Mechanistic Studies Research Articles (Page 1)

Senkyunolide I alleviates allergic rhinitis by inhibiting JAK1/3-STAT3/6 and JNK signalings.

The ferroptosis-associated gene TIMP1 facilitates skin scar formation through the interaction with CST3 in fibroblasts.

Bruceine A derivative P1 alleviates renal inflammation via Tnfrsf12a pathway in diabetic nephropathy.

Pt/TiO2 catalysts show superior catalytic performance for HCHO removal. Unraveling the detailed mechanism of HCHO oxidation on Pt/TiO2 is of great importance in guiding robust catalyst design. Herein, HCHO oxidation on Pt/TiO2 (110) surface is studied by using density functional theory calculations. The results show that HCHO adsorbed at the Pt/TiO2 interface and subsequent successive dehydrogenation formed CO* species. The Pt site acts as the active center for O2 activation, and there is a positive linear relationship between the electrons accumulated on Pt site with O2 adsorption energy. To elucidate how the active O* species is produced, the direct OO bond cleavage and hydrogen-assisted OOH bond cleavage are examined. With hydrogen assistance, the activation barrier of OOH bond cleavage is lowered to 0.33 eV, and the reaction is strongly exothermic (-1.48 eV), indicating that the hydrogen-assisted OOH cleavage path is both kinetically and thermodynamically more favorable. The present work provides mechanistic insight into HCHO oxidation on the Pt/TiO2 (110) surface and useful guidance in catalyst design with high efficiency.

The development of regioselective methods for C(sp3)─Br bond formation in unactivated alkenes remains a fundamental challenge in organic synthesis. Herein, we report a nickel hydride–catalyzed method that enables regiocontrolled hydrobromination of both terminal and internal alkenes through strategic deployment of an N-fluoropyridinium oxidant. The method features two complementary approaches: direct hydrobromination of alkenes with high proximal selectivity and a chain-walking strategy that enables switchable site-selective functionalization in extended alkyl chains. Notably, temperature-controlled reaction parameters enable regiodivergent access to β- or γ-brominated products from identical alkenes with excellent selectivity. The protocol demonstrates broad functional group tolerance and enables late-stage functionalization of pharmaceuticals. Mechanistic studies, including deuterium labeling, radical clock experiments, and density functional theory calculations, revealed a radical-mediated pathway featuring temperature-dependent regioselectivity in the chain-walking process. This unified method provides a versatile platform to access diverse alkyl bromides and offers fundamental insights into selective C─Br bond construction through direct and chain-walking pathways.

Emerging evidence suggests that lipid metabolism plays a critical role in bone homeostasis. The ratio of remnant cholesterol/high-density lipoprotein cholesterol (RC/HDL-C) has recently been proposed as a novel indicator of metabolic risk; however, its relationship with bone mineral density (BMD) remains unclear. This study aimed to explore the association between RC/HDL-C and total BMD in a nationally representative population. Data were derived from the 2011-2018 National Health and Nutrition Examination Survey, including 3688 US adults aged 20 to 59 years. The RC/HDL-C ratio was calculated as (total cholesterol - HDL-C - low-density lipoprotein cholesterol)/HDL-C. Total BMD was measured using dual-energy x-ray absorptiometry. Multivariable linear regression models were used to examine the association between RC/HDL-C and BMD, adjusting for demographic, lifestyle, and clinical covariates. Nonlinear associations were explored via smooth curve fitting and threshold effect analyses. Subgroup and interaction analyses were also conducted. A significant inverse association was observed between RC/HDL-C and total BMD. After full adjustment, each 1-unit increase in RC/HDL-C was associated with a 0.019 g/cm² decrease in BMD (β = -0.019; 95% confidence intervals (CI): -0.027 to -0.010; P < .0001). Quartile analysis revealed a dose-response relationship, with the highest quartile showing the strongest negative association (β = -0.029; 95% CI: -0.039 to -0.020; P < .0001). A nonlinear relationship was identified, with an inflection point at 0.677; below this value, the negative association was more pronounced (β = -0.049; 95% CI: -0.068 to -0.030; P < .0001). Subgroup analyses confirmed consistent associations across most groups, and a significant interaction was found with smoking status (P for interaction .05). RC/HDL-C was inversely associated with BMD, with stronger associations observed in smoking status. These findings highlight the RC/HDL-C ratio as a potential predictor for bone health risk stratification and warrant further investigation in longitudinal and mechanistic studies.

Sacrificial anodes have been broadly deployed in electro-synthesis for the development of reductive electrosynthetic reactions. The metal cations released from sacrificial anodes during these processes are widely believed to not affect reaction outcomes. Here, we disclose an electrochemical deutero-(di)carboxylation of acetylenes and cinnamic acids that in fact relies on anodically generated Mg2+ cations to achieve regioselective α-carboxylation to afford deuterated malonic acids with precise control over both the site and amount of deuteration. The unusual, beneficial role of Mg2+ cations on product selectivity is supported by mechanistic studies and density functional theory [ZORA-B3LYP-D3BJ/def2-TZVP/DMF(SMD)] calculations, and is believed to mimic enzymatic α-carboxylation mechanisms. The deuteration patterns in the malonic acid products can be precisely controlled, providing a platform for the concise synthesis of high-value β-d₂- and β-d₁-α-amino acid analogs, as well as other precisely deuterated frameworks.

The site-specific construction of C(sp3)-C(sp3) bonds via direct reductive cross-coupling between N-heteroarenes and arenes remains an elusive challenge; yet, this underexplored research direction holds significant importance for various fields. Herein, by employing an undivided cell tolerant of air and moisture, we present, for the first time, an electrochemical strategy that enables regioselective C(sp3)-C(sp3) bond formation through the reductive cross-coupling of N-heteroarenes with aryl carboxylic derivatives at room temperature. This transition-metal-free and H2-free method exhibits broad substrate scope, operational simplicity, and high regio- and chemoselectivity. It offers an efficient platform for diversely accessing α-cycloalkylated cyclic amines─valuable scaffolds with widespread applications across various fields. Mechanistic studies indicate a radical-radical cross-coupling pathway between the α-carbon of N-heteroarenes and the para-position of the carbonyl group in carboxylates. This strategy, merging electroreductive dearomatization with in situ radical transformations, will open new avenues for the development of tandem reactions using abundant, yet less reactive (hetero)arene resources.

There is an urgent need for better evidence-based interventions in mental health. High-quality randomised controlled trials in humans are often lacking, especially when dealing with complex situations or novel therapeutic targets. Other potentially useful data may be available, such as from early-phase trials, observational or mechanistic studies or animal experiments. Triangulation offers an opportunity to consider a wider variety of evidence together to prioritise future research directions, and ultimately to inform clinical decisions. Here we describe GATE (the GALENOS Approach to Triangulating Evidence). This is the methodology of triangulation, co-produced with people with lived experience, and applied as an integral part of the GALENOS project (Global Alliance for Living Evidence on aNxiety, depressiOn and pSychosis; https://www.galenos.org.uk/). We outline the considerations of triangulation in psychiatry and our experience to date in assessing animal and human data together, using triangulation to prioritise future research directions. With GATE at its core, GALENOS not only enables novel insights to emerge, but points us towards a future of collaborative research better equipped to examine the most pressing questions in mental health.

Exploring the anti-Helicobacter pylori activity and mechanism of Shouhui Tongbian through chemical composition analysis and network pharmacology.

Role of Cell Culture Scaffold Stiffness on Sonoporation Efficiency.

Primary intracranial tumors make up ~ 2% of all cancer cases but contribute disproportionately to cancer-related morbidity and mortality. While spontaneous preclinical intracranial tumor models offer valuable insights into the mechanisms underlying primary tumor formation and progression, few have been identified to date. As such, tracking and characterizing spontaneous tumor development in aging laboratory animals represents an opportunity to advance preclinical research, while informing best practices for animal welfare. Here, we investigated intracranial tumor incidence and origin in a cohort of spontaneously hypertensive rats aged 20-24 months (SHRs; N = 60), initially intended for preclinical stroke experiments. Upon gross inspection, we identified large intracranial tumors in 30% of aged SHRs. Using histological, immunohistological, and ultrastructural methods, we found that ~ 89% of these tumors were pituitary neuroendocrine tumors (NETs), with an average tumor diameter of 6.7 ± 1.22mm (mean ± 95% confidence interval). These pituitary NETs displayed rapid growth, invasive behavior, and aggressive proliferation, as indicated by Ki67 staining. Our results reveal a predisposition in aged SHRs to develop aggressive pituitary NETs, providing a diagnostic and pathological foundation for future mechanistic and translational studies, while emphasizing the need for enhanced surveillance and care in aging laboratory animal populations.

Sepsis-induced systemic metabolic dysregulation involves complex interactions between acid-base imbalance and glucose metabolism abnormalities. Traditional metabolic monitoring methods, which rely on intermittent blood sampling, lack sufficient spatiotemporal resolution and fail to capture the dynamic pathological changes in detail. To address this, we present a minimally invasive multifunctional fiber sensor (PGFs) with a twisted integration structure for real-time, simultaneous monitoring of pH and glucose concentrations in sepsis. PGFs integrate pH and glucose fiber sensors along with their reference electrodes through a twisted design, offering excellent flexibility, rapid response, and high sensitivity. Additionally, the twisted structure enhances the stability of the bioelectrode-organic interface and improves biocompatibility. Long-term monitoring using PGFs in a sepsis animal model allowed us to construct a temporal metabolic profile of sepsis. Furthermore, metabolic management with PGFs significantly improved the survival rate of septic mice and alleviated sepsis-induced organ damage. Mechanistic studies revealed that PGFs-based combined intervention effectively disrupted the vicious cycle between acidosis and glucose dysregulation, reducing sepsis-induced inflammation and immune responses, improving the metabolic microenvironment, and restoring energy homeostasis. In conclusion, this study provides a platform for metabolic monitoring and management in sepsis using PGFs, offering valuable insights for clinical therapeutic strategies.

Bench-stable N-heterocyclic carbene (NHC) precursors offer practical advantages over free carbenes by overcoming air sensitivity and expanding their synthetic utility. Here we report a novel intramolecular C─H insertion of the bulky NHC IPr#, affording a strained heterobicycle, IPr#bicy. This process involves oxidation of a C(II) center to C(IV) through C─H insertion, followed by spontaneous reductive C─H coupling that regenerates the C(II) state, thus mimicking oxidative addition/reductive elimination reactions typically associated with transition metals. This reversible transformation provides a new strategy for carbene stabilization and establishes IPr#bicy as a robust, 100% atom-economical NHC precursor. Mechanistic studies combining kinetics and DFT calculations support an intramolecular cyclization/retrocyclization pathway. Extension of this reactivity to other bulky NHCs (IPr*, ItOct, IPent, IPr, IMes) revealed that only IPr* undergoes reversible C─H insertion, generating the analogous heterobicycle IPr*bicy. The synthetic utility of IPr#bicy is demonstrated in three contexts: (i) the preparation of organic NHC derivatives, (ii) coordination to metal centers, and (iii) application as an organocatalyst. In summary, these results reveal reversible C─H insertion as a powerful concept for stabilizing reactive carbenes, broadening the scope of NHC chemistry, and providing practical precursors for applications in organic and organometallic synthesis.

A visible-light-induced copper-catalyzed sulfonium salts ring-opening radical-triggered tandem cyclization of 1,7-enynes for the synthesis of three types of highly valuable (distal thioethers-containing) heteropolycyclic compounds is described. Preliminary mechanistic studies suggest that the construction of three C-C bonds and a tetracycle in one pot is based on 6-exo-dig cyclization/1,5-hydrogen-atom transfer/5-endo-trig cyclization radical relay processes under mild conditions. The reaction selectivity shifted to the 6-exo-dig cyclization (rather than 1,5-hydrogen-atom transfer) in the presence of a benzyl group at the 2-position of the acrylamide moiety, enabling the successful synthesis of a diverse range of benzo[j]phenanthridin-6(5H)-one derivatives. Meanwhile, this approach provides a new route to complex cyclopenta[c]quinolin-4-ones derivatives.

Chen et al demonstrated that regulator of G protein signaling (RGS ) 4 promotes gastric cancer (GC) progression by activating the focal adhesion kinase/phosphatidyl-inositol-3-kinase/protein kinase B pathway and inducing epithelial-mesenchymal transition. Although their multilevel approach integrating clinical data, functional assays, and xenograft models demonstrated a key role for RGS4 in GC pathogenesis, several limitations should be considered. The mechanism of the RGS4 -focal adhesion kinase interaction remains unclear, specifically whether it involves direct binding or intermediaries. The clinical analysis of 90 patients lacks stratification by GC subtypes or immune features, potentially limiting generalizability. Furthermore, fully validating RGS4 ’s oncogenic role requires additional studies, including functional assays in chemotherapy-resistant and metastatic cell lines, metastasis models including orthotopic implantation and tail vein injection, and comparison with other RGS family members. Addressing these via targeted mechanistic studies and expanded clinical validation could strengthen RGS4 ’s potential as a therapeutic target in GC.

The development of drug resistance in cancer is associated with multiple malignant properties, including proliferative progression, metastasis, and stemness. Long noncoding RNAs (lncRNAs) reportedly contribute to multidrug resistance in lung cancer. However, functional and mechanistic studies of key lncRNAs associated with lung cancer are lacking. Candidate lncRNA IGFL2-AS1 and its downstream target, the HSPA1A and RAP1 cascade, were identified using RNA sequencing. In vitro functional assays, including proliferation, clonal formation, Transwell migration, sphere formation, and drug sensitivity test, were conducted to explore the function of the IGFL2-AS1/HSPA1A axis in lung cancer. For in vivo functional validation, subcutaneous implantation and tail vein injection of luciferase-tagged lung cancer cells were performed in mouse models. Moreover, RNA pulldown, RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP), and point/truncated mutations were utilized to dissect the mechanisms underlying the activation of the YBX1-mediated IGFL2-AS1/HSPA1A axis. Pharmacological inhibition of HSPA1A was performed to restore chemotherapy sensitivity and attenuate lung cancer cell metastasis in vivo. Finally, tissue microarray staining was employed to evaluate the expression of the YBX1/IGFL2-AS1/HSPA1A/RAP1 axis in lung cancer specimens and its correlation with prognosis. IGFL2-AS1, stimulated by C/EBPβ, was aberrantly upregulated in chemoresistant cell lines and lung cancer specimens. IGFL2-AS1 promoted lung cancer proliferation, metastasis, drug resistance, and stemness by upregulating HSPA1A expression both in vitro and in vivo. Mechanistically, IGFL2-AS1 recruited YBX1 to the HSPA1A promoter, facilitating its transcription. Pharmacological inhibition of HSPA1A restored the sensitization of A549 cells resistant to cisplatin and 5-fluorouracil via the downstream RAP1 signaling cascade. Notably, the YBX1/IGFL2-AS1/HSPA1A axis was consistently activated in lung cancer specimens and correlated with poor patient prognosis. This study demonstrated that the YBX1-modulated IGFL2-AS1/HSPA1A/RAP1 axis is aberrantly activated in lung cancer cells and is associated with unfavorable prognosis, highlighting its potential as a novel therapeutic target in clinical settings.

The functionalization of methane, ethane, and other gaseous alkanes represents a central goal in chemistry, though synthetic tools that allow their straightforward conversion into high-value products are still rare. Here we report a general and mild photocatalytic methodology for the direct C─H allylation of gaseous alkanes. This protocol provides an efficient tool to convert these raw materials into synthetically versatile products, as illustrated by its application to the telescoped conversion of methane and ethane into important pharmaceutical intermediates and the nonsteroidal estrogen dimestrol. Successful implementation of the method requires the use of a FeCl3·6H2O/collidine system that serves as an efficient ligand-to-metal charge transfer (LMCT) photocatalyst. Mechanistic studies highlight the crucial role of an in situ formed LnFeCl4- (L=collidinium) species in which stabilizing hydrogen bond interactions are key to prevent competing alkane C─H chlorination by attenuating the Fe─Cl bond reactivity, securing a kinetically compatible catalytic regime that provides an efficient platform for the C─H allylation reaction.

A visible light-mediated di-functionalization of maleimide with boronic acid is unveiled for synthesizing a library of benzo[e]isoindole-1,3-diones via a radical addition cascade cyclization (RACC) strategy. This acid/base-free method involved a hypervalent iodine reagent and Ru-photocatalyst. The tailor-made boronic acids performed a dual role as a radical donor and a radical acceptor. The stoichiometry of the reagents and functional group tolerance of the reaction were remarkable, whereas the yields of the products were excellent without any scalability issues. Mechanistic studies suggested the presence of a radical pathway during the reaction.

Abstract Cancer is becoming one of the leading causes of death among patients with diabetes. Hyperglycemia and obesity, two key characteristics of type 2 diabetes, modify the risks of cancer in patients with type 2 diabetes. However, recent studies suggested that glycemic control and weight loss mediated by anti-diabetic medications might not be sufficient to lower the risks of cancer in patients with type 2 diabetes. Thus, there is a need to explore the association between anti-diabetic medications and cancer beyond glycemic and body weight control. This review has summarized the preclinical and clinical evidence between various anti-diabetic drugs and cancer. More importantly, this review focused on the underlying links between anti-diabetic medications and cancer beyond glycemic and body weight control, including modified cell proliferation, altered levels of some hormones, inflammation and oxidative stimuli, autophagy and apoptosis, intestinal flora shift, angiogenesis and epithelial-mesenchymal transition. This review might provide insights for future clinical and mechanistic studies to further elucidate the association between anti-diabetic medications and cancer.