Endoplasmic reticulum stress: The underlying mechanism of chronic pain.

Chronic pain (CP) affects over 30 % of the global population, imposing significant financial burdens on individuals and society. However, existing treatments for CP offer limited efficacy and troublesome side effects, primarily owing to a lack of knowledge of its precise underlying mechanism. Pathological stimuli disrupt the intricate process of protein folding and endoplasmic reticulum (ER) homeostasis. This disruption leads to the accumulation of misfolded or unfolded proteins in the ER, generating a condition termed ER stress. Emerging data have indicated that ER stress, occurring in the peripheral and central nervous systems, contributes to the development and maintenance of CP. This review aimed to comprehensively explore the intersection of ER stress and CP within the lower and upper nervous systems and highlight the cell-specific contributions of the unfolded protein response in different CP types. We provide a comprehensive synthesis of evidence from animal models, examining neuronal and non-neuronal mechanisms and discuss the damaging ER stress-linked inflammation, autophagy, oxidative stress, and apoptosis, which collectively drive disease progression and contribute to a neurotoxic environment. However, the mechanisms through which ER stress influences the most advanced centre-of-pain projections in the brain remain unclear. Further investigation in this area is crucial to elucidate the relationship between ER stress and CP and facilitate the development of novel therapeutic drugs for this intractable dilemma.

Enhancing NIR-II Upconversion Monochromatic Emission for Temperature Sensing.

The upconversion luminescence (UCL) in the second near-infrared window (NIR-II) is highly attractive due to its excellent performance in high-resolution bioimaging, anticounterfeiting, and temperature sensing. However, upconvertion nanoparticles (UCNPs) are normally emitted in visible light, potentially impacting the imaging quality. Here, a monochromatic Er3+-rich (NaErF4:x%Yb@NaYF4) nanoparticles with excitation at 1532 nm and emission at 978 nm is proposed, both situated in the NIR-II region. The proper proportion of Yb3+ ions doping has a positive effect on the NIR-II emission, by enhancing the cross relaxation efficiency and accelerating the energy transfer rate. Owing to the interaction between the Er3+ and Yb3+ is inhibited at low temperatures, the UCL emission intensities at visible and NIR-II regions show opposite trend with temperature changing, which establishes a fitting formula to derive temperature from the luminous intensity ratio, promoting the potential application of UCL in NIR-II regions for the temperature sensing.

Bicyclol attenuates pulmonary fibrosis with silicosis via both canonical and non-canonical TGF-ß1 signaling pathways.

BACKGROUND: Silicosis is an irreversible fibrotic disease of the lung caused by chronic exposure to silica dust, which manifests as infiltration of inflammatory cells, excessive secretion of pro-inflammatory cytokines, and pulmonary diffuse fibrosis. As the disease progresses, lung function further deteriorates, leading to poorer quality of life of patients. Currently, few effective drugs are available for the treatment of silicosis. Bicyclol (BIC) is a compound widely employed to treat chronic viral hepatitis and drug-induced liver injury. While recent studies have demonstrated anti-fibrosis effects of BIC on multiple organs, including liver, lung, and kidney, its therapeutic benefit against silicosis remains unclear. In this study, we established a rat model of silicosis, with the aim of evaluating the potential therapeutic effects of BIC. METHODS: We constructed a silicotic rat model and administered BIC after injury. The FlexiVent instrument with a forced oscillation system was used to detect the pulmonary function of rats. HE and Masson staining were used to assess the effect of BIC on silica-induced rats. Macrophages-inflammatory model of RAW264.7 cells, fibroblast-myofibroblast transition (FMT) model of NIH-3T3 cells, and epithelial-mesenchymal transition (EMT) model of TC-1 cells were established in vitro. And the levels of inflammatory mediators and fibrosis-related proteins were evaluated in vivo and in vitro after BIC treatment by Western Blot analysis, RT-PCR, ELISA, and flow cytometry experiments. RESULTS: BIC significantly improved static compliance of lung and expiratory and inspiratory capacity of silica-induced rats. Moreover, BIC reduced number of inflammatory cells and cytokines as well as collagen deposition in lungs, leading to delayed fibrosis progression in the silicosis rat model. Further exploration of the underlying molecular mechanisms revealed that BIC suppressed the activation, polarization, and apoptosis of RAW264.7 macrophages induced by SiO2. Additionally, BIC inhibited SiO2-mediated secretion of the inflammatory cytokines IL-1ß, IL-6, TNF-α, and TGF-ß1 in macrophages. BIC inhibited FMT of NIH-3T3 as well as EMT of TC-1 in the in vitro silicosis model, resulting in reduced proliferation and migration capability of NIH-3T3 cells. Further investigation of the cytokines secreted by macrophages revealed suppression of both FMT and EMT by BIC through targeting of TGF-ß1. Notably, BIC blocked the activation of JAK2/STAT3 in NIH-3T3 cells required for FMT while preventing both phosphorylation and nuclear translocation of SMAD2/3 in TC-1 cells necessary for the EMT process. CONCLUSION: The collective data suggest that BIC prevents both FMT and EMT processes, in turn, reducing aberrant collagen deposition. Our findings demonstrate for the first time that BIC ameliorates inflammatory cytokine secretion, in particular, TGF-ß1, and consequently inhibits FMT and EMT via TGF-ß1 canonical and non-canonical pathways, ultimately resulting in reduction of aberrant collagen deposition and slower progression of silicosis, supporting its potential as a novel therapeutic agent.

Related barriers to using HIV pre-exposure prophylaxis among MSM: A multicentre cross-sectional survey.

OBJECTIVE: The objective of this study was to gain insight into the barriers hindering the use of pre-exposure prophylaxis (PrEP) among men who have sex with men (MSM) in five cities in China. METHODS: MSM were recruited via community-based organizations in an online "snowball" manner. Participants completed the questionnaire anonymously and shared it with key MSM peers (seeds) in five cities in China. Based on the results of univariate analysis, we used a structural equation model to analyse the role of PrEP knowledge awareness, PrEP counselling, and other behavioural variables on PrEP use. RESULTS: The study collected a total of 4223 valid questionnaires, and 18.2% of participants reported PrEP use. The results of the standardized total effects showed that the following paths were statistically significant (p < 0.05): from the age of first sex with men to PrEP knowledge awareness (ß = -0.113) and PrEP use (ß = 0.042); from high-risk sexual behaviour scores to PrEP counselling (ß = 0.039) and PrEP use (ß = 0.103); from the number of HIV tests in the last year to PrEP knowledge awareness (ß = 0.034), PrEP counselling (ß = 0.170), and PrEP use (ß = 0.197); from the level of self-perceived risk of HIV infection to PrEP counselling (ß = -0.115); from PrEP knowledge awareness to PrEP use (ß = -0.049); and from PrEP counselling to PrEP use (ß = 0.420). CONCLUSIONS: The proportion of PrEP use among MSM was relatively low. Age at first sex with men, number of HIV tests, high-risk sexual behaviour, and PrEP counselling had a positive effect on PrEP use, whereas PrEP knowledge awareness had an inverse effect on PrEP use.

Arabidopsis transcription factor STOP1 directly activates expression of NOD26-LIKE MAJOR INTRINSIC PROTEIN5;1, and is involved in the regulation of tolerance to low-boron stress.

Transcriptional regulation is a crucial component of plant adaptation to numerous different stresses; however, its role in how plants adapt to low-boron (B) stress remains unclear. In this study, we show that the C2H2-type transcription factor SENSITIVE TO PROTON RHIZOTOXICITY1 (STOP1) in Arabidopsis is essential for improving plant growth under low-B conditions. STOP1 and the boric acid-channel protein NOD26-LIKE MAJOR INTRINSIC PROTEIN5;1 (NIP5;1) were found to co-localize in root epidermal cells, and STOP1 binds to the 5´-untranslated region of NIP5;1 to activate its expression and enhance B uptake by the roots. Overexpression of STOP1 increased tolerance to low-B stress by up-regulating NIP5;1 transcript levels. Further genetic analyses revealed that STOP1 and NIP5;1 function together in the same pathway to confer low-B tolerance. These results highlight the importance of the STOP1-NIP5;1 module in improving plant growth under low-B conditions.

LincRNA-ROR/miR-145/ZEB2 regulates liver fibrosis by modulating HERC5-mediated p53 ISGylation.

The tumor suppressor p53 has been implicated in the pathogenesis of liver fibrosis. HERC5-mediated posttranslational ISG modification of the p53 protein is critical for controlling its activity. Here, we demonstrated that the expression of HERC5 and ISG15 is highly elevated, whereas p53 is downregulated, in fibrotic liver tissues of mice and transforming growth factor-ß1 (TGF-ß1)-induced LX2 cells. HERC5 siRNA clearly increased the protein expression of p53, but the mRNA expression of p53 was not obviously changed. The inhibition of lincRNA-ROR (ROR) downregulated HERC5 expression and elevated p53 expression in TGF-ß1-stimulated LX-2 cells. Furthermore, the expression of p53 was almost unchanged after TGF-ß1-stimulated LX-2 cells were co-transfected with a ROR-expressing plasmid and HERC5 siRNA. We further confirmed that miR-145 is a target gene of ROR. In addition, we also showed that ROR regulates the HERC5-mediated ISGylation of p53 through mir-145/ZEB2. Together, we propose that ROR/miR-145/ZEB2 might be involved in the course of liver fibrosis by regulating ISGylation of the p53 protein.

Sirtuins in kidney diseases: potential mechanism and therapeutic targets.

Sirtuins, which are NAD+-dependent class III histone deacetylases, are involved in various biological processes, including DNA damage repair, immune inflammation, oxidative stress, mitochondrial homeostasis, autophagy, and apoptosis. Sirtuins are essential regulators of cellular function and organismal health. Increasing evidence suggests that the development of age-related diseases, including kidney diseases, is associated with aberrant expression of sirtuins, and that regulation of sirtuins expression and activity can effectively improve kidney function and delay the progression of kidney disease. In this review, we summarise current studies highlighting the role of sirtuins in renal diseases. First, we discuss sirtuin family members and their main mechanisms of action. We then outline the possible roles of sirtuins in various cell types in kidney diseases. Finally, we summarise the compounds that activate or inhibit sirtuin activity and that consequently ameliorate renal diseases. In conclusion, targeted modulation of sirtuins is a potential therapeutic strategy for kidney diseases. Video Abstract.

MR defecography in assessing stress urinary incontinence with or without symptomatic pelvic organ prolapse.

PURPOSE: Utilize magnetic resonance defecography (MRD) to analyze the primary pelvic floor dysfunctions in patients with stress urinary incontinence (SUI) associated with pelvic organ prolapse (POP), and in SUI patients with asymptomatic POP. METHOD: We performed MRD in both SUI and POP subjects. As a primary analysis, the functional MR parameters were compared between the isolated POP and POP combined SUI groups. As a secondary analysis, the functional MR data were compared between the POP combined SUI and the SUI with asymptomatic POP (isolated SUI) groups. RESULTS: MRD noted the main characteristics of SUI combined moderate or severe POP, including the shorter closed urethra length (1.87 cm vs. 2.50 cm, p < 0.001), more prevalent urethral hypermobility (112.31° vs. 85.67°, p = 0.003), bladder neck funneling (48.28% vs. 20.51%, p = 0.020), lower position of vesicourethral junction (2.11 cm vs. 1.67 cm, p = 0.030), and more severe prolapse of the posterior bladder wall (6.26 cm vs. 4.35 cm, p = 0.008). The isolated SUI patients showed the shortest length of the closed urethra (1.56 cm vs. 1.87 cm, p = 0.029), a larger vesicourethral angle (153.80° vs. 107.58°, p < 0.001), the more positive bladder funneling (84.85% vs. 48.28%, p = 0.002) and a special urethral opening sign (45.45% vs. 3.45%, p < 0.001). CONCLUSIONS: Patients with SUI accompanying POP primarily exhibit excessive urethral mobility and a shortened urethral closure. SUI patients with asymptomatic POP mainly show dysfunction of the urethra and bladder neck, characterized by the opening of the urethra and bladder neck and a shortened urethral closure.

Eco-friendly one-step egg white gel preparation for sensitive detection of 13 trichothecenes in oats using UHPLC-MS/MS.

Oat products have gained widespread recognition as a health food due to their rich and balanced nutritional profile and convenience. However, the unique matrix composition of oats, which differs significantly from other cereals, presents specific challenges for mycotoxin analysis. This study presents an ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method enhanced with an innovative egg white gel pretreatment for the simultaneous analysis of 13 regulated and unregulated trichothecenes in oats. The method demonstrated excellent performance with high accuracy (> 87.5%), repeatability (< 5.7%), and reproducibility (< 8.1%). Analysis of 100 commercial oat products revealed a concerning detection rate (78%) for at least one of the 11 trichothecenes investigated. Notably, deoxynivalenol, exceeding the standard limit in 2% of samples, exhibited the highest detection rate (62%). Additionally, concerning co-occurrence patterns and positive correlations were observed, highlighting potential synergistic effects. The first-time detection of unregulated mycotoxins (T-2 triol, 4,15-diacetoxyscirpenol, 15-acetoxyscirpenol, and neosolaniol) underscores the need for comprehensive monitoring. This method, while developed for oats, shows potential for broader application to other cereals, though further investigation and confirmation are necessary. These findings suggest a potentially underestimated risk of trichothecenes in oats, necessitating continuous monitoring to ensure consumer safety.

Study on fingerprint and quantitative analysis of Verbena officinalis water extract by LC-MS and HPLC.

Verbena officinalis L. as a medical plant has been used to treat many diseases. However, the quality control underlying V. officinalis remains to be studied. HPLC fingerprint analysis and the qualitative and quantitative analysis of water extract from V. officinalis were carried out, and it was found that the quality varies according to habitat and batch. Verbenalin could be a crucial component in the quality evaluation of V. officinalis. This study contributes to better understanding of quality control for V. officinalis.

Angiographic demonstration of a cutoff sign as an unfavorable prognostic indicator for patients with acute ischemic stroke undergoing mechanical thrombectomy.

OBJECTIVES: The aim was to investigate whether the angiographic demonstration of a cutoff sign on the initial angiogram could predict recanalization and prognosis in acute ischemic stroke patients treated by endovascular thrombectomy. METHODS: The angiographic and clinical data of patients who underwent endovascular treatment from October 2018 to April 2023 were retrospectively reviewed. The pretreatment angiographic appearance of the thrombus's proximal part was assessed and classified as either the cutoff sign (+) or (-). Patients' baseline characteristics and angiographic and clinical outcomes between the two groups were analyzed using propensity score matching. Then, the two commonly used techniques, stent retrieval and contact aspiration, were compared in terms of successful reperfusion and clinical outcome in patients with the cutoff sign. RESULTS: The cutoff sign was observed in 77 (36.2%) of 213 patients. Patients with the cutoff sign were younger and were less likely to have involvement of the anterior circulation. Compared with the cutoff sign (-) group, the cutoff sign (+) group had a significantly longer procedure time (103 versus 80 min, P =0.002) and a lower percentage of 3-month good functional outcomes (18.2% versus 36%, P =0.006). After propensity score matching, the procedure time (100 versus 75 min, P =0.002) and the 3-month good outcome (19.2% versus 41.4%, P =0.004) remained significantly different. No significant differences were observed in the radiological (OR 0.758, 95% CI 0.157 to 3.658; P =0.730) and clinical (OR 0.747, 95% CI 0.147 to 3.787; P =0.725) outcomes between the two techniques. CONCLUSIONS: The cutoff sign might be an unfavorable prognostic indicator in patients undergoing mechanical thrombectomy, and the efficacy of mechanical thrombectomy techniques does not differ in patients positive for the cutoff sign.

Preparation and Application of Volatilized Wormwood Essence Derived Naturally into Green Insecticide.

Naturally occurring substances and their derivatives function as vital resources for pesticides that can be used in fields, such as insecticide production and fungicide development. As a botanical entity displaying multifaceted biological functions, wormwood has received thorough scrutiny across multiple sectors. The insect repellency potency combined with antibacterial and antifungal activities of wormwood position it as a potential candidate for prospective development into eco-friendly chemical pesticides. In this research, Wormwood essential oil was procured via ethanol water under ultrasonic scenarios and subsequently diluted with PEG 400 to formulate green chemical pesticides. The defensive efficacy of this green pesticide on plants was validated through 2 weeks of clustered plant growth experiments. Active constituents that exerted their effects were scrutinized by GC-MS. Furthermore, this green pesticide also displays efficacious effects on the prevention and management of aphids, exhibiting a dose-dependent relationship. 4-terpenol, eucalyptol, carvacrol, and L-borneol were identified by GC-MS as the predominant active constituents in this green chemical pesticide. Wormwood can be leveraged to develop green chemical pesticides, which can protect plants without contaminating the environment.

UPLC-MS/MS-Based Target Screening of 90 Phosphodiesterase Type 5 Inhibitors in 5 Dietary Supplements.

The aim of individuals consuming health supplements is to attain a robust state through nutritional regulation. However, some unscrupulous manufacturers, motivated by profit, fraudulently incorporate drugs or unauthorized components with therapeutic effects into the product for instant product performance enhancement. The long-term use of these products may inadvertently inflict harm on human health and fail to promote nutritive healthcare. The illegal inclusion of these substances is prevalent in kidney-tonifying and sexuality-enhancing products. Developing effective analytical methods to identify these products and screen for illegal added ingredients can effectively prevent such products from reaching and remaining on the market. A target screening method for the detection and quantification of 90 phosphodiesterase type 5 inhibitors (PDE-5is) in 5 kinds of health products was developed and validated. The type of dietary supplements varied from tablets, capsules, and protein powder to wine and beverages. Sample preparation was completed with a one-step liquid phase extraction. The screening process of 90 PDE-5is was done efficiently within 25 min by ultra-high performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) using the dynamic multiple reaction monitoring (dMRM) technique. The LODs of 90 PDE-5is were detected at levels ranging from 25 to 85 ng/g or ng/mL. This novel targeting methodology was effective and can be applied to routine market supervision. Among 286 batches of samples, 8 batches were found to be positive. Three kinds of PDE-5is were first detected in healthy products. The screening method demonstrated herein will be a promising and powerful tool for rapid screening of PDE-5is.

Anti-aging effect of peptides on Caenorhabditis elegans: a meta-analysis.

BACKGROUND: Recently, peptides have been studied in Caenorhabditis elegans for anti-aging research. Due to the lack of sufficient evidence, we conducted this meta-analysis focusing on the anti-aging effect of peptides in C. elegans to provide more convincing evidence. RESULTS: A literature search in PubMed, SCOUPUS, and Web of Science databases yielded 2879 articles. After removing duplicates and based on inclusion criteria and STAIR checklist quality assessment, nine articles were selected. Data extraction and analysis showed that, compared to the control group without peptide intervention, peptide supplementation significantly reduced nematode mortality risk [hazard ratio = 0.54, 95% confidence interval (CI) = 0.47, 0.62; P < 0.05], significantly increased the pharyngeal pumping rate [standardized mean difference (SMD) = 1.64, 95% CI = 0.87, 2.41; P < 0.05], bending frequency (SMD = 1.67, 95% CI = 1.16, 2.18; P < 0.05), and significantly decreased the accumulation of lipofuscin levels within nematodes (SMD = -4.48, 95% CI = -6.85, -2.12; P < 0.05). Additionally, subgroup analysis showed that doses ranging from 0.1 to 1 mg/mL (HR = 0.50, 95% CI = 0.38, 0.65; P < 0.05) displayed better anti-aging effects compared to other dose ranges. CONCLUSION: The findings suggest that peptides can significantly extend the lifespan of C. elegans under normal circumstances and improve three indicators of healthy life. More importantly, subgroup analysis revealed that a dosage of 0.1-1 mg/mL demonstrated superior anti-aging effects. This meta-analysis provides more convincing evidence that peptides can play an anti-aging role in C. elegans. © 2024 Society of Chemical Industry.

Insulator-Transition-Induced Degradation of Pyrochlore Ruthenates in Electrocatalytic Oxygen Evolution and Stabilization through Doping.

Ru-based pyrochlores (e.g., Y2Ru2O7-δ) are promised to replace IrO2 in polymer electrolyte membrane (PEM) electrolyzers. It is significant to reveal the cliff attenuation on the oxygen evolution reaction (OER) performance of these pyrochlores. In this work, we monitor the structure changes and electrochemical behavior of Y2Ru2O7-δ over the OER process, and it is found that the reason of decisive OER inactivation is derived from an insulator transition occurred within Y2Ru2O7-δ due to its inner "perfecting" lattice induced by continuous atom rearrangement. Therefore, a stabilization strategy of the Ir-substituted Y2Ru2O7-δ is proposed to alleviate this undesirable behavior. The double-exchange interaction between Ru and Ir in [RuO6] and [IrO6] octahedra leads the charge redistribution with simultaneous spin configuration adjustment. The electronic state in newly formed octahedrons centered with Ru 4d3 (with the state of eg'↑↑a1g ↑ eg 0) and Ir 5d6 (eg'↑↓↑↓a1g ↑↓ eg 0) relieves the uneven electron distributions in [RuO6] orbital. The attenuated Jahn-Teller effect alleviates atom rearrangement, represented as the mitigation of insulator transition, surface reconstruction, and metal dissolution. As results, the Ir-substituted Y2Ru2O7-δ presents the greatly improved OER stability and PEM durability. This study unveils the OER degradation mechanism and stabilization strategy for material design of Ru-based OER catalysts for electrochemical applications.

Fabrication of Scalable Covalent Organic Framework Membrane-based Electrolytes for Solid-State Lithium Metal Batteries.

The conventional covalent organic framework (COF)-based electrolytes with tailored ionic conducting behaviors are typically fabricated in the powder morphology, requiring further compaction procedures to operate as solid electrolyte tablets, which hinders the large-scale manufacturing of COF materials. In this study, we present a feasible electrospinning strategy to prepare scalable, self-supporting COF membranes (COMs) that feature a rigid COF skeleton bonded with flexible, lithiophilic polyethylene glycol (PEG) chains, forming an ion conduction network for Li+ transport. The resulting PEG-COM electrolytes exhibit enhanced dendrite inhibition and high ionic conductivity of 0.153 mS cm-1 at 30 °C. The improved Li+ conduction in PEG-COM electrolytes stems from the loose ion pairing in the structure and the production of higher free Li+ content, as confirmed by solid-state 7Li NMR experiments. These changes in the local microenvironment of Li+ facilitate its directional movement within the COM pores. Consequently, solid-state symmetrical Li|Li, Li|LFP, and pouch cells demonstrate excellent electrochemical performance at 60 °C. This strategy offers a universal approach for constructing scalable COM-based electrolytes, thereby broadening the practical applications of COFs in solid-state lithium metal batteries.

Role of MoOx Surficial Modification in Enhancing the OER Performance of Ru-Pyrochlore.

Pyrochlore ruthenate (Y2 Ru2 O7-δ ) is highlighted as a promising oxygen evolution reaction (OER) catalyst for water splitting in polymer electrolyte membrane electrolyzers. However, an efficient electronic modulation strategy for Y2 Ru2 O7-δ is required to overcome its electrochemical inertness. Herein, a surface manipulation strategy involving implanting MoOx moieties on nano Y2 Ru2 O7-δ (Mo-YRO) using wet chemical peroxone method is demonstrated. In contrast to electronic structure regulation by intramolecular charge transfer (i.e., substitutional strategies), the heterogeneous Mo-O-Ru micro-interfaces facilitate efficient intermolecular electron transfer from [RuO6 ] to MoOx . This eliminates the bandgap by inducing Ru 4d delocalization and band alignment rearrangement. The MoOx modifiers also alleviate distortion of [RuO6 ] by shortening Ru-O bond and enlarging Ru-O-Ru bond angle. This electronic and geometric structure tailoring enhances the OER performance, showing a small overpotential of 240 mV at 10 mA cm-2 . Moreover, the electron-accepting MoOx moieties provide more electronegative surfaces, which serve as a protective "fence" to inhibit the dissolution of metal ions, thereby stabilizing the electrochemical activity. This study offers fresh insights into the design of new-based pyrochlore electrocatalysts, and also highlights the versatility of surface engineering as a way of optimizing electronic structure and catalytic performance of other related materials.

Proteome-wide mendelian randomization study implicates therapeutic targets in common cancers.

BACKGROUND: The interest in targeted cancer therapies has been growing rapidly. While numerous cancer biomarkers and targeted treatment strategies have been developed and employed, there are still significant limitations and challenges in the early diagnosis and targeted treatment of cancers. Accordingly, there is an urgent need to identify novel targets and develop new targeted drugs. METHODS: The study was conducted using combined cis-Mendelian randomization (cis-MR) and colocalization analysis. We analyzed data from 732 plasma proteins to identify potential drug targets associated with eight site-specific cancers. These findings were further validated using the UK Biobank dataset. Then, a protein-protein interaction network was also constructed to examine the interplay between the identified proteins and the targets of existing cancer medications. RESULTS: This MR analysis revealed associations between five plasma proteins and prostate cancer, five with breast cancer, and three with lung cancer. Subsequently, these proteins were classified into four distinct target groups, with a focus on tier 1 and 2 targets due to their higher potential to become drug targets. Our study indicatied that genetically predicted KDELC2 (OR: 0.89, 95% CI 0.86-0.93) and TNFRSF10B (OR: 0.74, 95% CI 0.65-0.83) are inversely associated with prostate cancer. Furthermore, we observed an inverse association between CPNE1 (OR: 0.96, 95% CI 0.94-0.98) and breast cancer, while PDIA3 (OR: 1.19, 95% CI 1.10-1.30) were found to be associated with the risk of breast cancer. In addition, we also propose that SPINT2 (OR: 1.05, 95% CI 1.03-1.06), GSTP1 (OR: 0.82, 95% CI 0.74-0.90), and CTSS (OR: 0.91, 95% CI 0.88-0.95) may serve as potential therapeutic targets in prostate cancer. Similarly, GDI2 (OR: 0.85, 95% CI 0.80-0.91), ISLR2 (OR: 0.87, 95% CI 0.82-0.93), and CTSF (OR: 1.14, 95% CI 1.08-1.21) could potentially be targets for breast cancer. Additionally, we identified SFTPB (OR: 0.93, 95% CI 0.91-0.95), ICAM5 (OR: 0.95, 95% CI 0.93-0.97), and FLRT3 (OR: 1.10, 95% CI 1.05-1.15) as potential targets for lung cancer. Notably, TNFRSF10B, GSTP1, and PDIA3 were found to interact with the target proteins of current medications used in prostate or breast cancer treatment. CONCLUSIONS: This comprehensive analysis has highlighted thirteen plasma proteins with potential roles in three site-specific cancers. Continued research in this area may reveal their therapeutic potential, particularly KDELC2, TNFRSF10B, CPNE1, and PDIA3, paving the way for more effective cancer treatments.

One-Pot Access to Boron-Doped Fused Heterocycles via Domino Cyclization of Bis-Diazidoboranes with Isonitrile.

Boron-doped fused heterocycles have shown great potential in the field of functional materials. This study reports on the synthesis of a new class of bis-diazidoboranes and the discovery of their cycloaddition reaction with isonitriles. Triply fused boron-doped heterocyclic compounds were constructed in a one-pot process through a domino cycloaddition, providing an effective route for constructing complex boron-doped heterocyclic systems.

Distance-Triggered Distinct Aryl Migrations on Azidodiboranes.

Derived from structurally similar precursors, two different azidodiboranes went through distinct aryl migration reactions triggered by different boron-boron separation distances. Biphenylene based diborane with a shorter boron-boron distance underwent heterolateral aryl migration to form a seven-membered azadiborepin, while xanthrene based diborane with a longer boron-boron distance afforded a stable bis-azidoborane scaffold. The pyrolysis of such a bis-azidoborane led to eight-membered oxazadiborocine through homolateral aryl migration and subsequent [3+2] cycloaddition. Density functional theory (DFT) calculations unveiled that the boron-boron separation distances were the intrinsic factors for the distinct migrations.