Photoinduced reductive Reformatsky reaction of α-haloesters and aldehydes or ketones by cooperative dual-metal catalysis.

A photoinduced reductive Reformatsky reaction by cooperative dual-metal catalysis is described. This methodology enables the implementation of this venerable reaction in environmentally friendly conditions, obviating the need for a stoichiometric amount of metals. A broad range of synthetically useful ß-hydroxy esters can be efficiently prepared in moderate to high yields using this protocol.

Risk factor analysis and a new prediction model of venous thromboembolism after pancreaticoduodenectomy.

AIM: The present study aimed to identify risk factors for venous thromboembolism (VTE) after pancreaticoduodenectomy (PD) and to develop and internally validate a predictive model for the risk of venous thrombosis. METHODS: We retrospectively collected data from 352 patients who visited our hospital to undergo PD from January 2018 to March 2022. The number of patients recruited was divided in an 8:2 ratio by using the random split method, with 80% of the patients serving as the training set and 20% as the validation set. The least absolute shrinkage and selection operator (Lasso) regression model was used to optimize feature selection for the VTE risk model. Multivariate logistic regression analysis was used to construct a prediction model by incorporating the features selected in the Lasso model. C-index, receiver operating characteristic curve, calibration plot, and decision curve were used to assess the accuracy of the model, to calibrate the model, and to determine the clinical usefulness of the model. Finally, we evaluated the prediction model for internal validation. RESULTS: The predictors included in the prediction nomogram were sex, age, gastrointestinal symptoms, hypertension, diabetes, operative method, intraoperative bleeding, blood transfusion, neutrophil count, prothrombin time (PT), activated partial thromboplastin time (APTT), aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio (AST/ALT), and total bilirubin (TBIL). The model showed good discrimination with a C-index of 0.827, had good consistency based on the calibration curve, and had an area under the ROC curve value of 0.822 (P < 0.001, 95%confidence interval:0.761-0.882). A high C-index value of 0.894 was reached in internal validation. Decision curve analysis showed that the VTE nomogram was clinically useful when intervention was decided at the VTE possibility threshold of 10%. CONCLUSION: The novel model developed in this study is highly targeted and enables personalized assessment of VTE occurrence in patients who undergo PD. The predictors are easily accessible and facilitate the assessment of patients by clinical practitioners.

Copper-catalyzed direct decarboxylative fluorosulfonylation of aliphatic carboxylic acids.

Sulfonyl fluorides are emerging as key structural motifs in organic synthesis, medicinal chemistry, and materials science. Herein we report two efficient and complementary methods for direct decarboxylative fluorosulfonylation of carboxylic acids by the merging of copper catalysis with different N-centered HAT regents. A wide range of structurally diverse sulfonyl fluorides was readily accessed from primary, secondary, and tertiary carboxylic acids in a single step under mild conditions.

Patient-driven discovery of CCN1 to rescue cutaneous wound healing in diabetes via the intracellular EIF3A/CCN1/ATG7 signaling by nanoparticle-enabled delivery.

Diabetic ulcers (DUs), a devastating complication of diabetes, are intractable for limited effective interventions in clinic. Based on the clinical samples and bioinformatic analysis, we found lower level of CCN1 in DU individuals. Considering the accelerated proliferation effect in keratinocytes, we propose the therapeutic role of CCN1 supplementation in DU microenvironment. To address the challenge of rapid degradation of CCN1 in protease-rich diabetic healing condition, we fabricated a nanoformulation of CCN1 (CCN1-NP), which protected CCN1 from degradation and significantly raised CCN1 intracellular delivery efficiency to 6.2-fold. The results showed that the intracellular CCN1 exhibited a greater anti-inflammatory and proliferative/migratory activities once the extracellular signal of CCN1 was blocked in vitro. The nanoformulation unveils a new mechanism that CCN1 delivered into cells interacted with Eukaryotic translation initiation factor 3 subunit A (EIF3A) to downregulate autophagy-related 7 (ATG7). Furthermore, topical application of CCN1-NP had profound curative effects on delayed wound healing in diabetes both in vitro and in vivo. Our results illustrate a novel mechanism of intracellular EIF3A/CCN1/ATG7 axis triggered by nanoformulation and the therapeutic potential of CCN1-NP for DU management.

Post-Translational Modifications in Atopic Dermatitis: Current Research and Clinical Relevance.

Atopic dermatitis (AD) is a chronic and relapsing cutaneous disorder characterized by compromised immune system, excessive inflammation, and skin barrier disruption. Post-translational modifications (PTMs) are covalent and enzymatic modifications of proteins after their translation, which have been reported to play roles in inflammatory and allergic diseases. However, less attention has been paid to the effect of PTMs on AD. This review summarized the knowledge of six major classes (including phosphorylation, acetylation, ubiquitination, SUMOylation, glycosylation, o-glycosylation, and glycation) of PTMs in AD pathogenesis and discussed the opportunities for disease management.

Facile Benzylic Alkylation of Arenes with Alcohols by Catalysis with Spirocyclic NHC IrIII Pincer Complex.

A facile benzylic alkylation of indenes and other arenes was developed from readily available primary and secondary alcohols using our newly investigated CCC pincer IrIII catalyst (SNIr-H). Excellent regioselectivity and yield (89 %) of the C3-alkylated indenes were obtained. Additionally, the challenging sp2 C-alkylation was readily accomplished. This method could be utilized for the synthesis of the analogs of a histamine H1 receptor antagonist and the functional material template molecule, indeno[2,1-a]indene. A hemilabile IrIII -dihydride intermediate was proposed based on control experiments and previous density functional theory (DFT) calculations for the borrowing hydrogen mechanism and is key to the success of this IrIII catalyst in the reduction of unactivated multi-substituted olefin intermediates.

Catalytic Decarboxylative Fluorosulfonylation Enabled by Energy-Transfer-Mediated Photocatalysis.

Sulfonyl fluorides are useful building blocks in a wide array of fields. Herein, we report a catalytic decarboxylative fluorosulfonylation approach for converting abundant aliphatic carboxylic acids to the corresponding sulfonyl fluorides. This transformation is enabled by simple preactivation as aldoxime esters and energy-transfer-mediated photocatalysis. This operationally simple method proceeds with high functional-group tolerance under mild and redox-neutral conditions.

DNA Methylation and Transcription of HLA-F and Serum Cytokines Relate to Chinese Medicine Syndrome Classification in Patients with Chronic Hepatitis B.

OBJECTIVE: To explore the molecular bases of Chinese medicine (CM) syndrome classification in chronic hepatitis B (CHB) patients in terms of DNA methylation, transcription and cytokines. METHODS: Genome-wide DNA methylation and 48 serum cytokines were detected in CHB patients (DNA methylation: 15 cases; serum cytokines: 62 cases) with different CM syndromes, including dampness and heat of Gan (Liver) and gallbladder (CHB1, DNA methylation: 5 cases, serum cytokines: 15 cases), Gan stagnation and Pi (Spleen) deficiency (CHB2, DNA methylation: 5 cases, serum cytokines: 15 cases), Gan and Shen (Kidney) yin deficiency (CHB3, DNA methylation: 5 cases, serum cytokines: 16 cases), CHB with hidden symptoms (HS, serum cytokines:16 cases) and healthy controls (DNA methylation: 6 cases). DNA methylation of a critical gene was further validated and its mRNA expression was detected on enlarged samples. Genome-wide DNA methylation was detected using Human Methylation 450K Assay and furthered verified using pyrosequencing. Cytokines and mRNA expression of gene were evaluated using multiplex biometric enzyme-linked immunosorbent assay (ELISA)-based immunoassay and reverse transcription-quantitative polymerase chain reaction (RT-qPCR), respectively. RESULTS: Totally 28,667 loci, covering 18,403 genes were differently methylated among CHB1, CHB2 and CHB3 (P<0.05 and |Δß value| > 0.17). Further validation showed that compared with HS, the hg19 CHR6: 29691140 and its closely surrounded 2 CpG loci were demethylated and its mRNA expressions were significantly up-regulated in CHB1 (P<0.05). However, they remained unaltered in CHB2 (P>0.05). Levels of Interleukin (IL)-12 were higher in CHB3 and HS than that in CHB1 and CHB2 groups (P<0.05). Levels of macrophage inflammatory protein (MIP)-1α and MIP-1ß were higher in CHB3 than other groups and leukemia inhibitory factor level was higher in CHB1 and HS than CHB2 and CHB3 groups (P<0.05). IL-12, MIP-1α and MIP-1ß concentrations were positively correlated with human leukocyte antigen F (HLA-F) mRNA expression (R2=0.238, P<0.05; R2=0.224, P<0.05; R=0.447, P<0.01; respectively). Furthermore, combination of HLA-F mRNA and differential cytokines greatly improved the differentiating accuracy among CHB1, CHB2 and HS. CONCLUSIONS: Demethylation of CpG loci in 5' UTR of HLA-F may up-regulate its mRNA expression and HLA-F expression was associated with IL-12, MIP-1α and MIP-1ß levels, indicating that HLA-F and the differential cytokines might jointly involve in the classification of CM syndromes in CHB. REGISTRATION NO: ChiCTR-RCS-13004001.

Inhibition of drug-metabolizing enzymes by Jingyin granules: implications of herb-drug interactions in antiviral therapy.

Jingyin granules, a marketed antiviral herbal medicine, have been recommended for treating H1N1 influenza A virus infection and Coronavirus disease 2019 (COVID-19) in China. To fight viral diseases in a more efficient way, Jingyin granules are frequently co-administered in clinical settings with a variety of therapeutic agents, including antiviral drugs, anti-inflammatory drugs, and other Western medicines. However, it is unclear whether Jingyin granules modulate the pharmacokinetics of Western drugs or trigger clinically significant herb-drug interactions. This study aims to assess the inhibitory potency of the herbal extract of Jingyin granules (HEJG) against human drug-metabolizing enzymes and to clarify whether HEJG can modulate the pharmacokinetic profiles of Western drug(s) in vivo. The results clearly demonstrated that HEJG dose-dependently inhibited human CES1A, CES2A, CYPs1A, 2A6, 2C8, 2C9, 2D6, and 2E1; this herbal medicine also time- and NADPH-dependently inhibited human CYP2C19 and CYP3A. In vivo tests showed that HEJG significantly increased the plasma exposure of lopinavir (a CYP3A-substrate drug) by 2.43-fold and strongly prolonged its half-life by 1.91-fold when HEJG (3 g/kg) was co-administered with lopinavir to rats. Further investigation revealed licochalcone A, licochalcone B, licochalcone C and echinatin in Radix Glycyrrhizae, as well as quercetin and kaempferol in Folium Llicis Purpureae, to be time-dependent CYP3A inhibitors. Collectively, our findings reveal that HEJG modulates the pharmacokinetics of CYP substrate-drug(s) by inactivating CYP3A, providing key information for both clinicians and patients to use herb-drug combinations for antiviral therapy in a scientific and reasonable way.

PD-L1 Triggered by Binding eIF3I Contributes to the Amelioration of Diabetes-Associated Wound Healing Defects by Regulating IRS4.

Persistent chronic inflammation and delayed epithelialization lead to stalled healing in diabetic ulcers (DUs). PD-L1 shows anti-inflammatory and proliferative activities in healing defects, whereas its function in DU pathogenesis remains unknown. Lower levels of PD-L1 were found in DU tissues, and exogenous PD-L1 has therapeutic effects in the healing process by accelerating re-epithelialization and attenuating prolonged inflammation, which contributed to the delayed wound closure. We detected the downstream effectors of PD-L1 using transcriptional profiles and screened the interacting proteins using immunoprecipitation in combination with mass spectrometry and coimmunoprecipitation assays. The biological functions of eIF3I‒PD-L1‒IRS4 axis were tested both in vivo and in vitro. Finally, we validated the expression levels of eIF3I, PD-L1, and IRS4 in DU tissues from human clinical samples by immunohistochemistry staining. Mechanistically, PD-L1 binds to eIF3I and promotes cutaneous diabetic wound healing by downregulating IRS4. These findings identify that the eIF3I‒PD-L1‒IRS4 axis contributes to wound healing defects, which can serve as a potential therapeutic target in DUs.

Transcriptional profiling and network pharmacology analysis identify the potential biomarkers from Chinese herbal formula Huosu Yangwei Formula treated gastric cancer in vivo.

Huosu Yangwei (HSYW) Formula is a traditioanl Chinese herbal medicine that has been extensively used to treat chronic atrophic gastritis, precancerous lesions of gastric cancer and advanced gastric cancer. However, the effective compounds of HSYW and its related anti-tumor mechanisms are not completely understood. In the current study, 160 ingredients of HSYW were identified and 64 effective compounds were screened by the ADMET evaluation. Furthermore, 64 effective compounds and 2579 potential targets were mapped based on public databases. Animal experiments demonstrated that HSYW significantly inhibited tumor growth in vivo. Transcriptional profiles revealed that 81 mRNAs were differentially expressed in HSYW-treated N87-bearing Balb/c mice. Network pharmacology and PPI network showed that 12 core genes acted as potential markers to evaluate the curative effects of HSYW. Bioinformatics and qRT-PCR results suggested that HSYW might regulate the mRNA expression of DNAJB4, CALD, AKR1C1, CST1, CASP1, PREX1, SOCS3 and PRDM1 against tumor growth in N87-bearing Balb/c mice.

Development of a novel anti-liver fibrosis formula with luteolin, licochalcone A, aloe-emodin and acacetin by network pharmacology and transcriptomics analysis.

CONTEXT: Xiaoyaosan decoction (XYS), a classical Traditional Chinese Medicine (TCM) formula is used to treat liver fibrosis in clinics. OBJECTIVE: This study explores defined compound combinations from XYS decoction to treat liver fibrosis. MATERIALS AND METHODS: Network pharmacology combined with transcriptomics analysis was used to analyze the XYS decoction and liver depression and spleen deficiency syndrome liver fibrosis. From the constructed XYS-Syndrome-liver fibrosis network, the top 10 active formulas were developed by topological analysis according to network stability. The most active formula was determined by in vitro study. The anti-fibrosis effect was evaluated by in vitro and in vivo studies. RESULTS: According to the network XYS-Syndrome-liver fibrosis network, 8 key compounds and 255 combinations were predicted from in XYS. Luteolin, licochalcone A, aloe-emodin and acacetin formula (LLAAF) had a synergistic effect on the proliferation inhibition of hepatic stellate cells compared to individual compounds alone. The treatment of XYS and LLAAF showed a similar anti-liver fibrotic effect that reduced histopathological changes of liver fibrosis, Hyp content and levels of α-SMA and collagen I in CCl4-induced liver fibrosis in rats. Transcriptomics analysis revealed LLAAF regulated PI3K-Akt, AMPK, FoxO, Jak-STAT3, P53, cell cycle, focal adhesion, and PPAR signalling. Furthermore, LLAAF was confirmed to regulate Jak-STAT and PI3K-Akt-FoxO signalling in vitro and in vivo. CONCLUSIONS: This study developed a novel anti-liver formula LLAAF from XYS, and demonstrated its anti-liver fibrotic activity which may be involved in the regulation of Jak-STAT and PI3K-Akt-FoxO signalling.

An effective and versatile strategy for the synthesis of structurally diverse heteroarylsilanes via Ir(iii)-catalyzed C-H silylation.

A versatile silylation of heteroaryl C-H bonds is accomplished under the catalysis of a well-defined spirocyclic NHC Ir(iii) complex (SNIr), generating a variety of heteroarylsilanes. A significant advantage of this catalytic system is that multiple types of intermolecular C-H silylation can be achieved using one catalytic system at α, ß, γ, or δ positions of heteroatoms with excellent regioselectivities. Mechanistic experiments and DFT calculations indicate that the polycyclic ligand of SNIr can form an isolable cyclometalated intermediate, which leaves a phenyl dentate free and provides a hemi-open space for activating substrates. In general, favorable silylations occur at γ or δ positions of chelating heteroatoms, forming 5- or 6-membered C-Ir-N cyclic intermediates. If such an activation mode is prohibited sterically, silylations would take place at the α or ß positions. The mechanistic studies would be helpful for further explaining the reactivity of the SNIr system.

Total endoscopic sublay mesh repair for umbilical hernias.

ABSTRACT: Umbilical hernias constitute some of the most common surgical diseases addressed by surgeons. Endoscopic techniques have become standard of care together with the conventional open techniques for the treatment of umbilical hernias. Several different approaches were described to achieve laparoscopic sublay repair.We prospectively collected and reviewed the medical records of 10 patients with umbilical hernias underwent total endoscopic sublay repair (TES) at our institution from November 2017 to November 2019. All operations were performed by a same surgical team. The demographics, intraoperative details, and postoperative complications were evaluated.All TES procedures were successfully performed without conversion to an open operation. No intraoperative morbidity was encountered. The average operative time was 109.5 minutes (range, 80-140 minutes). All the patients resumed an oral diet within 6 hours after the intervention. The mean time to ambulation was 7.5 hours (range, 4-14 hours), and mean postoperative hospital stay was 2.2 day (range, 1-4 days). One patient developed postoperative seroma. No wound complications, chronic pain, or recurrence were registered during the follow-up.Initial experiences with this technique show that the TES is a safe, and effective procedure for the treatment of umbilical hernias.

Laparoscopic versus open pancreatic resection for ductal adenocarcinoma: separate propensity score matching analyses of distal pancreatectomy and pancreaticoduodenectomy.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a leading causes of cancer mortality worldwide. Currently, laparoscopic pancreatic resection (LPR) is extensively applied to treat benign and low-grade diseases related to the pancreas. The viability and safety of LPR for PDAC needs to be understood better. Laparoscopic distal pancreatectomy (LDP) and pancreaticoduodenectomy (LPD) are the two main surgical approaches for PDAC. We performed separate propensity score matching (PSM) analyses to assess the surgical and oncological outcomes of LPR for PDAC by comparing LDP with open distal pancreatectomy (ODP) as well as LPD with open pancreaticoduodenectomy (OPD). METHODS: We assessed the data of patients who underwent distal pancreatectomy (DP) and pancreaticoduodenectomy (PD) for PDAC between January 2004 and February 2020 at our hospital. A one-to-one PSM was applied to prevent selection bias by accounting for factors such as age, sex, body mass index, and tumour size. The DP group included 86 LDP patients and 86 ODP patients, whereas the PD group included 101 LPD patients and 101 OPD patients. Baseline characteristics, intraoperative effects, postoperative recovery, and survival outcomes were compared. RESULTS: Compared to ODP, LDP was associated with shorter operative time, lesser blood loss, and similar overall morbidity. Of the 101 patients who underwent LPD, 10 patients (9.9%) required conversion to laparotomy. The short-term surgical advantage of LPD is not as apparent as that of LDP due to conversions. Compared with OPD, LPD was associated with longer operative time, lesser blood loss, and similar overall morbidity. For oncological and survival outcomes, there were no significant differences in tumour size, R0 resection rate, and tumour stage in both the DP and PD subgroups. However, laparoscopic procedures appear to have an advantage over open surgery in terms of retrieved lymph nodes (DP subgroup: 14.4 ± 5.2 vs. 11.7 ± 5.1, p = 0.03; PD subgroup 21.9 ± 6.6 vs. 18.9 ± 5.4, p = 0.07). These two groups did not show a significant difference in the pattern of recurrence and overall survival rate. CONCLUSIONS: Laparoscopic DP and PD are feasible and oncologically safe procedures for PDAC, with similar postoperative outcomes and long-term survival among patients who underwent open surgery.

Xiaoyaosan decoction alleviated rat liver fibrosis via the TGFß/Smad and Akt/FoxO3 signaling pathways based on network pharmacology analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Liver fibrosis is an outcome of many chronic liver diseases and often results in cirrhosis, liver failure, and even hepatocarcinoma. Xiaoyaosan decoction (XYS) as a classical Traditional Chinese Medicine (TCM) formula is used to liver fibrosis in clinical practice while its mechanism is unclear. AIM OF THE STUDY: The aim of this study was to investigate the anti-fibrosis effect of XYS and to explore the molecular mechanisms by combining network pharmacology and transcriptomic technologies. MATERIALS AND METHODS: The carbon tetrachloride (CCl4)-induced liver fibrosis rat were treated with three doses of XYS. The liver fibrosis and function were evaluated by histopathological examination and serum biochemical detection. The fibrosis related protein a-SMA and collagen I were assessed by Western blot. Different expressed genes (DEGs) between XYS-treated group and model group were analyzed. The herb-component-target network was constructed combined the network pharmacology. The predict targets and pathways were validated by in vitro and in vivo experiments. RESULTS: With XYS treatment, the liver function was significantly improved, and fibrotic changes were alleviated. The a-SMA and collagen I expression levels in the liver were also decreased in XYS-treated rats compared with CCl4 model rats. 108 active components and 42 targets from 8 herbs constituted herb-compound-target network by transcriptomics and network pharmacology analysis. The KEGG pathway and GO enrichment analyses showed that the FoxO, TGFß, AMPK, MAPK, PPAR, and hepatitis B and C pathways were involved in the anti-fibrosis effects of XYS. In the liver tissues, p-FoxO3a and p-Akt expression levels were significantly increased in the CCl4 model group but decreased in the XYS-treated group. The TGFß1/Smad pathway and Akt/FoxO3 pathway were verified in LX2 cells by inhibiting phosphorylation of Smad3 and Akt activity, respectively. CONCLUSIONS: Our findings suggested that XYS markedly alleviated CCl4-induced liver fibrosis in histopathological and serum liver function analyses, and this effect may occur via the TGFß1/Smad and Akt/FoxO signaling pathways.

Trans-umbilical single-incision laparoscopic trans-abdominal pre-peritoneal hernioplasty of inguinal hernia by self-made glove port.

Laparoscopic inguinal herniorrhaphy has been well established for the management of primary and recurrent inguinal hernias. Single-incision laparoscopic surgery (SILS) has now been accepted as a less invasive alternative to conventional laparoscopic surgery. However, commercially available access devices for SILS had disadvantages such as rigidness and crowding. This series aimed to analyze the feasibility and safety of single-incision laparoscopic trans-abdominal pre-peritoneal hernioplasty (SILS-TAPP) by applying our self-made device for managing inguinal hernia.We collected and reviewed the medical records of patients who received SILS-TAPP using a self-made glove-port device between January 2014 and January 2016. All operations were performed by the same surgical team. The demographics and intra- and perioperative outcomes were evaluated.SILS-TAPP was successfully performed in 105 patients (131 inguinal hernia repairs). No major intra- and postoperative morbidities were encountered, and no conversion to a conventional 3-port approach or open surgery was required. The mean operative time was 73.5 min and the mean postoperative hospital stay was 2.1 days. Three minor short-term complications were noted, which were resolved without surgical intervention. One recurrence was diagnosed during follow-up and treated using a second TAPP procedure.SILS-TAPP was shown to be a feasible, safe procedure in patients with an inguinal hernia. A simple self-made glove-port device was proven as a practical method of SILS-TAPP.

Pharmacokinetic interaction between a Chinese herbal formula Huosu Yangwei oral liquid and apatinib in vitro and in vivo.

OBJECTIVES: This study aimed to evaluate the inhibitory effects of Huosu Yangwei oral liquid (HSYW) on cytochrome P450 enzymes (CYPs) and to investigate whether this herbal medicine could modulate the pharmacokinetic behaviour of the co-administered CYP-substrate drug apatinib. METHODS: Cytochrome P450 enzymes inhibition assays were conducted in human liver microsomes (HLM) by a LC-MS/MS method for simultaneous determination of the oxidative metabolites of eight probe substrates for hepatic CYPs. The modulatory effects of HSYW on the oxidative metabolism of apatinib were investigated in both HLM and rat liver microsomes (RLM). The influences of HSYW on the pharmacokinetic behaviour of apatinib were investigated in rats. KEY FINDINGS: Huosu Yangwei oral liquid inhibited all tested CYPs in human liver preparations, with the IC50 values ranged from 0.3148 to 2.642 mg/ml. HSYW could also inhibit the formation of two major oxidative metabolites of apatinib in liver microsomes from both human and rat. In-vivo assays demonstrated that HSYW could significantly prolong the plasma half-life of apatinib by 7.4-fold and increase the AUC0-inf (nm·h) of apatinib by 43%, when HSYW (10 ml/kg) was co-administered with apatinib (10 mg/kg) in rats. CONCLUSIONS: Huosu Yangwei oral liquid could inhibit mammalian CYPs and modulated the metabolic half-life of apatinib both in vitro and in vivo.