Modular Approach to Highly Substituted 3-Methylpyridones.

A method has been developed for the rapid synthesis of highly substituted 3-methylpyridones via the condensation of Baylis-Hillman amines and ketones under benzoic acid catalysis. The process features readily available starting materials, broad substrate scope, high functional group tolerance, excellent regioselectivity, and gram-scale synthesis. We envision that this on-demand construction of 3-methylpyridones will provide exciting opportunities in biological research, therapeutics, and material sciences.

Risk factors of transient and permanent hypoparathyroidism after thyroidectomy: a systematic review and meta-analysis.

BACKGROUND: Postoperative hypoparathyroidism (hypoPT) is a common complication following thyroid surgery. However, current research findings on the risk factors for post-thyroid surgery hypoPT are not entirely consistent, and the same risk factors may have different impacts on transient and permanent hypoPT. Therefore, there is a need for a comprehensive study to summarize and explore the risk factors for both transient and permanent hypoPT after thyroid surgery. MATERIALS AND METHODS: Two databases (PubMed and Embase) were searched from inception to 2024. The Newcastle-Ottawa Scale was used to rate study quality. Pooled odds ratios (OR) were used to calculate the relationship of each risk factor with transient and permanent hypoPT. Subgroup analyses were conducted for hypoPT with different definition-time (6 or 12 mo). Publication bias was assessed using Begg's test, and Egger's test. RESULTS: A total of 19 risk factors from the 93 studies were included in the analysis. Among them, sex and parathyroid autotransplantation were the most frequently reported risk factors. Meta-analysis demonstrated that sex (female vs. male), cN stage, central neck dissection, lateral neck dissection, extent of central neck dissection (bilateral vs. unilateral), surgery (total thyroidectomy (TT) vs. lobectomy), surgery type (TT vs. sub-TT), incidental parathyroidectomy, and pathology (cancer vs. benign) were significantly associated with transient and permanent hypoPT. Preoperative calcium and parathyroid autotransplantation were only identified as risk factors for transient hypoPT. Additionally, node metastasis and parathyroid in specimen were associated with permanent hypoPT. CONCLUSION: The highest risk of hypoPT occurs in female thyroid cancer patients with lymph node metastasis undergoing TT combined with neck dissection. The key to preventing postoperative hypoPT lies in the selection of surgical approach and intraoperative protection.

Clinical Manifestation, Risk Factors, and Immune Checkpoint Inhibitor Rechallenge of Checkpoint Inhibitor-Associated Pneumonitis in Patients With Lung Cancer.

SUMMARY: Immune-related adverse effects can lead to damage to various systems of the body, checkpoint inhibitor-associated pneumonitis (CIP) is one of the potentially lethal immune-related adverse effects. However, evidence regarding the risk factors associated with CIP is limited. To timely and accurate identification and prompt treatment of CIP, understanding the risk factors for multimorbidity among diverse study populations becomes crucial. We retrospectively analyzed the clinical data of 1131 patients with lung cancer receiving immunotherapy to identify 110 patients with CIP, the clinical characteristics and radiographic features of patients with CIP were analyzed. A case-control study was subsequently performed to identify the risk factors of CIP. The median treatment cycle was 5 cycles and the median time to onset of CIP was 4.2 months. CIP was mainly grade I or II. Most cases improved after discontinuation of immune checkpoint inhibitors (ICIs) or hormone therapy. Severe CIP tended to occur earlier in comparison to mild to moderate cases. The recurrence rate was 20.6% in ICI-rechallenged patients, and patients with relapsed CIP were usually accompanied by higher-grade adverse events than at first onset. Among the 7 patients with relapse, ICI-associated deaths occurred in 2 patients (28.6%). For rechallenging with ICIs after recovery from CIP, caution should be practiced. Male [odds ratio (OR): 2.067; 95% CI: 1.194-3.579; P = 0.009], history of chest radiation (OR: 1.642; 95% CI: 1.002-2.689; P = 0.049) and underlying lung disease (OR: 2.347; 95% CI: 1.008-5.464; P =0.048) was associated with a higher risk of CIP.

BDE-47-induced damage prevented by melatonin in grass carp hepatocytes (L8824).

Polybrominated diphenyl ethers (PBDEs) are toxic to organisms with melatonin (MT) providing protection for tissues and cells against these. This study investigates the mechanism of damage of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) and the cellular protection of MT on grass carp hepatocytes. Grass carp hepatocytes were exposed to 25 µmol/L BDE-47 and/or 40 µmol/L MT for 24 h before testing. Acridine orange/ethidium bromide (AO/EB) double fluorescence staining results showed that BDE-47 could induce cell apoptosis. The expression levels of the endoplasmic reticulum (ER) stress-related genes ire1, atf4, grp78, perk, and chop were also significantly up-regulated (P < 0.01). The levels of the apoptosis-related genes caspase3, bax, and caspase9 were significantly up-regulated (P < 0.0001), while the level of bcl-2 was significantly down-regulated (P < 0.01). Compared with the BDE-47 group, the BDE-47 + MT group showed reduced levels of ER and apoptosis of hepatocytes, while the expression of the ER stress-related genes ire1, atf4, grp78, perk, and chop and the apoptosis-related genes caspase3, bax, and caspase9 were down-regulated (P < 0.05), and the level of bcl-2 was up-regulated (P < 0.01). In conclusion, BDE-47 can activate ER and apoptosis in grass carp hepatocytes, while MT can reduce these responses.

New Insights into Decabromodiphenyl Ether-Induced Splenic Injury in Chickens: Involvement of ROS-Mediated Endoplasmic Reticulum Stress Pathway Triggering Autophagy and Apoptosis.

Decabromodiphenyl ether (BDE-209) is a widely used brominated flame retardant that can easily detach from materials and enter into feed and foodstuffs, posing a serious risk to human and animal health and food safety of animal origin. However, the immunotoxic effects of BDE-209 on the avian spleen and the exact mechanism of the toxicity remain unknown. Therefore, we established an experimental model of BDE-209-exposed chickens and a positive control model of cyclophosphamide-induced immunosuppression in vivo and treated MDCC-MSB-1 cells and chicken splenic primary lymphocytes with BDE-209 in vitro. The results showed that BDE-209 treatment caused morphological and structural abnormalities in the chicken spleens. Mechanistically, indicators related to oxidative stress, endoplasmic reticulum stress (ERS), autophagy, and apoptosis were significantly altered by BDE-209 exposure in both the spleen and lymphocytes, but the use of the N-acetylcysteine or the 4-phenylbutyric acid significantly reversed these changes. In addition, BDE-209 exposure decreased the spleen antimicrobial peptide and immunoglobulin gene expression. In conclusion, the present research revealed that BDE-209 exposure enhanced lymphocyte autophagy and apoptosis in chicken spleen via the ROS-mediated ERS pathway. This signaling cascade regulatory relationship not only opens up a new avenue for studying BDE-209 immunotoxicity but also provides important insights into preventing BDE-209 hazards to animal health.

Perfluorooctane sulfonate causes pyroptosis and lipid metabolism disorders through ROS-mediated NLRP3 inflammasome activation in grass carp hepatocyte.

The surfactant perfluorooctane sulfonate (PFOS) is widely produced worldwide. It is a persistent organic pollutant in the aquatic environment and poses a serious threat to aquatic organisms, as PFOS exposure can cause liver injury in a wide range of organisms. However, it is unclear whether PFOS exposure-induced hepatocellular injury in fish is associated with ROS-mediated activation of NLRP3 inflammasome. In this study, various PFOS concentrations were applied to L8824 cells, a cell line of grass carp hepatocytes. The detrimental impacts of PFOS on oxidative stress, pyroptosis, lipid metabolism, and the discharge of inflammatory factors were examined. MCC950 and N-acetylcysteine were employed to hinder the PFOS-stimulated activation of the NLRP3 inflammasome and the excessive generation of reactive oxygen species in L8824 cells, respectively. This study demonstrated that treatment with PFOS resulted in oxidative stress and activation of NLRP3 inflammasome in L8824 cells. This led to increased expression levels of indicators related to pyroptosis, accompanied by the upregulation of pro-inflammatory cytokine expression as well as downregulation of anti-inflammatory factors. In addition, following PFOS exposure, the expression levels of genes related to lipid synthesis were upregulated and lipid catabolism-related genes were downregulated. Surprisingly, both N-acetylcysteine and MCC950 interventions significantly reduced PFOS-induced L8824 cell pyroptosis and lipid metabolism disorders. In conclusion, this research demonstrated that PFOS drives NLRP3 inflammasome activation through oxidative stress induced by reactive oxygen species overload. This in turn leads to pyroptosis and lipid metabolism disorders.

Selenomethionine alleviates decabromodiphenyl ether-induced oxidative stress and ferroptosis via the NRF2/GPX4 pathway in the chicken brain.

Decabromodiphenyl ether (BDE209) is a toxic environmental pollutant that can cause neurotoxicity, behavioral abnormalities, and cognitive impairment in animals. However, the specific mechanisms of BDE209-induced neurological injury and effective preventative and therapeutic interventions are lacking. Even though selenomethionine (Se-Met) has a significant detoxification effect and protects the nervous system, it remains unclear whether Se-Met can counteract the toxic effects of BDE209. For the in vivo test, we randomly divided 60 1-week-old hy-line white variety chicks into the Con, BDE209, Se-Met, and BDE209 +Se-Met groups. In vitro experiments were performed, exposing chick embryo brain neurons to BDE209, Se-Met, N-Acetylcysteine (NAC, a ROS inhibitor), and RSL3 (a GPX4 inhibitor). We demonstrated that BDE209 induced oxidative stress and ferroptosis in the chicken brain, which mainly manifested as mitochondrial atrophy, cristae breakage, increased Fe2+ and MDA content, decreased antioxidant enzyme activity, and the inhibition of the NRF2/GPX4 signaling pathway in the brain neurons. However, Se-Met supplementation reversed these changes by activating the NRF2/GPX4 pathway, reducing mitochondrial damage, enhancing antioxidant enzyme activity, and alleviating ferroptosis. This study provides insight into the mechanism of BDE209-related neurotoxicity and suggests Se-Met as an effective preventative and control measure against BDE209 poisoning.

Internationalization of medical education in China: An investigation of medical graduates' global competence and its influencing factors.

AIM: Global competence has become an important competence for medical graduates in the globalized world. However, research on it is scarce. This study was built upon the scholarship published in the field to measure medical graduates' global competence. MATERIALS AND METHODS: A questionnaire was administered to China's medical graduates sampled from four institutions of medical education. Descriptive statistics were made to analyze the level of medical graduates GC. Influencing factors were investigated using multiple linear regression. Multiple levels of regression analysis were used to identify the influence of different independent variables on the dependent variable. RESULTS: The sample had a relatively good level of global competence in general, but lacked skills in cross-cultural communication and international academic communication. "Internationalization Concept and System" and "International Development of Teachers" in the school dimension and "Taking International Courses", "International Publication" and "Participation in International Conference" in the dimension of individual international involvement had a significant positive impact on the cultivation of global competence. CONCLUSIONS: The universities should aim for the construction of an effective institutional mechanism for internationalization to help improve students' global competence.

Design, synthesis, and pharmacological evaluation of quinazoline derivatives as novel and potent pan-JAK inhibitors.

Janus kinases (JAKs) play a critical role in modulating the function and expression of inflammatory cytokines related to rheumatoid arthritis (RA). Herein, we report the design, synthesis, and structure-activity relationships (SARs) of a series of novel quinazoline derivatives as JAK inhibitors. Among these inhibitors, compound 11n showed high potency against JAKs (JAK1/JAK2/JAK3/TYK2, IC50 = 0.40, 0.83, 2.10, 1.95 nM), desirable metabolic characters, and excellent pharmacokinetic properties. In collagen-induced arthritis (CIA) models, compound 11n exhibited significant reduction in joint swelling with good safety, which could be served as a potential therapeutic candidate for the treatment of inflammatory diseases.

SeNPs alleviates BDE-209-induced intestinal damage by affecting necroptosis, inflammation, intestinal barrier and intestinal flora in layer chickens.

As environmental pollutants, polybrominated diphenyl ethers (PBDEs) can have toxic effects on living organisms and has a bioaccumulative effect. Low doses of selenium nanoparticles (SeNPs) can exert antioxidant, anti-inflammatory and anti-toxin functions on the organism. This experiment evaluated SeNPs' ability to prevent chicken's intestinal damage from decabromodiphenyl ether (BDE-209) exposure. Sixty layer chickens were separated into four groups at randomly and equally: Control group, SeNPs group (1 mg/kg SeNPs), BDE-209 group (400 mg/kg BDE-209), and BDE-209 +SeNPs group (400 mg/kg BDE-209 and 1 mg/kg SeNPs), for 42 days. The results showed that BDE-209 increased MDA content, decreased the activities of T-SOD, T-AOC, GSH and iNOS, up-regulated the expression of TNF-α, RIPK1, RIPK3 and MLKL, promoted the production of inflammatory factors, reduced the levels of tight junction proteins (Claudin-1, Occludin, ZO-1). SeNPs attenuated intestinal oxidative stress, necroptosis, inflammation and intestinal barrier damage caused by BDE-209. This protective effect is associated with the MAPK/NF-κB signaling pathway. Moreover, SeNPs restores flora alpha and beta diversity, improves intestinal flora composition and its abundance. It shifts the dysbiosis of intestinal flora caused by BDE-209 to normal. Overall, SeNPs can alleviate BDE-209-induced intestinal barrier damage and intestinal flora disorders, which are associated with intestinal oxidative stress, necroptosis and inflammation.

Catalyst-Free α-Allylation of Dihydroisoquinolines with Morita-Baylis-Hillman Carbonates and Its Applications in the Construction of Benzo[a]quinolizidines.

In this work, a mild and efficient catalyst-free α-allylation of 3,4-dihydroisoquinoline imines with Morita-Baylis-Hillman (MBH) carbonates was reported. The scopes of 3,4-dihydroisoquinolines and MBH carbonates as well as gram-scale synthesis were investigated, and densely functionalized adducts were obtained in moderate to good yields. The synthetic utility of these versatile synthons was further demonstrated by the facile synthesis of diverse benzo[a]quinolizidine skeletons.

The complexing of cationic copolymer MPC30-DEA70 with TGF-ß1 antisense oligodeoxynucleotide and transfection into cardiomyocytes in vitro.

Although gene therapy is an attractive option for the treatment of cardiovascular diseases, the ideal gene delivery systems are still under investigation and must meet the following criteria: safety, adequate gene transfer efficiency, and stable expression of the transgene for a duration appropriate for treating the disease. In this study, we developed a cationic phosphorylcholine-containing diblock copolymer, namely MPC30-DEA70, as carrier systems to deliver a chemically synthesized transforming growth factor-beta 1(TGF-ß1) antisense oligonucleotide (AS-ODN) into cardiomyocytes (CMs) to observe the cell transfection efficiency of MPC30-DEA70 and the inhibition effect on the expression of TGF-ß1. MPC30-DEA70/TGF-ß1 AS-ODN complexes were formed through complexation between copolymer MPC30-DEA70 (N) and AS-ODN (P) at different N/P ratios and were characterized by DNA electrophoresis. Notably, the cytotoxicity and cell growth inhibition assay showed that the MPC30-DEA70 had low cytotoxicity to CMs within the effective transfection dosage range (<20 µL/mL). CLSM/TEM images displayed that most of the AS-ODN molecules engulfed by cells were located around the cell nuclei, and a few entered into the cell nuclei without harming the organelles in the cell. Transfection studies from CMs indicated a steady increase of transfection efficiency with increasing N/P ratios. The expression levels of TGF-ß1 mRNA and protein in CMs were significantly inhibited at high N/P ratios. This study shows that MPC30-DEA70 can function as an effective transgenic vector into CMs and that TGF-ß1 AS-ODN delivered by MPC30-DEA70 can silence the expression of the TGF-ß1 gene efficiently and specifically and thereafter antagonize TGF-ß1-mediated biological function in cardiomyocytes.

Electrooxidative Dearomatization of Inactive Biphenyls to Cyclohexadienones.

An efficient electrooxidative dearomatization of inactive biphenyls has been developed under mild and easy-to-operate conditions. The protocol provides a powerful tool for the rapid synthesis of cyclohexadienones in moderate to high yields with wide substrate scope and good functional group compatibility even to oxidation-sensitive motifs. This method provides an environment-friendly and direct approach for the construction of C-O bonds with high regioselectivity.

Design, synthesis, antibacterial activity evaluation and molecular docking study of pleuromutilin derivatives bearing amide side chains.

A seize of pleuromutilin derivatives containing amide side chains were designed and synthesized as potential antibiotics against Methicillin-resistant Staphylococcus aureus (MRSA). Among all target compounds (compounds 11-30), compound 25 was found to have the strongest antibacterial activity against MRSA (minimum inhibitory concentration = 0.5 µg/ml). The result of the time-kill curves indicated that compound 25 could repress the growth of MRSA in vitro obviously (-3.72 log10 CFU/ml reduction). Furthermore, molecular docking studies demonstrated that compound 25 was localized in the binding pocket of 50S ribosomal subunit (ΔGb = -8.99 kcal/mol). Besides, compound 25 displayed low cytotoxicity to RAW 264.7 cells. The results suggested that compound 25 might be further developed into a novel antimicrobial agent against MRSA.

Multi-Omics Characterization of a Glycerolipid Metabolism-Related Gene Enrichment Score in Colon Cancer.

Background: Glycerolipid metabolism is involved in the genesis and progression of colon cancer. The current study aims at exploring the prognostic value and potential molecular mechanism of glycerolipid metabolism-related genes in colon cancer from the perspective of multi-omics. Methods: Clinical information and mRNA expression data of patients with colon cancer were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Single-sample gene set enrichment analysis (ssGSEA) was applied to calculate the glycerolipid metabolism-related gene enrichment score (GLMS). Univariable and multivariable Cox regression analyses were used to study the prognostic value of GLMS in TCGA-COAD and GSE39582 cohorts. The molecular mechanism of the prognostic factor was investigated via immune cell infiltration estimation and correlation analysis of cancer hallmark pathways. Single-cell transcriptomic dataset GSE146771 was used to identify the cell populations which glycerolipid metabolism targeted on. Results: The GLMS was found to be associated with tumor location and consensus molecular types (CMSs) of colon cancer in TCGA-COAD cohort (P < 0.05). Patients in the low-GLMS group exhibited poorer overall survival (OS) in TCGA cohort (P = 0.03; HR, 0.63; 95% CI, 0.42-0.94), which was further validated in the GSE39582 dataset (P < 0.001; HR, 0.57; 95% CI, 0.43-0.76). The association between the GLMS and OS remained significant in the multivariable analysis (TCGA cohort: P = 0.04; HR, 0.64; 95% CI, 0.42-0.98; GSE39582 cohort: P < 0.001; HR, 0.60; 95% CI, 0.45-0.80). The GLMS was positively correlated with cancer hallmark pathways including bile acid metabolism, xenobiotic metabolism, and peroxisome and negatively correlated with pathways such as interferon gamma response, allograft rejection, apoptosis, and inflammatory response (P < 0.05). Increased immune infiltration and upregulated expression of immune checkpoints were observed in patients with lower GLMS (P < 0.05). Single-cell datasets verified the different distribution of GLMS in cell subsets, with significant enrichment of GLMS in malignant cells and Tprolif cells. Conclusion: We demonstrated that GLMS was a potential independent prognostic factor for colon cancer. The GLMS was also correlated with several cancer hallmark pathways, as well as immune microenvironment.

Pleiotrophin affects the susceptibility of prostate cancer cells to cisplatin.

Drug resistance is a major problem in cancer therapy with cisplatin. It has not been reported that pleiotrophin, which is anti-apoptotic in some cancer cells, is associated with cisplatin resistance. Pleiotrophin was exogenously expressed in 293 cells. Viability and apoptosis of PC3 cells treated with different concentrations of cisplatin in the presence or absence of purified pleiotrophin were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry, respectively. PC3 cells transfected with shRNAs were analyzed by reverse transcription-polymerase chain reaction (RT-PCR) and western blotting 24 h after transfection. MTT assay data indicated that the EC50 value of cisplatin for PC3 cells was significantly increased in the presence of pleiotrophin. Flow cytometry data demonstrated the pleiotrophin dose-dependent anti-apoptosis in PC3 cells treated with cisplatin. Knockdown of pleiotrophin with sh-RNA, as justified by RT-PCR and western blotting analysis, led to increased cisplatin induced-apoptosis in PC3 cells with an increased level of the cleaved poly ADP-ribose polymerase protein. Pleiotrophin may be a potential antiapoptotic protein associated with cisplatin susceptibility, which warrants further study on the role of pleiotrophin in cisplatin resistance.

Catalyst-Controlled Regiodivergent Synthesis of α/ß-Dipeptide Derivatives via N-Allylic Alkylation of O-Alkyl Hydroxamates with MBH Carbonates.

A controllable and regiodivergent N-allylation reaction involving readily available O-alkyl hydroxamates derived from natural α-amino acids has been developed, allowing regiospecific access to α/ß-dipeptides containing α-unsaturated ß-amino acids moieties in moderate to good yields. The regioselectivity could be conveniently switched by alternation of the catalysts and solvents.

Direct C(sp3)-H allylation of 2-alkylpyridines with Morita-Baylis-Hillman carbonates via a tandem nucleophilic substitution/aza-Cope rearrangement.

A base- and catalyst-free C(sp3)-H allylic alkylation of 2-alkylpyridines with Morita-Baylis-Hillman (MBH) carbonates is described. A plausible mechanism of the reaction might involve a tandem SN2' type nucleophilic substitution followed by an aza-Cope rearrangement. Various alkyl substituents on 2-alkylpyridines were tolerated in the reaction to give the allylation products in 26-91% yields. The developed method provides a straightforward and operational simple strategy for the allylic functionalization of 2-alkypyridine derivatives.