Si-Ni-San alleviates intestinal and liver damage in ulcerative colitis mice by regulating cholesterol metabolism.

ETHNOPHARMACOLOGICAL RELEVANCE: Si-Ni-San (SNS), a traditional Chinese medicinal formula derived from Treatise on Febrile Diseases, is considered effective in the treatment of inflammatory bowel diseases based upon thousands of years of clinical practice. However, the bioactive ingredients and underlying mechanisms are still unclear and need further investigation. AIM OF THE STUDY: This study aimed to evaluate the effect, explore the bioactive ingredients and the underlying mechanisms of SNS in ameliorating ulcerative colitis (UC) and associated liver injury in dextran sodium sulphate (DSS)-induced mouse colitis models. MATERIALS AND METHODS: The effect of SNS (1.5, 3, 6 g/kg) on 3% DSS-induced acute murine colitis was evaluated by disease activity index (DAI), colon length, inflammatory cytokines, hematoxylin-eosin (H&E) staining, tight junction proteins expression, ALT, AST, and oxidative stress indicators. HPLC-ESI-IT/TOF MS was used to analyze the chemical components of SNS and the main xenobiotics in the colon of UC mice after oral administration of SNS. Network pharmacological study was then conducted based on the main xenobiotics. Flow cytometry and immunohistochemistry techniques were used to demonstrate the inhibitory effect of SNS on Th17 cells differentiation and the amelioration of Th17/Treg cell imbalance. LC-MS/MS, Real-time quantitative polymerase chain reaction (RT-qPCR), and western blotting techniques were performed to investigate the oxysterol-Liver X receptor (LXRs) signaling activity in colon. Targeted bile acids metabolomics was conducted to reveal the change of the two major pathways of bile acid synthesis in the liver, and the expression of key metabolic enzymes of bile acids synthesis was characterized by RT-qPCR and western blotting techniques. RESULTS: SNS (1.5, 3, 6 g/kg) decreased the DAI scores, protected intestinal mucosa barrier, suppressed the production of pro-inflammatory cytokines, improved hepatic and splenic enlargement and alleviated liver injury in a dose-dependent manner. A total of 22 components were identified in the colon of SNS (6 g/kg) treated colitis mice, and the top 10 components ranked by relative content were regarded as the potential effective chemical components of SNS, and used to conduct network pharmacology research. The efficacy of SNS was mediated by a reduction of Th17 cell differentiation, restoration of Th17/Treg cell homeostasis in the colon and spleen, and the experimental results were consistent with our hypothesis and the biological mechanism predicted by network pharmacology. Mechanistically, SNS regulated the concentration of 25-OHC and 27-OHC by up-regulated CH25H, CYP27A1 protein expression in colon, thus affected the expression and activity of LXR, ultimately impacted Th17 differentiation and Th17/Treg balance. It was also found that SNS repressed the increase of hepatic cholesterol and reversed the shift of BA synthesis to the acidic pathway in UC mice, which decreased the proportion of non-12-OH BAs in total bile acids (TBAs) and further ameliorated colitis and concomitant liver injury. CONCLUSIONS: This study set the stage for considering SNS as a multi-organ benefited anti-colitis prescription based on the significant effect of ameliorating intestinal and liver damage, and revealed that derivatives of cholesterol, namely oxysterols and bile acids, were closely involved in the mechanism of SNS anti-colitis effect.

"Yin-Yang philosophy" for the design of anticancer drug delivery nanoparticles.

Understanding the in vivo transport process provides guidelines for designing ideal nanoparticles (NPs) with higher efficacy and fewer off-target effects. Many factors, such as particle size, morphology, surface potential, structural stability, and etc., may influence the delivering process of NPs due to the existence of various physiological barriers within the body. Herein, we summarise the distinct influences of NP physicochemical properties on the four consecutive in vivo transport steps: (1) navigating with bloodstream within blood vessels, (2) transport across vasculature walls into tumour tissues, (3) intratumoural transport through the interstitial space, and (4) cellular uptake & intracellular delivery by cancerous cells. We found that the philosophy behind the current consensus for NP design has certain similarities to the "Yin-Yang" theory in traditional Chinese culture. Almost all physicochemical properties, regardless of big or small sizes, long or short length, positive or negative zeta potentials, are double-edged swords. The balance of potential benefits and side effects, drug selectivity and accessibility should be fully considered when optimising particle design, similar to the "Yin-Yang harmony". This paper presents a comprehensive review of the advancements in NPs research, focusing on their distinct features in tumour targeting, drug delivery, and cell uptake. Additionally, it deliberates on future developmental trends and potential obstacles, thereby aiming to uncover the ways these characteristics influence the NPs' biological activity and provide theoretical guidance for the targeted delivery of NPs.

A reversible photochromic covalent organic framework.

Covalent organic frameworks are a type of crystalline porous materials that linked through covalent bond, and they have numerous potential applications in adsorption, separation, catalysis, and more. However, there are rarely relevant reported on photochromism. Fortunately, a hydrazone-linked DBTB-DETH-COF is rapidly generated through ultrasound method. The DBTB-DETH-COF is found to exhibit reversible photochromism (at least 50 cycles) from yellow to olive in the presence of light and air, and subsequently back to the original color upon heating. In addition, the structure of DBTB-DETH-COF remains unchanged after 15 days of light illumination. Furthermore, the reason of photochromic process is discussed by electron paramagnetic resonance, X-ray photoelectron spectroscopy, electrochemistry characterizations and transient absorption measurements. The reversible photochromic DBTB-DETH-COF can be used as anti-counterfeiting ink and optical switch in the presence of air. This work expands a stable organic photochromic material and broadens the applications of COFs.

Human adipose mesenchymal stem cell-derived exosomes alleviate fibrosis by restraining ferroptosis in keloids.

Background: Keloid is a fibroproliferative disease with unsatisfactory therapeutic effects and a high recurrence rate. exosomes produced by adipose-derived mesenchymal stem cells (ADSC-Exos) have attracted significant interest due to their ability to treat fibrosis. However, the molecular mechanisms of ADSC-Exos in keloids remain inconclusive. Objective: Our study revealed the relationship between ferroptosis and fibrosis in keloids. Subsequently, this study aimed to explore further the anti-fibrotic effect of ADSC-Exos on keloids through ferroptosis and the potential underlying mechanisms. Methods: To investigate the impact of ferroptosis on keloid fibrosis, Erastin and ferrostatin-1 (fer-1) were utilized to treat keloid fibroblast. Keloid keloids treated with Erastin and fer-1 were cocultured with ADSC-Exos to validate the impact of ferroptosis on the effect of ADSC-Exos on keloid anti-ferrotic protein, peroxidase 4 (GPX4) and anti-fibrotic effects in vivo and in vitro by Western blot, as well as variations in iron metabolite expression, malondialdehyde (MDA), liposomal peroxidation (LPO) and glutathione (GSH) were analyzed. The effect of solute carrier family 7-member 11 (SLC7A11) silencing on ADSC-Exo-treated keloid fibroblast was investigated. Results: Iron metabolite dysregulation was validated in keloids. Fibrosis progression is enhanced by Erastin-induced ferroptosis. The anti-fibrotic effects of ADSC-Exos and fer-1 are related to their ability to prevent iron metabolism. ADSC-Exos effectively suppressed keloid fibrosis progression and increased GSH and GPX4 gene expression. Additionally, the use of Erastin limits the effect of ADSC-Exos in keloids. Furthermore, the effect of ADSC-Exos on keloids was associated with SLC7A11-GPX4 signaling pathway. Conclusion: We demonstrated a new potential mechanism by which anti-ferroptosis inhibits the progression of keloid fibrosis and identified an ADSC-Exo-based keloid therapeutic strategy. Resisting the occurrence of ferroptosis and the existence of the SLC7A11-GPX4 signaling pathway might serve as a target for ADSC-Exos.

USP33 facilitates the ovarian cancer progression via deubiquitinating and stabilizing CBX2.

Post-translational modifications of proteins play a pivotal role in both the initiation and progression of ovarian cancer. Despite the recognition of USP33 as a significant factor in various cancers, its specific function and underlying mechanisms in ovarian cancer remain elusive. Proteomics and ubiquitinomics approaches were coupled to screen novel substrate proteins directly regulated by USP33. Our findings unveil that USP33 was observed to eliminate K27- and K48-linked ubiquitin chains from CBX2 at the K277 position. Notably, acetylation of CBX2 at K199, catalyzed by lysine acetyltransferase GCN5, was found to enhance its interaction with USP33, subsequently promoting further deubiquitination and stabilization. Functionally, our experiments demonstrate that USP33 significantly enhances ovarian cancer proliferation and metastasis in a CBX2-dependent manner. Furthermore, analysis revealed a direct positive correlation between the expression levels of USP33 and CBX2 proteins in human specimens, with elevated levels being associated with reduced survival rates in ovarian cancer patients. These findings elucidate the mechanism by which USP33 augments ovarian cancer progression through the stabilization of CBX2, underscoring the USP33-CBX2 axis as a promising therapeutic target in ovarian cancer management.

Structural identification, rheological properties and immunological receptor of a complex galacturonoglucan from fruits of Schisandra chinensis (Turcz.) Baill.

A complex heteropolysaccharide SCP-2 named schisanan B (Mw = 1.005 × 105 g/mol) was obtained from water extracts of Schisandra chinensis fruits, and its planar structure was finally deduced as a galacturonoglucan by a combination of monosaccharide compositions, methylation analysis, partial acid hydrolysis, enzymatic hydrolysis and 1D/2D-nuclear magnetic resonance spectroscopy. The conformation of SCP-2 exhibited a globular shape with branching in ammonium formate aqueous solutions. The rheological properties of SCP-2 were investigated on concentrations, temperature, pH and salts. The in vitro immunomodulatory activity assay demonstrated that SCP-2 significantly enhanced the production of nitric oxide (NO) and stimulated the secretion of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in macrophages. Through a combination of high-resolution live-cell imaging, surface plasmon resonance, and molecular docking techniques, SCP-2 exhibited a strong binding affinity with the Toll-like receptor 4 (TLR4). Moreover, western blot analysis revealed that SCP-2 effectively induced downstream signaling proteins associated with TLR4 activation, thereby promoting macrophage activation. The evidence strongly indicates that TLR4 functions as a membrane protein target in the activation of macrophages and immune regulation induced by SCP-2.

The subchronic toxicity of higher olefins in Han Wistar rats.

Higher olefins (HO) are a category of unsaturated hydrocarbons widely used in industry applications to make products essential for daily human life. Establishing safe exposure limits requires a solid data matrix that facilitates understanding of their toxicological profile. This in turn allows for data to be read across to other members of the category, which are structurally similar and have predictable physico-chemical properties. Five independent subchronic oral toxicity studies were conducted in Wistar rats with Oct-1-ene, Nonene, branched, Octadec-1-ene, Octadecene and hydrocarbon C12-30, olefin-rich, ethylene polymn. by product, at doses ranging from 20 to 1000 mg/kg bw. These HO were selected considering gut absorption, carbon chain length, double-bond position and carbon backbone structural variations. Generally, limited and non-adverse toxicity effects were observed at the end of the treatment for short carbon chain HO. For instance, alpha 2u-globulin nephropathy in the male rats and liver hypertrophy. No clear trend in systemic toxicity was linked to the double-bond position. Key factors for hazard assessment include absorption, carbon chain length, and branching, with Nonene, branched, identified as the worst-case substance. Taken together, the no observed adverse effect level (NOAEL) of each HO in these subchronic studies was set at the highest dose tested.

The m6A writer KIAA1429 regulates photoaging progression via MFAP4-dependent collagen synthesis.

BACKGROUND: N6-Methyladenosine (m6A) methylation, a common form of RNA modification, play an important role in the pathogenesis of various diseases and in the ontogeny of organisms. Nevertheless, the precise function of m6A methylation in photoaging remains unknown. OBJECTIVES: This study aims to investigate the biological role and underlying mechanism of m6A methylation in photoaging. METHODS: m6A dot blot, Real-time quantitative PCR (RT-qPCR), western blot and immunohistochemical (IHC) assays were employed to detect the m6A level and specific m6A methylase in ultraviolet ray (UVR)-induced photoaging tissue. The profile of m6A-tagged mRNA was identified by methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA-seq analysis. Finally, we investigated the regulatory mechanism of KIAA1429 by MeRIP-qPCR, RNA knockdown and immunofluorescence assay. RESULTS: m6A levels were increased in photoaging and were closely associated with the upregulation of KIAA1429 expression. 1331 differentially m6A methylated genes were identified in the UVR group compared with the control group, of which 1192 (90%) were hypermethylated. Gene ontology analysis showed that genes with m6A hypermethylation and mRNA downregulation were mainly involved in extracellular matrix metabolism and collagen metabolism-related processes. Furthermore, KIAA1429 knockdown abolished the downregulation of TGF-bRII and upregulation of MMP1 in UVR-irradiated human dermal fibroblasts (HDFs). Mechanically, we identified MFAP4 as a target of KIAA1429-mediated m6A modification and KIAA1429 might suppress collagen synthesis through an m6A-MFAP4-mediated process. CONCLUSIONS: The increased expression of KIAA1429 hinders collagen synthesis during UVR-induced photoaging, suggesting that KIAA1429 represents a potential candidate for targeted therapy to mitigate UVR-driven photoaging.

The genetic basis of leaf hair development in upland cotton (Gossypium hirsutum).

Trichomes, which originate from the epidermal cell of aerial organs, provide plants with defense and secretion functions. Although numerous genes have been implicated in trichome development, the molecular mechanisms underlying trichome cell formation in plants remain incompletely understood. Here, we using genome-wide association study (GWAS) across 1037 diverse accessions in upland cotton (Gossypium hirsutum) to identify three loci associated with leaf pubescence (hair) amount, located on chromosome A06 (LPA1), A08 (LPA2) and A11 (LPA3), respectively. GhHD1, a previously characterized candidate gene, was identified on LPA1 and encodes an HD-Zip transcription factor. For LPA2 and LPA3, we identified two candidate genes, GhGIR1 and GhGIR2, both encoding proteins with WD40 and RING domains that act as inhibitors of leaf hair formation. Expression analysis revealed that GhHD1 was predominantly expressed in hairy accessions, whereas GhGIR1 and GhGIR2 were expressed in hairless accessions. Silencing GhHD1 or overexpressing GhGIR1 in hairy accessions induced in a hairless phenotype, whereas silencing GhGIR2 in hairless accessions resulted in a hairy phenotype. We also demonstrated that GhHD1 interact with both GhGIR1 and GhGIR2, and GhGIR1 can interact with GhGIR2. Further investigation indicated that GhHD1 functions as a transcriptional activator, binding to the promoters of the GhGIR1 and GhGIR2 to active their expression, whereas GhGIR1 and GhGIR2 can suppress the transcriptional activation of GhHD1. Our findings shed light on the intricate regulatory network involving GhHD1, GhGIR1 and GhGIR2 in the initiation and development of plant epidermal hairs in cotton.

Stabilization of dimeric PYR/PYL/RCAR family members relieves abscisic acid-induced inhibition of seed germination.

Abscisic acid (ABA) is the primary preventing factor of seed germination, which is crucial to plant survival and propagation. ABA-induced seed germination inhibition is mainly mediated by the dimeric PYR/PYL/RCAR (PYLs) family members. However, little is known about the relevance between dimeric stability of PYLs and seed germination. Here, we reveal that stabilization of PYL dimer can relieve ABA-induced inhibition of seed germination using chemical genetic approaches. Di-nitrobensulfamide (DBSA), a computationally designed chemical probe, yields around ten-fold improvement in receptor affinity relative to ABA. DBSA reverses ABA-induced inhibition of seed germination mainly through dimeric receptors and recovers the expression of ABA-responsive genes. DBSA maintains PYR1 in dimeric state during protein oligomeric state experiment. X-ray crystallography shows that DBSA targets a pocket in PYL dimer interface and may stabilize PYL dimer by forming hydrogen networks. Our results illustrate the potential of PYL dimer stabilization in preventing ABA-induced seed germination inhibition.

TROPOMI unravels transboundary transport pathways of atmospheric carbon monoxide in Tibetan Plateau.

Numerous studies have reported in situ monitoring and source analysis in the Tibetan Plateau (TP), a region crucial for climate systems. However, a gap remains in understanding the comprehensive distribution of atmospheric pollutants in the TP and their transboundary pollution transport. Here, we analyzed the high-resolution satellite TROPOMI observations from 2018 to 2023 in Tibet and its surrounding areas. Our result reveals that, contrary to the results from in situ surface CO monitoring, Tibet exhibits a distinct seasonality in atmospheric carbon monoxide total column average mixing ratio (XCO), with higher levels in summer and lower levels in winter. This distinctive seasonal pattern may be related to the TP's 'air pump' effect and the Asia summer monsoon. Before 2022, the annual growth rate of XCO in Tibet was 1.63 %·year-1; however, it declined by 6.88 % in 2022. Source analysis and satellite observations suggest that CO from South Asia may enter Tibet either by crossing the Himalayas or through the Yarlung Zangbo Grand Canyon. We discovered that spring outbreaks of open biomass burning (OBB) in South and Southeast Asia led to an 11.57-27.98 % increase in XCO over Tibet. Favorable wind pattern and unique topography of the canyon promote the high concentrations CO transport to Tibet. Our greater concern is whether the TP will experience more severe transboundary pollution in the future.

Exosomal miR­194 from adipose­derived stem cells impedes hypertrophic scar formation through targeting TGF­ß1.

Hypertrophic scars, which result from aberrant fibrosis and disorganized collagen synthesis by skin fibroblasts, emerge due to disrupted wound healing processes. These scars present significant psychosocial and functional challenges to affected individuals. The current treatment limitations largely arise from an incomplete understanding of the underlying mechanisms of hypertrophic scar development. Recent studies, however, have shed light on the potential of exosomal non­coding RNAs interventions to mitigate hypertrophic scar proliferation. The present study assessed the impact of exosomes derived from adipose­derived stem cells (ADSCs­Exos) on hypertrophic scar formation using a rabbit ear model. It employed hematoxylin and eosin staining, Masson's trichrome staining and immunohistochemical staining techniques to track scar progression. The comprehensive analysis of the present study encompassed the differential expression of non­coding RNAs, enrichment analyses of functional pathways, protein­protein interaction studies and micro (mi)RNA­mRNA interaction investigations. The results revealed a marked alteration in the expression levels of long non­coding RNAs and miRNAs following ADSCs­Exos treatment, with little changes observed in circular RNAs. Notably, miRNA (miR)­194 emerged as a critical regulator within the signaling pathways that govern hypertrophic scar formation. Dual­luciferase assays indicated a significant reduction in the promoter activity of TGF­ß1 following miR­194 overexpression. Reverse transcription­quantitative PCR and immunoblotting assays further validated the decrease in TGF­ß1 expression in the treated samples. In addition, the treatment resulted in diminished levels of inflammatory markers IL­1ß, TNF­α and IL­10. In vivo evidence strongly supported the role of miR­194 in attenuating hypertrophic scar formation through the suppression of TGF­ß1. The present study endorsed the strategic use of ADSCs­Exos, particularly through miR­194 modulation, as an effective strategy for reducing scar formation and lowering pro­inflammatory and fibrotic indicators such as TGF­ß1. Therefore, the present study advocated the targeted application of ADSCs­Exos, with an emphasis on miR­194 modulation, as a promising approach to managing proliferative scarring.

Towards the automatic risk of bias assessment on randomized controlled trials: A comparison of RobotReviewer and humans.

RobotReviewer is a tool for automatically assessing the risk of bias in randomized controlled trials, but there is limited evidence of its reliability. We evaluated the agreement between RobotReviewer and humans regarding the risk of bias assessment based on 1955 randomized controlled trials. The risk of bias in these trials was assessed via two different approaches: (1) manually by human reviewers, and (2) automatically by the RobotReviewer. The manual assessment was based on two groups independently, with two additional rounds of verification. The agreement between RobotReviewer and humans was measured via the concordance rate and Cohen's kappa statistics, based on the comparison of binary classification of the risk of bias (low vs. high/unclear) as restricted by RobotReviewer. The concordance rates varied by domain, ranging from 63.07% to 83.32%. Cohen's kappa statistics showed a poor agreement between humans and RobotReviewer for allocation concealment (κ = 0.25, 95% CI: 0.21-0.30), blinding of outcome assessors (κ = 0.27, 95% CI: 0.23-0.31); While moderate for random sequence generation (κ = 0.46, 95% CI: 0.41-0.50) and blinding of participants and personnel (κ = 0.59, 95% CI: 0.55-0.64). The findings demonstrate that there were domain-specific differences in the level of agreement between RobotReviewer and humans. We suggest that it might be a useful auxiliary tool, but the specific manner of its integration as a complementary tool requires further discussion.

Unveiling MRI markers for Parkinson's Disease: GABAergic dysfunction and cortical changes.

OBJECTIVE: The study aimed to investigate changes in basal levels of the inhibitory γ-aminobutyric acid (GABA) neurotransmitter in the sensorimotor cortex (SMC) and cortical gyrification in patients with Parkinson's disease (PD), which could further identify potential imaging biomarkers for PD, particularly in patients with early-onset Parkinson's disease (EOPD). METHOD: Fifty patients with PD (EOPD: 10, late-onset Parkinson's disease [LOPD]: 40) and fifty-two age- and gender-matched healthy controls (HC) underwent GABA-edited 1H MRS of the SMC and high-resolution 3D T1-weighted brain imaging. GABA levels and local gyrification index (LGI) were calculated to assess GABAergic and cortical gyrification deficits in PD. RESULT: The Pearson correlation coefficients revealed significant negative associations between eight indicators, including GABA/Cr level and local gyrification index (LGI) of specific cortical regions (precentral, postcentral, entorhinal, superiortemporal, posteriorcingulate, cuneus, and transversetemporal cortex), and the likelihood of Parkinson's disease (r < -0.4, p < 0.001). Additionally, GABA levels were significantly lower in the SMC region of both EOPD and LOPD patients compared to healthy controls (mean ± SD [u.i.]: EOPD=0.081 ± 0.022 vs. Young-HC=0.112 ± 0.021, p = 0.003; LOPD=0.054 ± 0.024 vs. Old-HC=0.099 ± 0.021, p < 0.001). The logistic regression model was established by using multivariate analysis, identifying two statistically significant indicators: GABA/Cr and LGI of the transversetemporal. The combined model exhibited the highest AUC values in both younger and older populations. CONCLUSION: GABAergic dysfunction may play an important role in the pathogenesis of PD patients. Changes in neurotransmitter and morphological may serve as potential markers for the preclinical diagnosis and progression of PD, including EOPD.

Impact of vacancy defects on the thermal conductivity of BaAgBi: a comprehensive study using molecular dynamics simulations with neural network potentials.

The presence of vacancy defects significantly impacts thermal properties of materials. In this research, we delve into the effects of vacancy defects on the thermal conductivity of ternary alloy BaAgBi, employing molecular dynamics simulations coupled with a deep neural network potential (NNP). Initially, we validate the precision of our NNP by comparing their predictions for energy, atomic forces, phonon dispersion curves, phonon density of states, and vacancy formation energy with density functional theory calculations, ensuring a high degree of accuracy. Our findings reveal that the reduction in thermal conductivity due to vacancies aligns with the Debye-Callaway model, with variations depending on the type of vacancy. Specifically, Ba vacancies result in the most notable decrement in thermal conductivity, attributable to their low phonon participation ratio and high lattice distortion, both factors that enhance phonon scattering. Besides, we find that the high energy barrier (∼1.66 eV) indicates that Ba vacancies hardly migrate at 300 K. This study helps us understand how vacancies affect thermal conductivity in BaAgBi and how different vacancy types affect it.

A protracted war against cancer drug resistance.

Currently, even the most effective anti-cancer therapies are often limited by the development of drug resistance and tumor relapse, which is a major challenge facing current cancer research. A deep understanding of the molecular and biochemical bases of drug efficacy that can help predict the clinical drug resistance, coupled with the evolution of systematic genomic and proteomic technologies, have facilitated studies identifying and elucidating the underlying mechanisms. In this review, we focus on several important issues on cancer drug resistance and provide a framework for understanding the common ways by which cancers develop resistance to therapeutic agents. With the increasing arsenal of novel anticancer agents and techniques, there are now unprecedented opportunities to understand and overcome drug resistance. The proteolysis targeting chimera (PROTAC) technology, immunotherapy, nanomedicine, and real-time monitoring of drug response all provide effective approaches for combating drug resistance. In addition to the advancement of therapeutic technologies, the revolution of treatment concept is also of great importance. We can take advantage of the interplay between drug sensitive and resistant subclones for combating cancer. However, there remains a long way to go in the protracted war against cancer drug resistance.

Cobalt-Catalyzed Synthesis of Alkenyl Heterocycles via Regioselective Intramolecular 1,4-Hydrofunctionalization of Dienes.

We report a novel cobalt-catalyzed intramolecular 1,4-hydrofunctionalization of dienes. The reaction proceeds under mild conditions and is amenable to N- and O-nucleophiles. The protocol exhibits exclusive regioselectivity, yielding a number of different alkenyl heterocycles, including but not limited to dihydroisobenzofurans, isochromanes, tetrahydrofurans, morpholines, lactones, and isoindolines. Experimental studies were performed to offer some insight into the different mechanistic pathways and to rationalize the regio- and stereoselectivities of the reaction.

Discovery of Novel PROTAC SIRT6 Degraders with Potent Efficacy against Hepatocellular Carcinoma.

Sirtuin 6 (SIRT6), a member of the SIRT family, plays essential roles in the regulation of metabolism, inflammation, aging, DNA repair, and cancer development, making it a promising anticancer drug target. Herein, we present our use of proteolysis-targeting chimera (PROTAC) technology to formulate a series of highly potent and selective SIRT6 degraders. One of the degraders, SZU-B6, induced the near-complete degradation of SIRT6 in both SK-HEP-1 and Huh-7 cell lines and more potently inhibited hepatocellular carcinoma (HCC) cell proliferation than the parental inhibitors. In preliminary mechanistic studies, SZU-B6 hampered DNA damage repair, promoting the cellular radiosensitization of cancer cells. Our SIRT6 degrader SZU-B6 displayed promising antitumor activity, particularly when combined with the well-known kinase inhibitor sorafenib or irradiation in an SK-HEP-1 xenograft mouse model. Our results suggest that these PROTACs might constitute a potent therapeutic strategy for HCC.

High-Efficiency Condensation Heat Transfer Interfaces Based on Superwetting Copper Microgroove/Nanocone Structure.

Utilizing superhydrophobic micro/nanostructures to enhance condensation heat transfer (CHT) of copper surfaces has attracted intensive interest in recent years due to its significance in multiple industrial fields including nuclear power generation, thermal management, water harvesting, and desalination. However, superhydrophobic surfaces have instability risk caused by microcavity defect-induced vapor penetration and/or hydrophobic chemistry destruction. Here, we report a superwetting copper hierarchical microgroove/nanocone (MGNC) structure strategy that can realize high-efficiency CHT over a whole range of surface subcooling. By regulating groove width, fin width, groove depth, and nanostructure growth time, we obtain the optimal MGNC structure, where the CHT coefficient is 121% and 107% higher than that of hydrophilic flat surfaces at surface subcooling of 2 and 15 K, respectively. Such remarkable enhancement can be ascribed to the synergy of three interface effects: more nucleation sites for phase-change energy exchanging, thinner condensate films for reducing thermal resistance, and parallel microchannels for timely drainage. Compared with superhydrophobic strategies, our strategy not only can be mass-producible but also has other inherent advantages: no microcavity-induced performance failure risk as well as being free of chemistry modification, which makes the fabrication process simpler and more economic. Hierarchical micropillar/nanocone structure is also fabricated as the contrast sample for highlighting the superiority of the superwetting MGNC structure in enhancing CHT. This work not only enriches research systems of superwettability surfaces but also helps develop high-performance chips' cooling devices and explore more potential applications.

Sorafenib safety evaluation: Real-world analysis of adverse events from the FAERS database.

Background: Sorafenib is approved for the targeted therapy of cancers such as liver cancer and renal cancer. Given its widespread use, drug-related adverse events have received attention, and the post-marketing regulatory link is crucial. Objective: By using the FAERS database to mine the adverse events (AEs) related to sorafenib, comparing the association intensity of key AEs, and exploring potential drug-related AEs, it provides a reference for clinical medication. Methods: Collect ADE data related to sorafenib in the FAERS database from 2006 to 2023. Standardize the data, and map adverse events to system organ classes and preferred terms. Analyze using various signal quantification techniques such as ROR, PRR, BCPNN, and MGPS. Results: Among 18,520 adverse event reports (AERs) where sorafenib was the primary suspected drug, a total of 390 preferred terms (PTs) of adverse reactions were identified, covering 24 different system organ classes (SOCs). Specifically, the adverse events of sorafenib mainly involve the digestive system, skin and subcutaneous tissue, as well as non-specific physical discomfort including infection and injury. Among them, digestive system symptoms and skin toxicity are typical adverse reactions of sorafenib. We also observed uncommon but clearly strong AE signals, such as chloracne (n = 3, ROR 1756.39, PRR 1756.32, IC 8.78, EBGM 439.83), low-differentiated thyroid cancer (n = 4, ROR 585.47, PRR 585.44, IC 8.2, EBGM 293.22). It is worth noting that palmar-plantar erythrodysaesthesia syndrome (n = 2109, ROR 73.98, PRR 72.03, IC 6.01, EBGM 64.25) and hepatic encephalopathy (n = 457, ROR 37.44, PRR 37.23, IC 5.13, EBGM 35.07) have a higher incidence and signal intensity. In addition, we also observed some adverse events not mentioned in the official drug instructions, such as vitamin K deficiency or increased protein induced by antagonist II (PIVKA-II), abnormal alpha-fetoprotein, tumor metastasis, and splenic atrophy. Conclusion: Sorafenib carries the risk of various adverse reactions while providing therapeutic effects. In clinical applications, physicians should closely monitor the occurrence of digestive system reactions, skin lesions, endocrine system lesions, as well as injuries, infections, and other events.