Alkenyl oxindole is a novel PROTAC moiety that recruits the CRL4DCAF11 E3 ubiquitin ligase complex for targeted protein degradation.

Alkenyl oxindoles have been characterized as autophagosome-tethering compounds (ATTECs), which can target mutant huntingtin protein (mHTT) for lysosomal degradation. In order to expand the application of alkenyl oxindoles for targeted protein degradation, we designed and synthesized a series of heterobifunctional compounds by conjugating different alkenyl oxindoles with bromodomain-containing protein 4 (BRD4) inhibitor JQ1. Through structure-activity relationship study, we successfully developed JQ1-alkenyl oxindole conjugates that potently degrade BRD4. Unexpectedly, we found that these molecules degrade BRD4 through the ubiquitin-proteasome system, rather than the autophagy-lysosomal pathway. Using pooled CRISPR interference (CRISPRi) screening, we revealed that JQ1-alkenyl oxindole conjugates recruit the E3 ubiquitin ligase complex CRL4DCAF11 for substrate degradation. Furthermore, we validated the most potent heterobifunctional molecule HL435 as a promising drug-like lead compound to exert antitumor activity both in vitro and in a mouse xenograft tumor model. Our research provides new employable proteolysis targeting chimera (PROTAC) moieties for targeted protein degradation, providing new possibilities for drug discovery.

Modulation of deep neural circuits with sonogenetics.

Noninvasive control of neuronal activity in the deep brain can be illuminating for probing brain function and treating dysfunctions. Here, we present a sonogenetic approach for controlling distinct mouse behavior with circuit specificity and subsecond temporal resolution. Targeted neurons in subcortical regions were made to express a mutant large conductance mechanosensitive ion channel (MscL-G22S), enabling ultrasound to trigger activity in MscL-expressing neurons in the dorsal striatum and increase locomotion in freely moving mice. Ultrasound stimulation of MscL-expressing neurons in the ventral tegmental area could activate the mesolimbic pathway to trigger dopamine release in the nucleus accumbens and modulate appetitive conditioning. Moreover, sonogenetic stimulation of the subthalamic nuclei of Parkinson's disease model mice improved their motor coordination and mobile time. Neuronal responses to ultrasound pulse trains were rapid, reversible, and repeatable. We also confirmed that the MscL-G22S mutant is more effective to sensitize neurons to ultrasound compared to the wild-type MscL. Altogether, we lay out a sonogenetic approach which can selectively manipulate targeted cells to activate defined neural pathways, affect specific behaviors, and relieve symptoms of neurodegenerative disease.

The Peptide DHα-(4-pentenyl)-ANPQIR-NH2 Exhibits Antifibrotic Activity in Multiple Pulmonary Fibrosis Models Induced by Particulate and Soluble Chemical Fibrogenic Agents.

Interstitial lung diseases (ILDs) are a group of restrictive lung diseases characterized by interstitial inflammation and pulmonary fibrosis. The incidence of ILDs associated with exposure to multiple hazards such as inhaled particles, fibers, and ingested soluble chemicals is increasing yearly, and there are no ideal drugs currently available. Our previous research showed that the novel and low-toxicity peptide DHα-(4-pentenyl)-ANPQIR-NH2 (DR3penA) had a strong antifibrotic effect on a bleomycin-induced murine model. Based on the druggability of DR3penA, we sought to investigate its effects on respirable particulate silicon dioxide (SiO2)- and soluble chemical paraquat (PQ)-induced pulmonary fibrosis in this study by using western blot, quantitative reverse-transcription polymerase chain reaction (RT-qPCR), immunofluorescence, H&E and Masson staining, immunohistochemistry, and serum biochemical assays. The results showed that DR3penA alleviated the extent of fibrosis by inhibiting the expression of fibronectin and collagen I and suppressed oxidative stress and epithelial-mesenchymal transition (EMT) in vitro and in vivo. Further study revealed that DR3penA may mitigate pulmonary fibrosis by negatively regulating the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway and mitogen-activated protein kinase (MAPK) pathway. Unexpectedly, through the conversion of drug bioavailability under different routes of administration, DR3penA exerted antifibrotic effects equivalent to those of the positive control drug pirfenidone (PFD) at lower doses. In summary, DR3penA may be a promising lead compound for various fibrotic ILDs. SIGNIFICANCE STATEMENT: Our study verified that DHα-(4-pentenyl)-ANPQIR-NH2 (DR3penA) exhibited positive antifibrotic activity in pulmonary fibrosis induced by silicon dioxide (SiO2) particles and soluble chemical paraquat (PQ) and demonstrated a low-dose advantage compared to the small-molecule drug pirfenidone (PFD). The peptide DR3penA can be further developed for the treatment of multiple fibrotic lung diseases.

The novel peptide DR4penA attenuates the bleomycin- and paraquat-induced pulmonary fibrosis by suppressing the TGF-ß/Smad signaling pathway.

Pulmonary fibrosis (PF), which is caused by continuous alveolar epithelial cell injury and abnormal repair, is referred to as a difficult disease of the lung system by the World Health Organization due to its rapid progression, poor prognosis, and high mortality rate. However, there is still a lack of ideal therapeutic strategies. The peptide DR8 (DHNNPQIR-NH2 ), which is derived from rapeseed, exerted antifibrotic activity in the lung, liver, and kidney in our previous studies. By studying the structure-activity relationship and rational design, we introduced an unnatural hydrophobic amino acid (α-(4-pentenyl)-Ala) into DR8 and screened the novel peptide DR4penA (DHNα-(4-pentenyl)-APQIR-NH2 ), which had higher anti-PF activity, higher antioxidant activity and a longer half-life than DR8. Notably, DR4penA attenuated bleomycin- and paraquat-induced PF, and the anti-PF activity of DR4penA was equivalent to that of pirfenidone. Additionally, DR4penA suppressed the TGF-ß/Smad pathway in TGF-ß1-induced A549 cells and paraquat-induced rats. This study demonstrates that the novel peptide DR4penA is a potential candidate compound for PF therapy, and its antifibrotic activity in different preclinical models of PF provides a theoretical basis for further study.

Synthesis of Isoquinuclidines via Dearomative Diels-Alder Reaction of Cyclic Amidines with Indoles.

The development and utilization of new dienes and dienophiles for the controlled synthesis of isoquinuclidines is highly appealing. Herein, we describe a novel strategy for diastereoselective synthesis of indoline-fused isoquinuclidines via copper-catalyzed dearomative Diels-Alder reaction of cyclic amidines with indoles. This protocol avoids the use of unstable DHPs and activated alkenes, offering a more efficient and selective approach to synthesize isoquinuclidines.

LINC00472 Regulates Ferroptosis of Neurons in Alzheimer's Disease via FOXO1.

INTRODUCTION: The objective of the study was to explore the molecular mechanism of long noncoding RNA (lncRNA) LINC00472 in Alzheimer's disease (AD) and identify potential novel targets for AD therapy. METHOD: Ferroptosis-related lncRNAs were screened by GEO database. AD mouse model was constructed for in vivo experiments. The content of Aß protein and tau protein hyperphosphorylation were examined in hippocampal tissue samples of mice. Subsequently, HT22 cells were induced with Aß25-35 to establish a neuronal injury model of AD in vitro. The expression of FOXO1, a key gene for ferroptosis, was verified by overexpressing/knocking down the LINC00472. The effects of LINC00472 on ROS and lipid peroxidation content, GPX4, and tau protein in AD model cells were examined by ROS assay, MDA assay, Western blot, and qRT-PCR. Subsequently, the expression of iron ion, FTH, TfRC, and Fpn protein were detected in AD cells. RESULTS: The level of FOXO1 was positively correlated with the degree of AD. In vivo experiments showed that the expression of Aß and tau hyperphosphorylated were significantly reduced in the inhibitor group and iron was significantly reduced relative to the AD group. In the AD cell model, the content of lipid peroxide was upregulated, GPX4 protein and mRNA were decreased, and phosphorylation of tau protein was enhanced in the AD cell model relative to the control group. Whereas knocking down LINC00472 inhibited the upregulation of lipid peroxide, decreased the level of GPX4, and enhanced tau protein phosphorylation, and reduced iron accumulation in AD cells. CONCLUSIONS: LINC00472 affects ferroptosis in AD by regulating iron accumulation in neuronal cells.

Asiaticoside ameliorates DSS-induced colitis in mice by inhibiting inflammatory response, protecting intestinal barrier and regulating intestinal microecology.

Ulcerative colitis (UC) is one of the most prevalent inflammatory bowel diseases and poses a serious threat to human health. Currently, safe and effective preventive measures are unavailable. In this study, the protective effects of asiaticoside (AS) on dextran sodium sulfate (DSS)-induced colitis in mice and the underlying molecular mechanism were investigated. In this experiment, colitis was induced in mice with DSS. Subsequently, the role of AS in colitis and its underlying mechanisms were examined using H&E staining, immunofluorescence staining, western blot, Elisa, FMT, and other assays. The results showed that AS significantly attenuated the related symptoms of DSS-induced colitis in mice. In addition, AS inhibited the activation of signaling pathways TLR4/NF-κB and MAPK reduced the release of inflammatory factors, thereby attenuating the inflammatory response in mice. AS administration also restored the permeability of the intestinal barrier by increasing the levels of tight junction-associated proteins (claudin-3, occludin, and ZO-1). In addition, AS rebalanced the intestinal flora of DSS-treated mice by increasing the diversity of the flora. AS can alleviate DSS-induced ulcerative colitis in mice by maintaining the intestinal barrier, thus inhibiting the signaling pathways TLR4/NF-κB and MAPK activation, reducing the release of inflammatory factors, and regulating intestinal microecology.

Structured-light displacement detection method using split-waveplate for dual-beam optical tweezers.

Structured-light displacement detection method is an innovative approach with extremely high sensitivity for measuring the displacement of a levitated particle. This scheme includes two key components, a split-waveplate (SWP) and a single-mode fiber. In this work, we further investigated the influence of SWP installation on this method regarding the sensitivity of displacement detection. The results indicate that the sensitivity increases with the expanding of SWP offset in the effective range. In addition, we found this method has a significant tolerance rate, with an extensive SWP offset effective range of 5%-25%. However, an excessive offset can render this method ineffective. More interestingly, we demonstrated the feasibility of rotating the SWP to detect displacement in different directions. Our research contributes to guiding the structured-light detection methods in practical applications and expanding their applications in fundamental physics.

Synthesis and Biological Evaluation of Phthalideisoquinoline Derivatives.

A photo and Cu-mediated radical-radical approach enabling the one-step synthesis of the phthalideisoquinoline skeleton has been reported. Under mild reaction conditions, a series of N-aryl phthalideisoquinolines containing various substituents were synthesized in moderate to good yields. Bioactivity data demonstrated that a new compound 4x can efficiently inhibit the growth of multiple tumor cell lines with enhancements of more than 10-fold by significantly increasing G2/M arrest compared with noscapine.

Comparing the efficacy and safety of different analgesic strategies after open hemorrhoidectomy: a systematic review and network meta-analysis.

PURPOSE: To evaluate the clinical efficacy and safety of different analgesic interventions in the treatment of pain after open hemorrhoidectomy by systematic review and network meta-analysis. METHODS: Randomized controlled trials that met the inclusion criteria in PubMed, Cochrane Library, Embase, Web of Science, Scopus, CNKI, WANFANG DATA, and VIP were searched from the date of database construction to June 28, 2022. RESULTS: Among the 13 randomized controlled trials (RCTs), 731 patients were included in the network meta-analysis. Most interventions are more effective than placebo in relieving postoperative pain. 24 h postoperative Visual Analogue Scale (VAS): glyceryl trinitrate (GTN) (mean difference (MD) - 4.20, 95% CI - 5.35, - 3.05), diltiazem (MD - 1.97, 95% CI - 2.44, - 1.51), botulinum toxin (BT) (MD - 1.50, 95% CI - 2.25, - 0.75), sucralfate (MD - 1.01, 95% CI - 1.53, - 0.49), and electroacupuncture (EA) (MD - 0.45, 95% CI - 0.87, - 0.04). 48 h postoperative VAS: diltiazem (MD - 2.45, 95% CI - 2.74, - 2.15), BT (MD - 2.18, 95% CI - 2.52, - 1.84), and sucralfate (MD - 1.41, 95% CI - 1.85, - 0.97). 7 d postoperative VAS: diltiazem (MD - 2.49, 95% CI - 3.20, - 1.78) and sucralfate (MD - 1.42, 95% CI - 2.00, - 0.85). The first postoperative defecation VAS: EA (MD - 0.70, 95% CI - 0.95, - 0.46). There are few data on intervention safety, and additional high-quality RCTs are expected to study this topic in the future. CONCLUSION: Diltiazem ointment may be the most effective medication for pain relief following open hemorrhoidectomy, and it can dramatically reduce pain within one week of surgery. The second and third recommended medications are BT and sucralfate ointment. GTN has a significant advantage in alleviating pain 24 h after open hemorrhoidectomy, but whether it causes headache is debatable; thus, it should be used with caution. EA's analgesic efficacy is still unknown. There was limited evidence on the safety of the intervention in this study, and it was simply presented statistically.

Comparing the efficacy and safety of different thread-drawing surgery method for treating high complex anal fistula: a systematic review and network meta-analysis.

PURPOSE: To evaluate the effect of different surgical methods in the treatment of high complex anal fistula by systematic review and network meta-analysis. METHODS: Randomized controlled trials that met the inclusion criteria in PubMed, Cochrane Library, Embase, Web of Science, CBM, CNKI, WANFANG DATA, VIP were searched from the date of database construction to May 23, 2023. RESULTS: Among the 48 randomized controlled trials (RCTs), 4205 patients were included in the network meta-analysis. Incision thread-drawing counter-drainage procedure (ITCP) in improving the effective rate, the cure rate; reduce the recurrence rate, reduce the anal canal damage has a huge advantage. Directional line-hanging method (DLM) is optimal for safety and postoperative pain relief. Directional line-hanging method (ITSS) protect the optimal anal function after surgery. Sphincter preserving thread-hanging method (SPTM) has a significant advantage in accelerating wound healing time. Main tube incision combined with thread-hanging branch tube drainage (MIBD) is second only to incision thread-drawing counter-drainage procedure (ITCP) in improving effective rate, cure rate, reducing recurrence rate and reduce complication rate. CONCLUSION: In general, different thread-drawing surgery methods have good clinical effect for the treatment of high complex anal fistula. In general, these methods provide evidence-based medical evidence for early treatment in terms of improving clinical efficacy, relieving anal pain and reducing wound healing time. However, there are differences in the number of included literature studies, and further verification by large-sample, high-quality, multicenter RCTS is still needed in the next stage.

RNA-seq reveals novel mechanistic targets of Livin in bladder cancer.

BACKGROUND: Bladder cancer is a very common malignancy with a high recurrence rate. The survival of patients with muscle-invasive bladder cancer is poor, and new therapies are needed. Livin has been reported to be upregulated in bladder cancer and influence the proliferation of cancer cells. MATERIALS AND METHODS: The Livin gene in human bladder cancer cell line T24 was knocked out, and the differentially expressed genes were identified by RNA-seq and qPCR. RESULTS: Livin knockdown affects gene expression and has strong negative effects on some cancer-promoting pathways. Furthermore, combined with bladder cancer clinical sample data downloaded from TCGA and GEO, 2 co-up-regulated genes and 58 co-down-regulated genes were identified and validated, which were associated with cancer proliferation and invasion. CONCLUSION: All these results suggest that Livin plays an important role in bladder cancer and could be a potential anticancer target in clinical therapy.

A longitudinal study on the effect of extreme temperature on non-accidental deaths in Hulunbuir City based on DLNM model.

OBJECTIVE: To explore the frequency and effect of extreme temperature on the non-accidental death rate in Hulunbuir, a Chinese ice city. METHODS: From 2014 to 2018, mortality data of residents residing in Hulunbuir City were collected. The lag and cumulative effects of extreme temperature conditions on non-accidental death and respiratory and circulatory diseases were analyzed by distributed lag non-linear models (DLNM). RESULTS: The risk of death was the highest during high-temperature conditions, the RR value was 1.111 (95% CI 1.031 ~ 1.198). The effect was severe and acute. The risk of death during extreme low-temperature conditions peaked on the fifth day, (RR 1.057; 95% CI 1.012 ~ 1.112), then decreased and was maintained for 12 days. The cumulative RR value was 1.289 (95% CI 1.045 ~ 1.589). Heat significantly influenced the incidence of non-accidental death in both men (RR 1.187; 95% CI 1.059-1.331) and women (RR 1.252; 95% CI 1.085-1.445). CONCLUSIONS: Regardless of the temperature effect, the risk of death in the elderly group (≥ 65 years) was significantly higher than that of the young group (0-64 years). High-temperature and low-temperature conditions can contribute to the increased number of deaths in Hulunbei. While high-temperature has an acute effect, low-temperature has a lagging effect. Elderly and women, as well as people with circulatory diseases, are more sensitive to extreme temperatures.

Advance Progress in Assembly Mechanisms of Carrier-Free Nanodrugs for Cancer Treatment.

Nanocarriers have been widely studied and applied in the field of cancer treatment. However, conventional nanocarriers still suffer from complicated preparation processes, low drug loading, and potential toxicity of carriers themselves. To tackle the hindrance, carrier-free nanodrugs with biological activity have received increasing attention in cancer therapy. Extensive efforts have been made to exploit new self-assembly methods and mechanisms to expand the scope of carrier-free nanodrugs with enhanced therapeutic performance. In this review, we summarize the advanced progress and applications of carrier-free nanodrugs based on different types of assembly mechanisms and strategies, which involved noncovalent interactions, a combination of covalent bonds and noncovalent interactions, and metal ions-coordinated self-assembly. These carrier-free nanodrugs are introduced in detail according to their assembly and antitumor applications. Finally, the prospects and existing challenges of carrier-free nanodrugs in future development and clinical application are discussed. We hope that this comprehensive review will provide new insights into the rational design of more effective carrier-free nanodrug systems and advancing clinical cancer and other diseases (e.g., bacterial infections) infection treatment.

Differential displacement measurement of the levitated particle using D-shaped mirrors in the optical tweezers.

Displacement measurement using a D-shaped mirror is a key technology in optical tweezers, which have emerged as an important tool for precision measurement. In this paper, we first study the influences of installation errors for the D-shaped mirror on the displacement measurement. The calibration factor and sensitivity of the different installation parameters are quantified. The results show that the variation of the calibration factor obeys the cosine curve with the angle error, and the sensitivity increases exponentially with the translation error. Besides, we find that the translation error will also lead to crosstalk between transverse and axial displacement. Our work will contribute to improving the performance of optical tweezers for the application in precision measurement and basic physics.

Organocatalytic enantioselective construction of axially chiral (1H)-isochromen-1-imines.

Heterocycloalkenyl atropisomers, derived from biaryl atropisomers and axially chiral styrenes, have emerged as a new class of nonbiaryl C-C atropisomers due to the benefit in improving the pharmacological activity and structural diversity. This paper proposes an intramolecular annulation strategy for constructing the heterocycloalkenyl atropisomers (1H)-isochromen-1-imines by organocatalysis. Various heterocycloalkenyl atropisomers (1H)-isochromen-1-imines were prepared in good to excellent yields with excellent enantioselectivity (up to 98% ee), and could be easily converted to atropisomeric lactones isocoumarins.

Glucosamine-phosphate N-acetyltransferase 1 and its DNA methylation can be biomarkers for the diagnosis and prognosis of lung cancer.

OBJECTIVE: Lung cancer ranking high in the cancer-related list has long perplexed patients, in which glucosamine-phosphate N-acetyltransferase 1 (GNPNAT1) is found to be highly expressed. Besides, DNA methylation is perceived as a biomarker to assess the prognosis of patients with various cancers. However, the correlation between GNPNAT1 and DNA methylation and the role of GNPNAT1 in lung cancer remain vague. METHODS: Principal component analysis (PCA), heatmap, volcano map, Venn diagram, gene ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were used to screen out the candidate genes. The viability, migration, and invasion of lung cancer cells were detected by CCK-8 and Transwell assays. An xenograft tumor mouse model was established. The relative expressions of GNPNAT1, E-cadherin, vimentin, Matrix metalloproteinase-2 (MMP-2), tissue inhibitor of metalloproteinase-2 (TIMP-2), E2F1, and cyclin D1 in cells or xenograft tumor tissues were quantified by Western blot, RT-qPCR, or immunohistochemistry assay. RESULTS: GNPNAT1 was screened as the research object. GNPNAT1 methylation was downregulated, while GNPNAT1 expression was upregulated in lung cancer tissues. The methylation and mRNA levels of GNPNAT1 were correlated with the patient prognosis. GNPNAT1 increased cell viability, migration and invasion, and promoted the xenograft tumor volume and weight, whereas shGNPNAT1 acted oppositely. Moreover, expressions of Vimentin, MMP-2, E2F1, and cyclin D1 were increased, but E-cadherin and TIMP-2 expressions were decreased by overexpressed GNPNAT1, whilst GNPNAT1 knockdown ran conversely. CONCLUSION: GNPNAT1 and methylated GNPNAT1 coverage are biomarkers for the diagnosis and prognosis of lung cancer.

Prognostic factors in the treatment of gastric mucosal atypical hyperplasia by endoscopic submucosal dissection.

BACKGROUND: Endoscopic submucosal dissection (ESD) is becoming increasingly popular as a treatment for precancerous lesions and early cancers of the stomach. However, there have been few studies on the factors associated with the recurrence of precancerous lesions after ESD. METHODS: To investigate the prognostic factors of gastric intraepithelial neoplasia, we retrospectively analyzed 115 patients who were treated with ESD between February 2018 and January 2020. Chi-square test and Fisher's extract test were used to select factors for further investigation, and prognostic analysis was carried out with the Kaplan-Meier method and a Cox regression model. RESULTS: Platelet counts (P = 0.027) and albumin levels (P = 0.011) were both lower in patients with recurrence than in patients without recurrence of gastric mucosal atypical hyperplasia after ESD. CONCLUSIONS: This study reveals that low platelet counts and albumin levels were probably unfavorable prognostic factors in mucosal atypical hyperplasia of the stomach.

Development of Thyroid Hormones and Synthetic Thyromimetics in Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is the fastest-growing liver disease in the world. Despite targeted agents which are needed to provide permanent benefits for patients with NAFLD, no drugs have been approved to treat NASH. Thyroid hormone is an important signaling molecule to maintain normal metabolism, and in vivo and vitro studies have shown that regulation of the 3,5,3'-triiodothyronine (T3)/ thyroid hormone receptor (TR) axis is beneficial not only for metabolic symptoms but also for the improvement of NAFLD and even for the repair of liver injury. However, the non-selective regulation of T3 to TR subtypes (TRα/TRß) could cause unacceptable side effects represented by cardiotoxicity. To avoid deleterious effects, TRß-selective thyromimetics were developed for NASH studies in recent decades. Herein, we will review the development of thyroid hormones and synthetic thyromimetics based on TR selectivity for NAFLD, and analyze the role of TR-targeted drugs for the treatment of NAFLD in the future.

Natural Polyphenols for Treatment of Colorectal Cancer.

Colorectal cancer (CRC) is a prevalent and serious gastrointestinal malignancy with high mortality and morbidity. Chemoprevention refers to a newly emerged strategy that uses drugs with chemopreventive properties to promote antioxidation, regulate cancer cell cycle, suppress proliferation, and induce cellular apoptosis, so as to improve cancer treatment outcomes. Natural polyphenols are currently recognized as a class of chemopreventive agents that have shown remarkable anticarcinogenic properties. Numerous in vitro and in vivo studies have elucidated the anti-CRC mechanisms of natural polyphenols, such as regulation of various molecular and signaling pathways. Natural polyphenols are also reportedly capable of modulating the gut microbiota and cancer stem cells (CSCs) to suppress tumor formation and progression. Combined use of different natural polyphenols is recommended due to their low bioavailability and instability, and combination treatment can exert synergistical effects, reduce side effects, and avoid drug resistance in CRC treatment. In summary, the application of polyphenols in the chemoprevention and treatment of CRC is promising. Further clinical evaluation of their effectiveness is warranted and anticipated.