatments did not affect the activities of those four soil enzyme; but the ET treatment had great impact on soil ALP and PPO activities. The activities of four kinds of soil enzyme were significantly diffe-rent between the ET and ECO2+T treatments. Compared with ET treatment, ECO2+T treatment increased soil ßG activity at the JS, decreased NAG activity at the JS, increased ALP activity at both AS and FS, decreased PPO activity in the JS and increased in the AS. The interaction of elevated CO2 concentration and warming had significant effect on soil NAG and ALP activities with and without winter wheat planting. The interaction of warming and expe-rimental stage had significant effect on four kinds of soil enzyme activities without winter wheat planting, but the interaction of warming and crop growth stage had significant effect on ALP and PPO activities with winter wheat planting. The interaction of elevated CO2 concentration, warming and experimental period had significant effect on soil ßG, ALP and PPO activities without winter wheat growth, while with winter wheat growth, it had significant impact on NAG, ALP and PPO activities. The winter wheat growth had significantly inhibitory effect on ßG, NAG and ALP activities in the two early growth periods (JS+AS), significant promoting effect in the later growth periods (FS+MS), and significantly inhibitory effect on PPO activity during whole growth period. Overall, elevated CO2 concentration did not affect soil enzyme activities, while the elevation of CO2 concentration and temperature on soil enzyme activities differed among the soil enzymes at different growth stages. In addition, the responses of four soil enzyme activities to the interaction of elevated CO2 concentration and warming varied with and without winter wheat planting.

Potential drug discovery for COVID-19 treatment targeting Cathepsin L using a deep learning-based strategy.

Cathepsin L (CTSL), a cysteine protease that can cleave and activate the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, could be a promising therapeutic target for coronavirus disease 2019 (COVID-19). However, there is still no clinically available CTSL inhibitor that can be used. Here, we applied Chemprop, a newly trained directed-message passing deep neural network approach, to identify small molecules and FDA-approved drugs that can block CTSL activity to expand the discovery of CTSL inhibitors for drug development and repurposing for COVID-19. We found 5 molecules (Mg-132, Z-FA-FMK, leupeptin hemisulfate, Mg-101 and calpeptin) that were able to significantly inhibit the activity of CTSL in the nanomolar range and inhibit the infection of both pseudotype and live SARS-CoV-2. Notably, we discovered that daptomycin, an FDA-approved antibiotic, has a prominent CTSL inhibitory effect and can inhibit SARS-CoV-2 pseudovirus infection. Further, molecular docking calculation showed stable and robust binding of these compounds with CTSL. In conclusion, this study suggested for the first time that Chemprop is ideally suited to predict additional inhibitors of enzymes and revealed the noteworthy strategy for screening novel molecules and drugs for the treatment of COVID-19 and other diseases with unmet needs.

Berberine is an insulin secretagogue targeting the KCNH6 potassium channel.

Coptis chinensis is an ancient Chinese herb treating diabetes in China for thousands of years. However, its underlying mechanism remains poorly understood. Here, we report the effects of its main active component, berberine (BBR), on stimulating insulin secretion. In mice with hyperglycemia induced by a high-fat diet, BBR significantly increases insulin secretion and reduced blood glucose levels. However, in mice with hyperglycemia induced by global or pancreatic islet ß-cell-specific Kcnh6 knockout, BBR does not exert beneficial effects. BBR directly binds KCNH6 potassium channels, significantly accelerates channel closure, and subsequently reduces KCNH6 currents. Consequently, blocking KCNH6 currents prolongs high glucose-dependent cell membrane depolarization and increases insulin secretion. Finally, to assess the effect of BBR on insulin secretion in humans, a randomized, double-blind, placebo-controlled, two-period crossover, single-dose, phase 1 clinical trial (NCT03972215) including 15 healthy men receiving a 160-min hyperglycemic clamp experiment is performed. The pre-specified primary outcomes are assessment of the differences of serum insulin and C-peptide levels between BBR and placebo treatment groups during the hyperglycemic clamp study. BBR significantly promotes insulin secretion under hyperglycemic state comparing with placebo treatment, while does not affect basal insulin secretion in humans. All subjects tolerate BBR well, and we observe no side effects in the 14-day follow up period. In this study, we identify BBR as a glucose-dependent insulin secretagogue for treating diabetes without causing hypoglycemia that targets KCNH6 channels.

Cathepsin L plays a key role in SARS-CoV-2 infection in humans and humanized mice and is a promising target for new drug development.

To discover new drugs to combat COVID-19, an understanding of the molecular basis of SARS-CoV-2 infection is urgently needed. Here, for the first time, we report the crucial role of cathepsin L (CTSL) in patients with COVID-19. The circulating level of CTSL was elevated after SARS-CoV-2 infection and was positively correlated with disease course and severity. Correspondingly, SARS-CoV-2 pseudovirus infection increased CTSL expression in human cells in vitro and human ACE2 transgenic mice in vivo, while CTSL overexpression, in turn, enhanced pseudovirus infection in human cells. CTSL functionally cleaved the SARS-CoV-2 spike protein and enhanced virus entry, as evidenced by CTSL overexpression and knockdown in vitro and application of CTSL inhibitor drugs in vivo. Furthermore, amantadine, a licensed anti-influenza drug, significantly inhibited CTSL activity after SARS-CoV-2 pseudovirus infection and prevented infection both in vitro and in vivo. Therefore, CTSL is a promising target for new anti-COVID-19 drug development.

Emerging relationship between RNA helicases and autophagy.

RNA helicases, the largest family of proteins that participate in RNA metabolism, stabilize the intracellular environment through various processes, such as translation and pre-RNA splicing. These proteins are also involved in some diseases, such as cancers and viral diseases. Autophagy, a self-digestive and cytoprotective trafficking process in which superfluous organelles and cellular garbage are degraded to stabilize the internal environment or maintain basic cellular survival, is associated with human diseases. Interestingly, similar to autophagy, RNA helicases play important roles in maintaining cellular homeostasis and are related to many types of diseases. According to recent studies, RNA helicases are closely related to autophagy, participate in regulating autophagy, or serve as a bridge between autophagy and other cellular activities that widely regulate some pathophysiological processes or the development and progression of diseases. Here, we summarize the most recent studies to understand how RNA helicases function as regulatory proteins and determine their association with autophagy in various diseases.

Comparison of volatile profiles and bioactive components of sun-dried Pu-erh tea leaves from ancient tea plants on Bulang Mountain measured by GC-MS and HPLC.

To explore the volatile profiles and the contents of ten bioactive components (polyphenols and caffeine) of sun-dried Pu-erh tea leaves from ancient tea plants on Bulang Mountain, 17 samples of three tea varieties were analyzed by headspace-solid phase microextraction-gas chromatography-mass spectrometry (HS-SPME-GC-MS) and high-performance liquid chromatography (HPLC). A total of 75 volatile components were tentatively identified. Laomaner (LME), Laobanzhang (LBZ), and other teas on Bulang Mountain (BL) contained 70, 53, and 71 volatile compounds, respectively. Among the volatile compounds, alcohols (30.2%-45.8%), hydrocarbons (13.7%-17.5%), and ketones (12.4%-23.4%) were qualitatively the most dominant volatile compounds in the different tea varieties. The average content of polyphenol was highest in LME (102.1 mg/g), followed by BL (98.7 mg/g) and LBZ (88.0 mg/g), while caffeine showed the opposite trend, 27.3 mg/g in LME, 33.5 mg/g in BL, and 38.1 mg/g in LBZ. Principal component analysis applied to both the volatile compounds and ten bioactive components showed a poor separation of samples according to varieties, while partial least squares-discriminant analysis (PLS-DA) showed satisfactory discrimination. Thirty-four volatile components and five bioactive compounds were selected as major discriminators (variable importance in projection (VIP) >1) among the tea varieties. These results suggest that chromatographic data combined with multivariate analysis could provide a useful technique to characterize and distinguish the sun-dried Pu-erh tea leaves from ancient tea varieties on Bulang Mountain.