Palladium-Catalyzed Cascade Heck Coupling and Allylboration of Iododiboron Compounds via Diboryl Radicals.

Geminal bis(boronates) are versatile synthetic building blocks in organic chemistry. The fact that they predominantly serve as nucleophiles in the previous reports, however, has restrained their synthetic potential. Herein we disclose the ambiphilic reactivity of α-halogenated geminal bis(boronates), of which the first catalytic utilization was accomplished by merging a formal Heck cross-coupling with a highly diastereoselective allylboration of aldehydes or imines, providing a new avenue for rapid assembly of polyfunctionalized boron-containing compounds. We demonstrated that this cascade reaction is highly efficient and compatible with various functional groups, and a wide range of heterocycles. In contrast to a classical Pd(0/II) scenario, mechanistic experiments and DFT calculations have provided strong evidence for a catalytic cycle involving Pd(I)/diboryl carbon radical intermediates.

Two new dinor-eudesmane sesquiterpenoids from the roots of Chloranthus multistachys.

Two new dinor-eudesmane sesquiterpenoids, named multistalin A (1), and multistalin B (2), together with three sesquiterpene glycosides (3-5), and a norlabdane-type diterpene (6) were isolated from the root extract of Chloranthus multistachys Pei. Their structures were elucidated on the basis of spectroscopic analysis including 1D, 2D NMR techniques and HR-ESI-MS. In addition, the cytotoxicity activities of the isolated compounds against selected cancer cells (Hela and A-549) were evaluated by MTT assay.

Suppressing Non-Radiative Relaxation through Single-Atom Metal Modification for Enhanced Fluorescence Efficiency in Molybdenum Disulfide Quantum Dots.

To enhance the fluorescence efficiency of semiconductor nanocrystal quantum dots (QDs), strategies via enhancing photo-absorption and eliminating non-radiative relaxation have been proposed. In this study, we demonstrate that fluorescence efficiency of molybdenum disulfide quantum dots (MoS2 QDs) can be enhanced by single-atom metal (Au, Ag, Pt, Cu) modification. Four-fold enhancement of the fluorescence emission of MoS2 QDs is observed with single-atom Au modification. The underlying mechanism is ascribed to the passivation of non-radiative surface states owing to the new defect energy level of Au in the forbidden band that can trap excess electrons in n-type MoS2 , increasing the recombination probability of conduction band electrons with valence band holes of MoS2 . Our results open an avenue for enhancing the fluorescence efficiency of QDs via the modification of atomically dispersed metals, and extend their scopes and potentials in a fundamental way for economic efficiency and stability of single-atom metals.

Comparison of outcomes between neoadjuvant imatinib and upfront surgery in patients with localized rectal GIST: An inverse probability of treatment weighting analysis.

BACKGROUND AND OBJECTIVES: This study aimed to compare outcomes between neoadjuvant imatinib and upfront surgery in patients with localized rectal gastrointestinal stromal tumors (GIST) patients. METHODS: Eighty-five patients with localized rectal GIST were divided into two groups: upfront surgery ± adjuvant imatinib (Group A, n = 33) and the neoadjuvant imatinib + surgery + adjuvant imatinib (Group B, n = 52). Baseline characteristics between groups were controlled for with inverse probability of treatment weighting (IPTW) adjusted analysis. RESULTS: The response rate to neoadjuvant imatinib was 65.9%. After the IPTW-adjusted analysis, patients who underwent neoadjuvant therapy had better distant recurrence-free survival (DRFS) and disease-specific survival (DSS) compared with those who underwent upfront surgery (5-year DRFS 97.8 vs. 71.9%, hazard ratio [HR], 0.15; 95% CI, 0.03-0.87; p = 0.03; 5-year DSS 100 vs. 77.1%; HR, 0.11; 95% CI, 0.01-0.92; p = 0.04). While no significant association was found between overall survival (OS) and treatment groups (p = 0.07), 5-year OS was higher for the neoadjuvant group than upfront surgery group (97.8% vs. 71.9%; HR, 0.2; 95% CI, 0.03-1.15). CONCLUSIONS: In patients with localized rectal GIST, neoadjuvant imatinib not only shrunk the tumor size but also decreased the risk of metastasis and tumor-related deaths when compared to upfront surgery and adjuvant imatinib alone.

Pulmonary pathology of early-phase COVID-19 pneumonia in a patient with a benign lung lesion.

AIMS: An ongoing outbreak of 2019 novel coronavirus (CoV) disease (COVID-19), caused by severe acute respiratory syndrome (SARS) CoV-2, has been spreading in multiple countries. One of the reasons for the rapid spread is that the virus can be transmitted from infected individuals without symptoms. Revealing the pathological features of early-phase COVID-19 pneumonia is important for understanding of its pathogenesis. The aim of this study was to explore the pulmonary pathology of early-phase COVID-19 pneumonia in a patient with a benign lung lesion. METHODS AND RESULTS: We analysed the pathological changes in lung tissue from a 55-year-old female patient with early-phase SARS-CoV-2 infection. In this case, right lower lobectomy was performed for a benign pulmonary nodule. Detailed clinical, laboratory and radiological data were also examined. This patient was confirmed to have preoperative SARS-CoV-2 infection by the use of real-time reverse transcription polymerase chain reaction and RNA in-situ hybridisation on surgically removed lung tissues. Histologically, COVID-19 pneumonia was characterised by exudative inflammation. The closer to the visceral pleura, the more severe the exudation of monocytes and lymphocytes. Perivascular inflammatory infiltration, intra-alveolar multinucleated giant cells, pneumocyte hyperplasia and intracytoplasmic viral-like inclusion bodies were seen. However, fibrinous exudate and hyaline membrane formation, which were typical pulmonary features of SARS pneumonia, were not evident in this case. Immunohistochemical staining results showed an abnormal accumulation of CD4+ helper T lymphocytes and CD163+ M2 macrophages in the lung tissue. CONCLUSION: The results highlighted the pulmonary pathological changes of early-phase SARS-CoV-2 infection, and suggested a role of immune dysfunction in the pathogenesis of COVID-19 pneumonia.

Enteral nutrition is associated with a decreased risk of surgical intervention in Crohn's disease patients with spontaneous intra-abdominal abscess.

BACKGROUND: The impact of enteral nutrition (EN) on surgical risk in Crohn's disease (CD) patients suffering from spontaneous intra-abdominal abscess (IAA) was evaluated. METHODS: CD patients diagnosed with spontaneous IAA from 2008 to 2015 were included in the study. The impact of EN on surgical risk was evaluated using both univariate and multivariate analyses. RESULTS: A total of 87 patients were enrolled, 66 (75.9%) were male. The mean age at the development of an abscess was 30.2 ± 10.1 years and the median duration of illness from CD diagnosis until the development of an abscess was three (2-6) years. After a median follow-up of 1.9 (1.1-2.9) years, surgical intervention was performed in 42 patients (48.3%). Patients treated with EN were less likely to require surgical intervention (26.1% vs 56.3%, p = 0.01). Multivariate analysis showed that EN was an independent protective factor for the risk of surgery with a hazard ratio of 0.27 (95% confidence interval: 0.11-0.65, p = 0.004) after adjusting for abdominal pain, history of abdominal surgery, concomitant intestinal stenosis and prior use of antibiotics within three months. CONCLUSIONS: Surgical intervention is common for CD patients with IAA. Appropriate application of EN may help obviate the need for surgical treatment.

Simultaneous determination of eight flavonoids in the flowers of Matricaria chamomilla by high performance liquid chromatography.

An HPLC method was developed for simultaneous determination of five flavones (apigenin, three apigenin 7-O-glucoside acylated derivatives, and luteolin) and three methoxylated flavonols in Matricaria chamomilla. Full validation of the assay was carried out including linearity, LODs, LOQs, precision, repeatability, stability, and accuracy. The results demonstrated that the method developed was simple, accurate, and reliable. Five batches of M. chamomilla samples were determined using the developed method, and total contents of the eight flavonoids ranged from 1.843 to 2.134 mg/g. Among them, the content of apigenin was the highest with values of 0.538 to 0.618 mg/g. In addition, the extract solution from M. chamomilla exhibited a significant dose-dependent inhibition of 2,2-diphenyl-1-picrylhydrazyl (DPPH) activity, with a 50% inhibition (SC50) at a concentration of 3.06 +/- 0.09 mg/mL, and the flavonoids apigenin-7-O-(6"-acetyl)-glucoside, luteolin, apigenin, eupatolitin, and chrysosplenol D played an important role in the antioxidant activities of the extract solution from M. chamomilla.

Uridine diphosphate glucuronosyltransferase 1A1 prevents the progression of liver injury.

BACKGROUND: Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) plays a crucial role in metabolizing and detoxifying endogenous and exogenous substances. However, its contribution to the progression of liver damage remains unclear. AIM: To determine the role and mechanism of UGT1A1 in liver damage progression. METHODS: We investigated the relationship between UGT1A1 expression and liver injury through clinical research. Additionally, the impact and mechanism of UGT1A1 on the progression of liver injury was analyzed through a mouse model study. RESULTS: Patients with UGT1A1 gene mutations showed varying degrees of liver damage, while patients with acute-on-chronic liver failure (ACLF) exhibited relatively reduced levels of UGT1A1 protein in the liver as compared to patients with chronic hepatitis. This suggests that low UGT1A1 levels may be associated with the progression of liver damage. In mouse models of liver injury induced by carbon tetrachloride (CCl4) and concanavalin A (ConA), the hepatic levels of UGT1A1 protein were found to be increased. In mice with lipopolysaccharide or liver steatosis-mediated liver-injury progression, the hepatic protein levels of UGT1A1 were decreased, which is consistent with the observations in patients with ACLF. UGT1A1 knockout exacerbated CCl4- and ConA-induced liver injury, hepatocyte apoptosis and necroptosis in mice, intensified hepatocyte endoplasmic reticulum (ER) stress and oxidative stress, and disrupted lipid metabolism. CONCLUSION: UGT1A1 is upregulated as a compensatory response during liver injury, and interference with this upregulation process may worsen liver injury. UGT1A1 reduces ER stress, oxidative stress, and lipid metabolism disorder, thereby mitigating hepatocyte apoptosis and necroptosis.

[Status and thinking of supervision and management of Chinese herbal medicine].

The article briefly introduces the status of the supervision and administration of Chinese herbal medicine, and summarizes the problems existing in the process of supervision and management. Meanwhile provides the countermeasures and suggestions of strengthening the supervision and administration of Chinese herbal medicine.

[Understanding of strengthen supervision and administration of herbal extracts].

The article briefly introduces the development history and status of the supervision and administration of herbal extracts, and summarizes the problems existing in the process of supervision and management. Meanwhile provides the countermeasures and suggestions of strengthening the supervision and administration of herbal extracts.

[Chemical constituents from rizomes of Homalomena occulta].

Column chromatography on silica gel and Sephadex LH-20 was used to study the chemical constituents of Homalomena occulta. The chemical structures of the separated compounds were elucidated by spectroscopic data analyseS. Twelve compounds were obtained and identified as 5-pentylresorcinol-b-glucoside (1), protocatechuic acid (2), 4-hydroxybenzoic acid (3), vanillic acid (4), 5-hydroxymethyl-2-furancarboxylic acid (5), 2-furoic acid (6), 5-hydroxymethyl-2-furfural (7), (R) -malic acid (8), (R) -dimethyl malate (9), trimethyl 1,2,3-propanetricarboxylate (10), 4-hydroxytetrahydrofuran-2-one (11) and (1S, 2S, 4S)-p-menthane-1,2, 4-triol (12). Among them, compound 1 was a new natural product, and compounds 4-12 were isolated from the genus for the first time.

Sulfonamides (SAs) exposure causes neurobehavioral toxicity at environmentally relevant concentrations (ERCs) in early development of zebrafish.

Antibiotics, due to their stability and persistence in the environment, can have chronic impacts on various ecosystems and organisms. However, the molecular mechanisms underlying antibiotic toxicity at environmental concentrations, particularly the neurotoxic effects of sulfonamides (SAs), remain poorly understood. In this study, we assessed the neurotoxicity of six SAs including the sulfadiazine (SD), sulfathiazole (ST), sulfamethoxazole (SMX), sulfisoxazole (SIZ), sulfapyridine (SPD), and sulfadimethoxine (SDM) by exposing zebrafish to environmentally relevant concentrations (ERCs). The SAs exhibited concentration-dependent effects on zebrafish behavior, including spontaneous movement, heartbeat, survival rate, and body metrics, ultimately leading to depressive-like symptoms and sublethal toxicity during early life stages. Notably, even the lowest SA concentration (0.05 µg/L) induced neurotoxicity and behavioral impairment in zebrafish. We observed a dose-dependent increase in melancholy behavior as indicated by increased resting time and decreased motor activity in zebrafish larvae. Following exposure to SAs from 4 to 120 h post-fertilization (hpf), key genes involved in folate synthesis [sepiapterin reductase a (spra), phenylalanine hydroxylase (pah), tyrosine hydroxylase (th), and tryptophan hydroxylase 1 (tryptophan 5-monooxygenase) a tryptophan hydroxylase (tph1a)] and carbonic anhydrase (CA) metabolism [carbonic anhydrase II (ca2), carbonic anhydrase IV a (ca4a), carbonic anhydrase VII (ca7), and carbonic anhydrase XIV (ca14)] were significantly downregulated or inhibited at different concentrations. Our findings demonstrate that acute exposure to six SAs at environmentally relevant concentrations induces developmental and neurotoxic effects in zebrafish, impacting folate synthesis pathways and CA metabolism. These results provide valuable insights into the potential role of antibiotics in depressive disorders and neuroregulatory pathways.

Fibulin2: a negative regulator of BMSC osteogenic differentiation in infected bone fracture healing.

Bone fracture remains a common occurrence, with a population-weighted incidence of approximately 3.21 per 1000. In addition, approximately 2% to 50% of patients with skeletal fractures will develop an infection, one of the causes of disordered bone healing. Dysfunction of bone marrow mesenchymal stem cells (BMSCs) plays a key role in disordered bone repair. However, the specific mechanisms underlying BMSC dysfunction caused by bone infection are largely unknown. In this study, we discovered that Fibulin2 expression was upregulated in infected bone tissues and that BMSCs were the source of infection-induced Fibulin2. Importantly, Fibulin2 knockout accelerated mineralized bone formation during skeletal development and inhibited inflammatory bone resorption. We demonstrated that Fibulin2 suppressed BMSC osteogenic differentiation by binding to Notch2 and inactivating the Notch2 signaling pathway. Moreover, Fibulin2 knockdown restored Notch2 pathway activation and promoted BMSC osteogenesis; these outcomes were abolished by DAPT, a Notch inhibitor. Furthermore, transplanted Fibulin2 knockdown BMSCs displayed better bone repair potential in vivo. Altogether, Fibulin2 is a negative regulator of BMSC osteogenic differentiation that inhibits osteogenesis by inactivating the Notch2 signaling pathway in infected bone.

Sesquiterpenoids from the rhizomes of Homalomena occulta.

Phytochemical investigation on the rhizomes of Homalomena occulta resulted in the isolation of five new sesquiterpenoids, namely cadinane-4ß,5α,10α-triol (1), 5(11)-epoxycadinane-4ß,5ß,10ß,11-tetraol (2), bullatantiol-1ß-methyl malate (3), 1ß,4ß,7α-trihydroxyeudesmane-1ß-methyl malate (6), and 1ß,4α,7-trihydroxyeudes-mane (7), together with five known sesquiterpenoids, bullatantriol (4), acetylbullatantriol (5), 1ß,4ß,7α-trihydroxyeudesmane (8), 1ß,4ß,7ß-trihydroxyeude-smane (9), and pterodontriol (10). Their structures were elucidated on the basis of spectroscopic evidences, including various 1D and 2D NMR and HR-ESI-MS. The structure of 1 was further confirmed by single-crystal X-ray diffraction analysis.

Radical modulated regioselective difunctionalization of vinyl enynes: tunable access to naphthalen-1(2H)-ones and allenic alcohols.

A novel and efficient radical-modulated difunctionalization of vinyl enynes has been disclosed using TEMPO as a radical regulator. Facile access to structurally diverse 3-bromo-naphthalen-1(2H)-ones and 4-bromo-allenic alcohols was realized via 1,2-addition/1,2-migration or 1,4-addition, respectively. This protocol represents the first example of radical-modulated metal-free difunctionalization of 1,3-enynes with high regioselectivity.

Identifying novel therapeutic targets in gastric cancer using genome-wide CRISPR-Cas9 screening.

Genome-scale CRISPR-Cas9 screening technology is a powerful tool to systematically identify genes essential for cancer cell survival. Herein, TKOv3, a genome-scale CRISPR-Cas9 knock-out library, was screened in the gastric cancer (GC) cells, and relevant validation experiments were performed. We obtained 854 essential genes for the AGS cell line, and 184 were novel essential genes. After knocking down essential genes: SPC25, DHX37, ABCE1, SNRPB, TOP3A, RUVBL1, CIT, TACC3 and MTBP, cell viability and proliferation were significantly decreased. Then, we analysed the detected essential genes at different time points and proved more characteristic genes might appear with the extension of selection. After progressive selection using a series of open datasets, 41 essential genes were identified as potential drug targets. Among them, methyltransferase 1 (METTL1) was over expressed in GC tissues. High METTL1 expression was associated with poor prognosis among 3 of 6 GC cohorts. Furthermore, GC cells growth was significantly inhibited after the down-regulation of METTL1 in vitro and in vivo. Function analysis revealed that METTL1 might play a role in the cell cycle through AKT/STAT3 pathways. In conclusion, compared with existing genome-scale screenings, we obtained 184 novel essential genes. Among them, METTL1 was validated as a potential therapeutic target of GC.

K63 Ubiquitination of P21 Can Facilitate Pellino-1 in the Context of Chronic Obstructive Pulmonary Disease and Lung Cellular Senescence.

Chronic obstructive pulmonary diseases (COPD) is a kind of age-related, airflow-obstruction disease mostly caused by cigarette smoke. However, the relationship between COPD and lung cellular senescence is still not fully understood. Here, we found silencing Pellino-1 could inhibit the protein level of P21. Then, through constructing cell lines expressed ubiquitin-HA, we found that the E3 ubiquitin ligase Pellino-1 could bind to senescence marker p21 and modify p21 by K63-site ubiquitination by co-IP assays. Furthermore, we found that p21-mediated lung cellular senescence could be inhibited by silencing Pellino-1 in a D-galactose senescence mice model. Moreover, by constructing a COPD mouse model with shPellino-1 adenovirus, we found that silencing Pellino-1 could inhibit COPD and inflammation via reduction of SASPs regulated by p21. Taken together, our study findings elucidated that silencing E3 ligase Pellino-1 exhibits therapeutic potential for treatment to attenuate the progression of lung cellular senescence and COPD.

Increased expression of microRNA-26a-5p predicted a poor survival outcome in osteosarcoma patients: An observational study.

ABSTRACT: MicroRNA (miR)-26a-5p is an oncogene significantly associated with osteosarcoma. We try to evaluate expression of circulating miR-26a-5p in osteosarcoma patients and evaluate its significance.A total of 243 consecutive osteosarcoma patients and 96 healthy participates were enrolled. Circulating miR-26a-5p levels were evaluated by using real-time quantitative reverse transcription polymerase chain reactions (RT-PCR). The association between circulating miR-26a-5p level and survival outcomes was evaluated by univariate and multivariate analysis.Circulating miR-26a-5p levels in osteosarcoma patients was significantly higher than that of healthy volunteers (P < .05). Upregulated miR-26a-5p was significantly related to advanced cancer and metastasis (both P < .05). Moreover, patients with a high serum miR-26a-5p had a poorer overall survival than those with a low serum miR-26a-5p levels (P < .05). Circulating miR-26a-5p level also been showed as independent risk factor for osteosarcoma in multivariate analysis (hazard ratio [HR], 0.38; 95% confidence interval [CI]: 0.11-0.98; P < .01).Circulating miR-26a-5p was significantly upregulated in osteosarcoma patients and remarkably associated with poor prognosis, indicating that circulating miR-26a-5p might serve as a useful diagnostic and prognostic biomarker for osteosarcoma.

Visible-Light-Induced 1,4-Hydroxysulfonylation of Vinyl Enynes with Sulfonyl Chlorides: The Bridge of Chloride Linking Water and Enynes.

A novel visible-light-induced 1,4-hydroxysulfonylation of vinyl enynes with sulfonyl chlorides has been established, providing a highly efficient protocol to access multisubstituted sulfonyl allenic alcohols. Control experiments and mechanistic studies disclose that the target products result from sequential reactions of hydroxyl and tosyl radicals, among which chloride anion plays a key role to generate the requisite •OH, thus bridging water and enynes. Moreover, the vinyl pendant is believed to decisively affect the site-selectivity of hydroxyl radical.

Role of Tenascin-X in regulating TGF-ß/Smad signaling pathway in pathogenesis of slow transit constipation.

BACKGROUND: Chronic constipation is a gastrointestinal functional disease that seriously harms physical and mental health and impacts the quality of life of patients. Its incidence rate is 2%-27%. Slow transit constipation (STC) is a common type of chronic functional constipation, accounting for 10.3%-45.5% of such cases. Scholars have performed many studies on the pathogenesis of STC. These studies have indicated that the occurrence of STC may be related to multiple factors, such as dysfunction of the enteric nervous system, interstitial cells of Cajal (ICC) damage, and changes in neurotransmitters regulating intestinal peristalsis. AIM: To investigate the role of Tenascin-X (TNX) in regulating the TGF-ß/Smad signaling pathway in the pathogenesis of STC. METHODS: This study included an experimental group and a control group. The experimental group included 28 patients with severe colonic STC, and the control group included 18 patients with normal colon tissues. Immunohistochemistry (IHC) was used to detect c-Kit, a specific marker of the ICC. Western blot, immunofluorescence, and IHC were used to detect the localization and expression of TNX and TGF-ß/Smad. RESULTS: IHC showed that the number of ICC with positive c-Kit expression was significantly reduced in the colon of STC patients (22.17 ± 3.28 vs 28.69 ± 3.53, P < 0.05) and that the distribution was abnormal. Western blot results showed that c-Kit and Smad7 levels were significantly decreased in the colon of STC patients (c-kit: 0.462 ± 0.099 vs 0.783 ± 0.178, P < 0.01; Smad7: 0.626 ± 0.058 vs 0.799 ± 0.03, P < 0.01) and that TNX and Smad2/3 levels were higher in the STC group (TNX: 0.868 ± 0.028 vs 0.482 ± 0.032, P < 0.01). There was no significant difference in TGF-ß between the two groups (0.476 ± 0.028 vs 0.511 ± 0.044, P = 0.272). Pearson correlation analysis showed that the TNX protein exhibited a strong correlation with Smad2/3 and Smad7 (P < 0.05, |R| > 0.8) and TGF-ß (P < 0.05, |R| = 0.7). CONCLUSION: The extracellular matrix protein TNX may activate the TGF-ß/Smad signaling pathway by upregulating the Smad 2/3 signaling protein and thereby induce slight or complete epithelial stromal cell transformation, leading to an abnormal distribution and dysfunction of ICC in the diseased colon, which promotes the occurrence and development of STC.