Photoinduced Redox Cascade Reaction of Isatins and Aliphatic Carboxylic Acids to Access 6-Hydroxyindoloquinazolinones.

A visible-light-induced cascade reaction is described for the one-pot synthesis of 6-hydroxyindoloquinazolinones using isatins (or isatins and isatoic anhydrides) and aliphatic carboxylic acids. The method provides 36 desired products in 33-96% yield, exhibiting broad substrate scope and good functional group tolerance. This approach utilizes inexpensive and commercially available starting materials, enabling the direct construction of high-value complex structures under mild conditions without the need for photocatalyst, showcasing significant applicability and environmental friendliness.

Visible Light-Induced Hydroacylation of Benzylidenemalononitriles with Aroyl Chlorides Using Silane as a Hydrogen Donor.

A novel photoredox-catalyzed direct hydroacylation of benzylidenemalononitriles is described. In this method, aroyl chlorides are employed as a readily available and affordable source of acyl groups, while commercially available tris(trimethylsilyl)silane acts as both the hydrogen atom donor and electron donor. By eliminating the requirement for complex synthesis of acyl precursors and hydrogen atom-transfer (HAT) reagents, this approach offers a convenient and efficient strategy for the hydroacylation of benzylidenemalononitriles.

Visible-Light Induced Radical Addition-Elimination Reaction for Constructing Allylic Sulfones from Sulfonyl Chlorides and Allyl Bromides.

Allyl sulfones are commonly present in bioactive compounds and organic building blocks. This work introduces a photocatalytic radical addition-elimination reaction involving readily accessible sulfonyl chlorides and allyl bromides. It delivers structurally diverse allylic sulfones in moderate to excellent yields, showcasing a high tolerance to functional groups. Notably, this method operates under mild reaction conditions without the need for oxidants, stoichiometric reducing metals, or additives.

Electrochemical Synthesis of Selenosulfonates from Diselenides and Sulfonyl Hydrazides.

The electrochemical oxidative radical-radical cross-coupling of sulfonyl hydrazides with diselenides for the synthesis of selenosulfonates was successfully accomplished. The method is applicable to a wide range of aromatic/aliphatic sulfonyl hydrazides and diselenides, providing products in good to excellent yields. Notably, this protocol stands out for its green and sustainable nature, as it does not rely on transition metals and oxidizing agents, and the starting materials are cost-effective and readily available.

Impact of chemotherapy delay on long-term prognosis of laparoscopic radical surgery for locally advanced gastric cancer: a pooled analysis of four randomized controlled trials.

BACKGROUND: Adjuvant chemotherapy following curative surgery for locally advanced gastric cancer (AGC) significantly improves long-term patient prognosis. However, delayed chemotherapy (DC), in which patients are unable to receive timely treatment, is a common phenomenon in clinical practice for various reasons. This study aimed to investigate the impact of DC on the prognosis of patients with stage II-III locally AGC and explore the associated risk factors. METHODS: Data from four prospective studies were included in the pooled analysis. The planned chemotherapy (PC) group was defined as the time interval between surgery and the first chemotherapy ≤ 49 d, while the DC group was defined as the time interval between surgery and chemotherapy > 49 d. The prognosis, recurrence, and risk factors were compared, and a nomogram for predicting DC was established. RESULTS: In total, 596 patients were included, of whom 531 (89.1%) had PC and 65 (10.9%) had DC. Survival analysis revealed that the 5-year overall survival (OS) and disease-free survival (DFS) were significantly lower in the DC group than those in the PC group (log-rank P < 0.001). Cox univariable and multivariable analyses showed that DC was an independent risk factor for OS and DFS in stage II-III patients (P < 0.05). Based on the significant factors for DC, a prediction model was established that had a good fit, high accuracy (AUC = 0.780), and clinical applicability in both the training and validation sets. CONCLUSION: Delayed chemotherapy after gastrectomy is associated with poor long-term prognosis in patients with locally advanced stage II-III GC disease. But standardized, full-cycle adjuvant chemotherapy after surgery may play a remedial role, and can to a certain extent compensate the poor effects caused by delayed chemotherapy.

Long-term oncological outcomes of 3D versus 2D laparoscopic gastrectomy for gastric cancer: a randomized clinical trial.

BACKGROUND: Laparoscopy-assisted gastrectomy (LG) is rapidly gaining popularity owing to its minimal invasiveness. Previous studies have found that compared with two-dimensional (2D)-LG, three-dimensional (3D)-LG showed better short-term outcomes. However, the long-term oncological outcomes in patients with locally resectable gastric cancer (GC) remain controversial. METHODS: In this noninferiority, open-label, randomized clinical trial, a total of 438 eligible GC participants were randomly assigned in a 1:1 ratio to either 3D-LG or 2D-LG from January 2015 to April 2016. The primary endpoint was operating time, while the secondary endpoints included 5-year overall survival (OS), disease-free survival (DFS), and recurrence pattern. RESULTS: Data from 401 participants were included in the per-protocol analysis, with 204 patients in the 3D group and 197 patients in the 2D group. The 5-year OS and DFS rates were comparable between the 3D and 2D groups (5-year OS: 70.6% vs. 71.1%, Log-rank P = 0.743; 5-year DFS: 68.1% vs. 69.0%, log-rank P = 0.712). No significant differences were observed between the 3D and 2D groups in the 5-year recurrence rate (28.9% vs. 28.9%, P = 0.958) or recurrence time (mean time, 22.6 vs. 20.5 months, P = 0.412). Further stratified analysis based on the type of gastrectomy, postoperative pathological staging, and preoperative BMI showed that the 5-year OS, DFS, and recurrence rates of the 3D group in each subgroup were similar to those of the 2D group (all P > 0.05). CONCLUSIONS: For patients with locally resectable GC, 3D-LG performed by experienced surgeons in high-volume professional institutions can achieve long-term oncological outcomes comparable to those of 2D-LG. REGISTRATION NUMBER: NCT02327481 ( http://clinicaltrials.gov ).

Appraisal of surgical outcomes and oncological efficiency of intraoperative adverse events in robotic radical gastrectomy for gastric cancer.

BACKGROUND: Surgical quality control is a crucial determinant of evaluating the tumor efficacy. OBJECTIVE: To assess the ClassIntra grade for quality control and oncological outcomes of robotic radical surgery for gastric cancer (GC). METHODS: Data of patients undergoing robotic radical surgery for GC at a high-volume center were retrospectively analyzed. Patients were categorized into two groups, the intraoperative adverse event (iAE) group and the non-iAE group, based on the occurrence of intraoperative adverse events. The iAEs were further classified into five sublevels (ranging from I to V according to severity) based on the ClassIntra grade. Surgical performance was assessed using the Objective Structured Assessment of Technical Skill (OSATS) and the General Error Reporting Tool. RESULTS: This study included 366 patients (iAE group: n = 72 [19.7%] and non-iAE group: n = 294 [80.3%]). The proportion of ClassIntra grade II patients was the highest in the iAE group (54.2%). In total and distal gastrectomies, iAEs occurred most frequently in the suprapancreatic area (50.0% and 54.8%, respectively). In total gastrectomy, grade IV iAEs were most common during lymph node dissection in the splenic hilum area (once for bleeding [grade IV] and once for injury [grade IV]). The overall survival (OS) and disease-free survival of the non-iAE group were significantly better than those of the iAE group (Log rank P < 0.001). Uni- and multi-variate analyses showed that iAEs were key prognostic indicators, independent of tumor stage and adjuvant chemotherapy (P < 0.001). CONCLUSION: iAEs in patients who underwent robotic radical gastrectomy significantly correlated with the occurrence of postoperative complications and a poor long-term prognosis. Therefore, utilization and inclusion of ClassIntra grading as a crucial surgical quality control and prognostic indicator in the routine surgical quality evaluation system are recommended.

Robot-assisted versus laparoscopic-assisted gastrectomy among malnourished patients with gastric cancer based on textbook outcome.

BACKGROUND: Textbook outcome (TO) has been widely employed as a comprehensive indicator to assess the short-term prognosis of patients with cancer. Preoperative malnutrition is a potential risk factor for adverse surgical outcomes in patients with gastric cancer (GC). This study aimed to compare the TO between robotic-assisted gastrectomy (RAG) and laparoscopic-assisted gastrectomy (LAG) in malnourished patients with GC. METHODS: According to the diagnostic consensus of malnutrition proposed by Global Leadership Initiative on Malnutrition (GLIM) and Nutrition Risk Index (NRI), 895 malnourished patients with GC who underwent RAG (n = 115) or LAG (n = 780) at a tertiary referral hospital between January 2016 and May 2021 were included in the propensity score matching (PSM, 1:2) analysis. RESULTS: After PSM, no significant differences in clinicopathological characteristics were observed between the RAG (n = 97) and LAG (n = 194) groups. The RAG group had significantly higher operative time and lymph nodes harvested, as well as significantly lower blood loss and hospital stay time compared to the LAG group. More patients in the RAG achieved TO. Logistic regression analysis revealed that RAG was an independent protective factor for achieving TO. There were more adjuvant chemotherapy (AC) cycles in the RAG group than in the LAG group. After one year of surgery, a higher percentage of patients (36.7% vs. 22.8%; P < 0.05) in the RAG group recovered from malnutrition compared to the LAG group. CONCLUSIONS: For malnourished patients with GC, RAG performed by experienced surgeons can achieved a higher rate of TO than those of LAG, which directly contributed to better AC compliance and a faster restoration of nutritional status.

Periploca forrestii Schltr. ameliorate liver injury caused by fluorosis in rat.

To investigate the impact of the ethanoic fractions of Periploca forrestii Schltr. (P. forrestii) in ameliorating the liver injury caused by fluoride ingestion and to explore the potential mechanisms. Initially, an in vitro fluorosis cell model was constructed using the human normal liver cell line (L-02) induced by fluoride. Cell viability was assessed using the CCK-8 assay kit. The lactate dehydrogenase (LDH) assay kit was utilized to measure LDH content in the cell supernatant, while the malonic dialdehyde (MDA) assay kit was employed to determine MDA levels within the cells. Subsequently, a fluorosis rat model was established, and LDH content in the cell supernatant was measured using the LDH assay kit. Various parameters, including MDA, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and reactive oxygen species (ROS) content within the cells, were detected using appropriate assay kits. Additionally, cell apoptosis rate was determined using the Annexin V-FITC/PI cell apoptosis assay kit. The protein expression levels of B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), Caspase-3, Cleaved Caspase-3, Caspase-9, and Cleaved Caspase-9 were analyzed through Western blotting. Compared to the model group, the ethanolic fraction D of P.forrestii (Fr.D) increased cell viability (P < 0.01) and decreased LDH and MDA levels (P < 0.01). In the high-dose Fr.D treatment group of fluoride-poisoned rats, serum ALT, AST, LDH and MDA levels significantly decreased (P < 0.01). Results from rat primary cells exhibited that the Fr.D administration group exhibited significantly higher cell survival rates than the fluoride group (P < 0.01). Similarly, primary rat cells treated with Fr.D showed enhanced cell viability (P < 0.05) and reduced apoptosis rate, LDH, MDA, SOD, GSH-Px, CAT, and ROS levels (P < 0.05) compared to the model group. Western blot analysis indicated that the Fr.D treatment group elevated the Bcl-2/Bax protein expression ratio and reduced Caspase-3 and Caspase-9 activation levels (P < 0.01) compared to the model group. The results suggest that components within the Fr.D from Periploca forrestii may alleviate fluoride-induced liver injury by potentially counteracting oxidative stress and cell apoptosis.

Regulating effect of miR-132-3p on the changes of MAPK pathway in rat brains and SH-SY5Y cells exposed to excessive fluoride by targeting expression of MAPK1.

BACKGROUND: Although the changes of mitogen-activated protein kinase (MAPK) pathway in the central nervous system (CNS) induced by excessive fluoride has been confirmed by our previous findings, the underlying mechanism(s) of the action remains unclear. Here, we investigate the possibility that microRNAs (miRNAs) are involved in the aspect. METHODS: As a model of chronic fluorosis, SD rats received different concentrations of fluoride in their drinking water for 3 or 6 months and SH-SY5Y cells were exposed to fluoride. Literature reviews and bioinformatics analyses were used to predict and real-time PCR to measure the expression of 12 miRNAs; an algorithm-based approach was applied to identify multiply potential target-genes and pathways; the dual-luciferase reporter system to detect the association of miR-132-3p with MAPK1; and fluorescence in situ hybridization to detect miR-132-3p localization. The miR-132-3p inhibitor or mimics or MAPK1 silencing RNA were transfected into cultured cells. Expression of protein components of the MAPK pathway was assessed by immunofluorescence or Western blotting. RESULTS: In the rat hippocampus exposed with high fluoride, ten miRNAs were down-regulated and two up-regulated. Among these, miR-132-3p expression was down-regulated to the greatest extent and MAPK1 level (selected from the 220 genes predicted) was corelated with the alteration of miR-132-3p. Furthermore, miR-132-3p level was declined, whereas the protein levels MAPK pathway components were increased in the rat brains and SH-SY5Y cells exposed to high fluoride. MiR-132-3p up-regulated MAPK1 by binding directly to its 3'-untranslated region. Obviously, miR-132-3p mimics or MAPK1 silencing RNA attenuated the elevated expressions of the proteins components of the MAPK pathway induced by fluorosis in SH-SY5Y cells, whereas an inhibitor of miR-132-3p just played the opposite effect. CONCLUSION: MiR-132-3p appears to modulate the changes of MAPK signaling pathway in the CNS associated with chronic fluorosis.

Visible Light-Induced Cross-Dehydrocoupling of 3-Cyanocoumarins with Unactivated Aliphatic Aldehydes Enables Access to 4-Acylated Coumarins.

We report visible light-induced cross-dehydrocoupling of 3-cyanocoumarins with unactivated aliphatic aldehydes for the direct synthesis of 4-acylated coumarins. Inexpensive and readily available (n-Bu)4NBr was used as a precursor of the hydrogen atom transfer (HAT) catalyst and [Ir(ppy)2(dtbbpy)PF6] as a photocatalyst. A variety of aldehydes including linear, branched, cyclic, and α,ß-unsaturated aliphatic aldehydes were suitable for this reaction yielding the desired acylated coumarin derivatives in 41-98% yields. This method provides a mild, atom-economical, and environmentally friendly synthetic route for the direct acylation of 3-cyanocoumarins. This is the first example so far of C-4 aliphatic acylation of coumarins.

Photoredox-Catalyzed Radical-Radical Cross-Coupling of Sulfonyl Chlorides with Trifluoroborate Salts.

Sulfones are widely found in natural products and drug molecules. Here, we disclose a strategy for direct synthesis of sulfone compounds with diverse structures by visible-light-catalyzed radical-radical cross-coupling of sulfonyl chlorides and trifluoroborate salts. Allyl, benzyl, vinyl, and aryl trifluoroborates can be successfully cross-coupled with (hetero)aryl and alkyl sulfonyl chlorides, respectively. This strategy features redox neutrality, good substrate generality, simple operation, and benign reaction conditions.

Electrochemical Cross-Dehydrogenative Coupling of Isochroman and Unactivated Ketones.

An unprecedented electrochemical cross-dehydrogenative coupling reaction between isochroman and unactivated ketones to directly synthesize α-substituted isochromans has been developed. This strategy provides a facile and efficient procedure to the direct activation of C(sp3)-H bond adjacent to the O atom of isochroman. The method features high atom economy, chemical oxidant-free, and mild conditions, in which methanesulfonic acid (MsOH) acts as both electrolyte and catalyst, making the process more convenient and environmentally friendly. Gram-scale experiment and synthesis of antitumor active compounds demonstrate the great potential of this protocol for practical applications.

Electroreductive Hydroxymethylation of Imines with Ketones To Access ß-Amino Alcohols.

In this article, an electrochemical method for the direct synthesis of ß-amino alcohols from imines and ketones is described. Mechanistic studies, including a radical trapping experiment, electron paramagnetic resonance, cyclic voltammetry, and divided-cell electrolysis experiment, support the radical-involved reductive cross coupling of imines with ketones at the cathode. The use of abundant and easily prepared starting materials, high atom- and step-economy, and insensitivity to air and moisture make this synthetic strategy more efficient for the construction of various ß-amino alcohol derivatives.

Electrochemical Synthesis of ß-Iodoesters by 1,2-Iodoesterization of Unactivated Alkenes with Carboxylic Acids and Tetrabutylammonium Iodide.

We report a novel and highly selective electrochemical method for the synthesis of ß-iodoesters via difunctionalization of alkenes. The reaction is carried out in an undivided cell under constant current conditions without any additives, catalysts, oxidants, and sacrificial reagents. Inexpensive and readily available tetrabutylammonium iodide not only acts as an electrolyte but also serves as an iodine source. The reaction shows high selectivity and good functional group tolerance, providing products in yields of up to 98%. This method is applicable not only to the iodofunctionalization of alkenes but also to the chloro- and bromofunctionalization of alkenes. The successful modification of drugs and natural products demonstrates the potential utility of this approach.

Direct Hydroxylarylation of Benzylic Carbons (sp3/sp2/sp) via Radical-Radical Cross-Coupling Powered by Paired Electrolysis.

Diaryl alcohol moieties are widespread in pharmaceuticals. Existing methods for the synthesis of diaryl alcohols require the use of pre-functionalized benzylic alcohols, aromatic aldehydes, or ketones as starting materials. Herein, the first convergent paired electrochemical approach to the direct hydroxylarylation of unactivated benzylic carbons (sp3/sp2/sp) is proposed. This protocol features direct functionalization of unactivated benzylic C(sp3)-H bonds and benzylic sp2/sp-carbons, mild conditions (open air, room temperature), an environmentally friendly procedure (without any external catalyst/mediator/additive), and direct access to sterically hindered alcohols from inexpensive and readily available alkyl/alkenyl/alkynylbenzenes. Mechanistic studies, including divided-cell experiments, isotope labeling, radical trapping, electron paramagnetic resonance, reaction kinetics, and cyclic voltammetry, strongly support the proposed radical-radical cross-coupling between transient ketyl radicals and persistent radical anions. Gram-scale synthesis and diversification of drug derivatives have visualized the tremendous potential of this protocol for practical applications.

Electrochemical C(sp2)-H/N-H "formal" cross-dehydrogenative coupling of olefins with benzotriazoles for synthesis of N-vinyl benzotriazoles.

The paper details an electrochemical method that couples olefins with benzotriazoles to form C(sp2)-N bonds, enabling the synthesis of N-vinyl benzotriazoles in moderate to good yields. nBu4NI functions as both an electrolyte and an iodine mediator, and the method does not require oxidants or metals. It is a highly atom-economical and clean reaction, with hydrogen as the sole byproduct.

[Pathways and Mechanisms of Periodontitis Contributing to Adverse Pregnancy Outcomes].

Periodontitis is a chronic oral inflammatory disease with a high incidence in the global population. Periodontal pathogens can colonize and infect multiple human tissues and organs through blood transmission, which is an important risk factor of many systemic diseases. Recently, the correlation between periodontitis and adverse pregnancy outcomes (APOs) has attracted growing research interest. Herein, we systematically reviewed the research progress in the relationship between periodontitis and APOs and summarized reported findings on the pathways and mechanisms by which periodontitis contributes to APOs. We also clarified that intrauterine infection caused by oral pathogens transmitted through blood is an important pathway by which periodontitis interferes with pregnancy. In addition, further research focused on the discovery of more APOs-related oral pathogenic bacteria and their virulence factors, analysis of the interaction between pathogenic bacteria and placental tissue, and pathogenic pathways of oral bacterial invasion of the fetus will promote thorough analysis of the specific molecular mechanism of how periodontitis affects APOs. Furthermore, the validation of the results of human population-based studies through animal/cell experiments and the translation into effective intervention strategies are of great clinical significance to the prevention and control of the occurrence and development of APOs.

[Modern research progress in external application of traditional Chinese medicine to acupoints].

Traditional Chinese medicine(TCM) has a long history and abundant experience in external therapy, which marks human wisdom. In the early history of human, people found that fumigation, coating, and sticking of some tree branches and herb stems can help alleviate scabies and remove parasites in productive labor, which indicates the emergence of external therapy. Pathogen usually enters the body through the surface, so external therapy can be used to treat the disease. External therapy is among the major characteristic of surgery of TCM. As one of the external therapies in TCM, external application to acupoints smooths the zang-fu organs through meridians and collaterals, thereby harmonizing yin and yang. This therapy emerged in the early society, formed the Spring and Autumn Period and the Warring States Period, improved in the Song and Ming dynasties, and matured in the Qing dynasty. With the efforts of experts in history, it has had a mature theory. According to modern research, it can avoid the first-pass effect of liver and the gastrointestinal irritation and improve the bioavailability of Chinese medicine. Based on the effect of Chinese medicine and the theory of meridian and collateral, it can stimulate the acupoints, exert regulatory effect on acupoints, and give full play to the efficacy of TCM and the interaction of the two. Thereby, it can regulate qi and blood and balance yin and yang, thus being widely used in the treatment of diseases. In this paper, the use of external application to acupoints, the effect on skin immunity, the regulation of neuro-inflammatory mechanism, the relationship between acupoint application and human circulation network, and the development of its dosage form were summarized through literature review. On this basis, this study is expected to lay a foundation for further research.

An NF-κB/OVOL2 circuit regulates glucose import and cell survival in non-small cell lung cancer.

BACKGROUND: Tumor cells tend to utilize glycolysis rather than aerobic respiration even under aerobic conditions. OVOL2, an inhibitory C2H2 zinc finger transcription factor, is a potential tumor suppressor in cancers. However, the association between OVOL2 and tumor energy metabolism is unknown. METHODS: Western blotting was used to determine the expression of OVOL2 in different non-small cell lung cancer (NSCLC) cell lines and mouse models. The metabolic parameters in NSCLC cells following overexpression or knockdown OVOL2 were examined. To define the mechanism by which OVOL2 regulates aerobic glycolysis, interacting protein of OVOl2 and downstream molecular events were identified by luciferase assay and co-immunoprecipitation. We documented the regulatory mechanism in mouse xenograft models. Finally, clinical relevance of OVOL2, NF-κB signaling and GLUT1 was measured by immunostaining. RESULTS: OVOL2 is downregulated in NSCLC and overexpression of OVOL2 inhibits the survival of cancer cells. Moreover, OVOL2 directly binds to P65 and inhibits the recruitment of P300 but facilitates the binding of HDAC1 to P65, which in turn negatively regulates NF-κB signaling to suppress GLUT1 translocation and glucose import. In contrast, OVOL2 expression is negatively regulated by NF-κB signaling in NSCLC cells via the ubiquitin-proteasome pathway. Re-expression of OVOL2 significantly compromise NF-κB signaling-induced GLUT1 translocation, aerobic glycolysis in NSCLC cells and mouse models. Immunostaining revealed inverse correlations between the OVOL2 and phosphorylated P65 levels and between the OVOL2 and membrane GLUT1 levels, and a strong correlation between the phosphorylated P65 and membrane GLUT1 levels. CONCLUSIONS: These results suggest a regulatory circuit linking NF-κB and OVOL2, which highlights the role of NF-κB signaling and OVOL2 in the modulation of glucose metabolism in NSCLC. Video Abstract.