Dimethylsulfoniopropionate (DMSP) Increases Longevity and Mitochondrial Function in Caenorhabditis elegans: Implications for the Role of the Global Sulfur Cycle in Terrestrial Ecosystems.

Dimethylsulfoniopropionate (DMSP) is a compound synthesized by marine phytoplankton that contributes to the oceanic sulfur cycle. Interestingly, DMSP has also been found in algal species and several terrestrial plants, forming part of the global sulfur cycle. However, compared to its role in the marine environment, the impact of DMSP on terrestrial ecosystems remains relatively unexplored. In this study, DMSP was shown to promote longevity and prevent age-associated functional decline in Caenorhabditis elegans (C. elegans), a soil-dwelling organism. DMSP decreased mitochondrial content and improved mitochondrial function in C. elegans at the old stage, which was via enhancing autophagy flux. It was demonstrated that DMSP significantly increased the expression of autophagy and mitophagy genes during aging. Furthermore, DMSP protected against Parkinson's disease (PD) induced by α-synuclein (α-syn) aggregation via autophagy. Mechanistic studies showed that DMSP directly activated nuclear translocation of the Skinhead-1 (SKN-1) transcription factor from the cytoplasm. Moreover, SKN-1 was involved in DMSP-induced autophagy and played a key role in lifespan extension and α-syn clearance in C. elegans. In conclusion, DMSP delays physiological aspects of aging in C. elegans, providing insights into the interplay between the global sulfur cycle and terrestrial organisms.

Drug-Free Mesoporous Silica Nanoparticles Enable Suppression of Cancer Metastasis and Confer Survival Advantages to Mice with Tumor Xenografts.

Despite advancements in nanomedicine for drug delivery, many drug-loaded nanoparticles reduce tumor sizes but often fail to prevent metastasis. Mesoporous silica nanoparticles (MSNs) have attracted attention as promising nanocarriers. Here, we demonstrated that MSN-PEG/TA 25, with proper surface modifications, exhibited unique antimetastatic properties. In vivo studies showed that overall tumor metastasis decreased in 4T1 xenografts mice treated with MSN-PEG/TA 25 with a notable reduction in lung tumor metastasis. In vitro assays, including wound-healing, Boyden chamber, tube-formation, and real-time cell analyses, showed that MSN-PEG/TA 25 could modulate cell migration of 4T1 breast cancer cells and interrupt tube formation by human umbilical vein endothelial cells (HUVECs), key factors in suppressing cancer metastasis. The synergistic effect of MSN-PEG/TA 25 combined with liposomal-encapsulated doxorubicin (Lipo-Dox) significantly boosted mouse survival rates, outperforming Lipo-Dox monotherapy. We attributed the improved survival to the antimetastatic capabilities of MSN-PEG/TA 25. Moreover, Dox-loaded MSN-PEG/TA 25 suppressed primary tumors while retaining the antimetastatic effect, thereby enhancing therapeutic outcomes and overall survival. Western blot and qPCR analyses revealed that MSN-PEG/TA 25 interfered with the phosphorylation of ERK, FAK, and paxillin, thus impacting focal adhesion turnover and inhibiting cell motility. Our findings suggest that drug-free MSN-PEG/TA 25 is highly efficient for cancer treatment via suppressing metastatic activity and angiogenesis.

Photoconductivity and Photovoltaic Effect Strengthened via Microstructural Cotuning in Ferroelectrics: Intuitively Assessed by Macroscopic Transparency.

Photoferroelectrics that involve strong light-matter coupling are regarded as promising candidates for realizing bulk photovoltaic and photoelectric effects via light absorption. Nonetheless, understanding the photoresponse mechanism or modulation of performance from a microscopic point of view is scarcely explored through quantification of macroscopic properties. Herein, we design a model material, Gd3+-doped (K0.5Na0.5)NbO3 ferroelectric-transparent ceramics, and present an advantageous strategy to enhance the optoelectronic coupling through joint modulations of lattice distortion and oxygen vacancies, along with inner defects and ferroelectric domains. Significantly, their microcosmic manipulation can be intuitively and facilely evaluated by the optical transparency of each ceramic. An approximately 104 fold increase in conductivity under ultraviolet irradiation was produced. Under the cocoupling between external physical fields, the synergy of photoelectric stimulation increased the photoconductivity of the ceramics by 13.89 times. Additionally, a significant increase (4.5-fold) in the current output from the photovoltaic effect was achieved via ferroelectric domains of moderate size, whose size could be easily assessed by optical transmittance. In situ microscopic observations confirmed that the configuration of oxygen vacancy-dependent ferroelectric domains contributes to the enhanced optoelectronic response. This research provides a distinct way to develop inexpensive optocoupler devices and meet the requirements for multifunctional integration in single photoferroelectrics.

Anti-inflammatory effects of MerTK by inducing M2 macrophage polarization via PI3K/Akt/GSK-3ß pathway in gout.

Mer tyrosine kinase (MerTK) has been found to regulate the secretion of inflammatory factors and exert immunosuppressive effects, but its role in gout remains unclear. In this study, we aimed to clarify the immnue effects of MerTK in gout. MerTK in synovium or serum of gout patients was determined by immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), and real-time quantitative polymerase chain reaction (RT-qPCR). In monosodium urate (MSU)-induced gout mice, the effect of MerTK inhibitor (UNC2250) on inflammation and polarization was also assessed. After inhibition, knockdown or overexpression of MerTK, inflammatory response and polarization level in THP1-derived macrophages were evaluated by RT-qPCR and flow cytometry. Regulation of MerTK inhibitors on mitochondrial function and downstream pathway in THP1-derived macrophages were detected. MerTK in synovium and serum of gout patients were increased. MerTK inhibitor stimulated the inflammation and M1 polarization in MSU-induced gout mice. MerTK inhibition, knock-down, or overexpression affected inflammatory response, polarization and mitochondrial function in vitro in gout model. The PI3K/Akt/GSK-3ß pathway was identified to reduce after MerTK inhibition and the relevant results were as expected, validated by knock-down or overexpressing MerTK. In conclusion, MerTK was detected to increase in both gout patients and model. MerTK influenced inflammatory response and polarization markers through PI3K/Akt/GSK-3ß pathway. Interfering MerTK/PI3K/Akt/GSK-3ß axis may provide a new therapeutic target for gout.

Giant Capacitive Energy Storage in High-Entropy Lead-Free Ceramics with Temperature Self-Check.

Considering the large demand for electricity in the era of artificial intelligence and big data, there is an urgent need to explore novel energy storage media with higher energy density and intelligent temperature self-check functions. High-entropy (HE) ceramic capacitors are of great significance because of their excellent energy storage efficiency and high power density (PD). However, the contradiction between configurational entropy and polarization in traditional HE systems greatly restrains the increase in energy storage density. Herein, the contradiction is effectively solved by regulating the octahedral tilt and cationic displacement in ABO3-type perovskite HE ceramics, i.e., (1-x)[0.6(Bi0.47Na0.47Yb0.03Tm0.01)TiO3-0.4(Ba0.5Sr0.5)TiO3]-xSr(Zr0.5Hf0.5)O3 (BNYTT-BST-xSZH). Combining the tape-casting process and cold isostatic pressing, the optimal BNYTT-BST-0.06SZH ceramic displays a large recoverable energy storage density (10.46 J cm-3) at 685 kV cm-1 and a high PD (332.88 MW cm-3). More importantly, due to Tm/Yb codoping, abnormal fluorescent negative thermal expansion and excellent real-time temperature sensing are developed, thus the application of fault detection and warning in high-voltage transmission line systems is conceptualized. This study provides an effective strategy for enhancing the polarization of energy-storing HE ceramics and offers a promising material for overcoming the problems of insufficient capacitor density and thermal runaway in terminal communication.

Depression exacerbates myocardial ischemia-reperfusion injury in mice via CNR2 gene and MIF-AMPK signaling pathway.

BACKGROUND: Myocardial ischemia-reperfusion(I/R)injury constitute the fundamental pathophysiology of acute myocardial infarction (AMI). Ischemic heart releases macrophage migration inhibitory factor (MIF), which activates MIF- AMPK signaling pathway. Depression is a significant risk factor for AMI. In a state of depression, peripheral expression of cannabinoid receptor 2 (CNR2) genes was downregulated. AIMS: We investigated the mechanism by which depression exacerbates myocardial I/R injury through the CNR2 and MIF-AMPK signaling pathways. METHODS: We established mouse models of depression and myocardial I/R. Left ventricular function was assessed using cardiac ultrasound and TTC staining. The protein levels of myocardial CNR2, MIF, AMPK, and ACC were determined by Western blot, while the expression level of CNR2 was measured using RT-qPCR. Additionally, MIF content in peripheral blood was quantified using ELISA. RESULTS: After I/R, the expression level of CNR2 was found to be lower in the depression group, leading to a deterioration in left heart function. Depressed mice exhibited lower secretion of MIF, accompanied by a decrease in the activation of the MIF-AMPK signaling pathway. However, injection of CNR2 agonist JWH133 prior to ischemia increased the activation of the MIF-AMPK signaling pathway, while CNR2 inhibitor AM630 decreased the activation. LIMITATIONS: Further research is needed to investigate the specific neuroendocrine mechanism affecting myocardial CNR2 expression in depression. And these experimental conclusions require further verification at the cellular level. CONCLUSIONS: The activation of CNR2 in myocardium following I/R is impeded by depression, thereby exacerbating myocardial I/R injury through attenuation of the MIF-AMPK signaling pathway activation.

Photoangiolysis with the 445-nm Blue Laser and the Potassium-Titanyl-Phosphate Laser: A Comparison.

OBJECTIVES: Photoangiolytic lasers have yielded significant innovation in laryngeal surgery in the last 25 years. After the discontinuation of the potassium titanyl phosphate (KTP) laser, a novel 445-nm blue laser was developed. The optimal balance between a laser's desired tissue effects and collateral tissue damage is a major determinant of laser selection in microlaryngeal surgery. The shell-less incubation system for the chick chorioallantoic membrane (CAM) simulates the microvasculature of the human vocal fold and is useful for testing effects of laser settings and in simulated surgery. The aim of this study is to compare the tissue effects of the KTP and blue lasers using the shell-less CAM model. METHODS: The shell-less incubation system contains: polymethylpentene film (used as a culture vessel), calcium lactate and distilled water supplementations. By using this system, the chick chorioallantoic membrane (CAM) can be fully exposed with a good field for surgery simulation. The effects of the 2 lasers (532 nm KTP and 445 nm blue) were quantified at clinically relevant energy settings and laser distances from target. Measures included imaging real-time vascular reactions in the CAM model, post-procedure histologic analysis of CAM tissue and temperature changes. RESULTS: Vessel coagulation and rupture rates were less common with the blue laser compared with the KTP laser. Histologic analysis demonstrated less tissue disruption with the blue laser. Temperature changes were less with the blue laser. CONCLUSION: In this CAM model with specific conditions, the blue laser reveals less tissue damage than the KTP laser. Suitable working distance and power setting of the laser are necessary for desired tissue effects.Level of Evidence: Level 3.

[Effect of Selinexor on Proliferation and Apoptosis of Acute Myeloid Leukemia Kasumi-1 Cells].

OBJECTIVE: To investigate the effects of selinexor, a inhibitor of nuclear export protein 1 (XPO1) on the proliferation inhibition and apoptosis of Kasumi-1 cells in acute myeloid leukemia (AML). METHODS: MTS method was used to detect the inhibitory effect of different concentrations of selinexor on the proliferation of Kasumi-1 cells at different time points. The apoptosis rate and cell cycle changes after treatment with different concentration of selinexor were detected by flow cytometry. RESULTS: Selinexor inhibited the growth of Kasumi-1 cells at different time points in a concentration-dependent manner (r 24 h=0.7592, r 48 h=0.9456, and r 72 h=0.9425). Selinexor inhibited Kasumi-1 cells growth in a time-dependent manner (r =0.9057 in 2.5 µmol/L group, r =0.9897 in 5 µmol/L group and r =0.9994 in 10 µmol/L group). Selinexor could induce apoptosis of Kasumi-1 cells in a dose-dependent manner (r =0.9732), and the apoptosis of Kasumi-1 cells was more obvious with the increase of drug concentration. The proportion of G0/G1 phase was significantly increased and the proportion of S phase was significantly decreased after the treatment of Kasumi-1 cells by selinexor. With the increase of drug concentration, the proportion of Kasumi-1 cells cycle arrest in G0/G1 phase was increased and the cell synthesis was decreased. CONCLUSION: Selinexor can promote the death of tumor cells by inhibiting Kasumi-1 cells proliferation, inducing apoptosis and blocking cell cycle.

Prognostic genome and transcriptome signatures in colorectal cancers.

Colorectal cancer is caused by a sequence of somatic genomic alterations affecting driver genes in core cancer pathways1. Here, to understand the functional and prognostic impact of cancer-causing somatic mutations, we analysed the whole genomes and transcriptomes of 1,063 primary colorectal cancers in a population-based cohort with long-term follow-up. From the 96 mutated driver genes, 9 were not previously implicated in colorectal cancer and 24 had not been linked to any cancer. Two distinct patterns of pathway co-mutations were observed, timing analyses identified nine early and three late driver gene mutations, and several signatures of colorectal-cancer-specific mutational processes were identified. Mutations in WNT, EGFR and TGFß pathway genes, the mitochondrial CYB gene and 3 regulatory elements along with 21 copy-number variations and the COSMIC SBS44 signature correlated with survival. Gene expression classification yielded five prognostic subtypes with distinct molecular features, in part explained by underlying genomic alterations. Microsatellite-instable tumours divided into two classes with different levels of hypoxia and infiltration of immune and stromal cells. To our knowledge, this study constitutes the largest integrated genome and transcriptome analysis of colorectal cancer, and interlinks mutations, gene expression and patient outcomes. The identification of prognostic mutations and expression subtypes can guide future efforts to individualize colorectal cancer therapy.

Nicotine Enantioselectively Targets Myeloid Differentiation Protein 2 and Inhibits the Toll-like Receptor 4 Signaling.

Psychoactive substances, including morphine and methamphetamine, have been shown to interact with the classic innate immune receptor Toll-like receptor 4 (TLR4) and its partner protein myeloid differentiation protein 2 (MD2) in a nonenantioselective manner. (-)-Nicotine, the primary alkaloid in tobacco and a key component of highly addictive cigarettes, targets the TLR4/MD2, influencing TLR4 signaling pathways. Existing as two enantiomers, the stereoselective recognition of nicotine by TLR4/MD2 in the context of the innate immune response remains unclear. In this study, we synthesized (+)-nicotine and investigated its effects alongside (-)-nicotine on lipopolysaccharide (LPS)-induced TLR4 signaling. (-)-Nicotine dose-dependently inhibited proinflammatory factors such as tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and cyclooxygenase-2 (COX-2). In contrast, (+)-nicotine showed no such inhibitory effects. Molecular dynamics simulations revealed that (-)-nicotine exhibited a stronger affinity with the TLR4 coreceptor MD2 than (+)-nicotine. Additionally, in silico simulations revealed that both nicotine enantiomers initially attach to the entrance of the MD2 cavity, creating a metastable state before they fully enter the cavity. In the metastable state, (-)-nicotine established more stable interactions with the surrounding residues at the entrance of the MD2 cavity compared to those of (+)-nicotine. This highlights the crucial role of the MD2 cavity entrance in the chiral recognition of nicotine. These findings provide valuable insights into the distinct interactions between nicotine enantiomers and the TLR4 coreceptor MD2, underscoring the enantioselective effect of nicotine on modulating TLR4 signaling.

Characteristics, sources analysis, and risk assessment of polycyclic aromatic hydrocarbon contamination in surface sediments surrounding tourist island.

Surface sediment samples were collected from the surrounding sea areas of the two largest tourist islands in Sanya City, China, to compare and assess the sources, distribution, and ecological risks of 16 polycyclic aromatic hydrocarbons (PAHs). The total PAHs concentrations ranged from 31.16 to 163.3 ng/g, with an average concentration of 102.46 ng/g, which is still lower than the levels detected in most other sediment studies worldwide. PAHs from coal combustion (Flu, Pyr, Fl, Phe) showed positive correlations with TOC, Silt, and Clay, indicating that these PAHs are easily adsorbed in muddy and silty sediments. Sanya Bay is primarily composed of mud and silt, whereas Haitang Bay is mainly sandy. This corresponds to the significantly higher concentrations of Fl, Phe, and Pyr in Sanya Bay compared to Haitang Bay. The main industrial activities in the study area are related to power and heat production and supply. The results indicate that the primary sources of sediment PAHs are high-temperature combustion during heavy industrial production, followed by maritime transportation and petroleum sources. Overall, the PAHs pollution levels in the study area range from slight to moderate. Sediment quality assessments show that only Ace and Phe have higher individual risk values. Six stations in Sanya Bay have higher adverse impact risks, while in Haitang Bay, only HT07 poses a high risk to biological impact. These two areas require enhanced monitoring and pollution source control.

A multibranch and multiscale neural network based on semantic perception for multimodal medical image fusion.

Medical imaging is indispensable for accurate diagnosis and effective treatment, with modalities like MRI and CT providing diverse yet complementary information. Traditional image fusion methods, while essential in consolidating information from multiple modalities, often suffer from poor image quality and loss of crucial details due to inadequate handling of semantic information and limited feature extraction capabilities. This paper introduces a novel medical image fusion technique leveraging unsupervised image segmentation to enhance the semantic understanding of the fusion process. The proposed method, named DUSMIF, employs a multi-branch, multi-scale deep learning architecture that integrates advanced attention mechanisms to refine the feature extraction and fusion processes. An innovative approach that utilizes unsupervised image segmentation to extract semantic information is introduced, which is then integrated into the fusion process. This not only enhances the semantic relevance of the fused images but also improves the overall fusion quality. The paper proposes a sophisticated network structure that extracts and fuses features at multiple scales and across multiple branches. This structure is designed to capture a comprehensive range of image details and contextual information, significantly improving the fusion outcomes. Multiple attention mechanisms are incorporated to selectively emphasize important features and integrate them effectively across different modalities and scales. This approach ensures that the fused images maintain high quality and detail fidelity. A joint loss function combining content loss, structural similarity loss, and semantic loss is formulated. This function not only guides the network in preserving image brightness and texture but also ensures that the fused image closely resembles the source images in both content and structure. The proposed method demonstrates superior performance over existing fusion techniques in objective assessments and subjective evaluations, confirming its effectiveness in enhancing the diagnostic utility of fused medical images.

Pt-decorated spinel MnCo2O4 nanosheets enable ampere-level hydrazine assisted water electrolysis.

Coupling hydrazine oxidation reaction (HzOR) with hydrogen evolution reaction (HER) has been widely concerned for high efficiency of green hydrogen preparation with low energy consumption. However, the lacking of bifunctional electrodes with ampere-level performance severely limits its industrialization. Herein, we put forward an efficient active site anchored strategy for MnCo2O4 nanosheet arrays on nickel foam (NF) by introducing Pt species (denoted as Pt-MnCo2O4/NF), which is standing for excellent bifunctional electrodes. The Pt-MnCo2O4/NF delivers ultralow potentials of -195 mV and 350 mV at 1000 mA cm-2 as well as robust stability for HzOR and HER, respectively. The study of in-situ Raman and reaction kinetics reveal that the formation of key adsorbed *NH2 and *N2H4 intermediates and the rapidly oxidization of intermediates with a fast interfacial charge transfer on Pt-MnCo2O4/NF. Remarkably, the Pt-MnCo2O4/NF assembled two-electrode hydrazine assisted water electrolyzer realizes current density of 100 mA cm-2 and 1000 mA cm-2 at 0.16 V and 0.62 V with over 80 h stability. This work provides a promising way to design efficient electrodes for energy-saving H2 generation under ampere-level current density.

Specific and efficient knockdown of intracellular miRNA using partially neutralized phosphate-methylated DNA oligonucleic acid-loaded mesoporous silica nanoparticles.

Antisense oligonucleotides (ASOs) are molecules used to regulate RNA expression by targeting specific RNA sequences. One specific type of ASO, known as neutralized DNA (nDNA), contains site-specific methyl phosphotriester (MPTE) linkages on the phosphate backbone, changing the negatively charged DNA phosphodiester into a neutralized MPTE with designed locations. While nDNA has previously been employed as a sensitive nucleotide sequencing probe for the PCR, the potential of nDNA in intracellular RNA regulation and gene therapy remains underexplored. Our study aims to evaluate the regulatory capacity of nDNA as an ASO probe in cellular gene expression. We demonstrated that by tuning MPTE locations, partially and intermediately methylated nDNA loaded onto mesoporous silica nanoparticles (MSNs) can effectively knock down the intracellular miRNA, subsequently resulting in downstream mRNA regulation in colorectal cancer cell HCT116. Additionally, the nDNA ASO-loaded MSNs exhibit superior efficacy in reducing miR-21 levels over 72 hours compared to the efficacy of canonical DNA ASO-loaded MSNs. The reduction in the miR-21 level subsequently resulted in the enhanced mRNA levels of tumour-suppressing genes PTEN and PDCD4. Our findings underscore the potential of nDNA in gene therapies, especially in cancer treatment via a fine-tuned methylation location.

Dihydroartemisinin alleviates doxorubicin-induced cardiotoxicity and ferroptosis by activating Nrf2 and regulating autophagy.

Although the use of Doxorubicin (Dox) is extensive in the treatment of malignant tumor, the toxic effects of Dox on the heart can cause myocardial injury. Therefore, it is necessary to find an alternative drug to alleviate the Dox-induced cardiotoxicity. Dihydroartemisinin (DHA) is a semisynthetic derivative of artemisinin, which is an active ingredient of Artemisia annua. The study investigates the effects of DHA on doxorubicin-induced cardiotoxicity and ferroptosis, which are related to the activation of Nrf2 and the regulation of autophagy. Different concentrations of DHA were administered by gavage for 4 weeks in mice. H9c2 cells were pretreated with different concentrations of DHA for 24 h in vitro. The mechanism of DHA treatment was explored through echocardiography, biochemical analysis, real-time quantitative PCR, western blotting analysis, ROS/DHE staining, immunohistochemistry, and immunofluorescence. In vivo, DHA markedly relieved Dox-induced cardiac dysfunction, attenuated oxidative stress, alleviated cardiomyocyte ferroptosis, activated Nrf2, promoted autophagy, and improved the function of lysosomes. In vitro, DHA attenuated oxidative stress and cardiomyocyte ferroptosis, activated Nrf2, promoted clearance of autophagosomes, and reduced lysosomal destruction. The changes of ferroptosis and Nrf2 depend on selective degradation of keap1 and recovery of lysosome. We found for the first time that DHA could protect the heart from the toxic effects of Dox-induced cardiotoxicity. In addition, DHA significantly alleviates Dox-induced ferroptosis through the clearance of autophagosomes, including the selective degradation of keap1 and the recovery of lysosomes.

Polyphyllin I ameliorates gefitinib resistance and inhibits the VEGF/VEGFR2/p38 pathway by targeting HIF-1a in lung adenocarcinoma.

BACKGROUND: Lung adenocarcinoma (LUAD) is the most common pathological type of lung cancer. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been administered as the first-line therapy for patients with EGFR mutations in LUAD, but it is almost inevitable that resistance to EGFR-TKIs therapy eventually arises. Polyphyllin I (PPI), derived from Paris polyphylla rhizomes, has been shown to have potent anti-cancer properties in a range of human cancer types including LUAD. However, the role of PPI in gefitinib resistance and the underlying mechanism remain elusive. PURPOSE: To evaluate the antitumor impacts of PPI on gefitinib resistance cells and investigate its molecular mechanism. METHODS: CCK-8, wound healing, transwell assay, and xenograft model were performed to determine the anti-cancer effects of PPI as well as its ability to overcome gefitinib resistance. Immunoblotting, co-immunoprecipitation, phospho-RTK antibody array, qRT-PCR, and immunofluorescence were utilized to explore the mechanism by which PPI overrides gefitinib resistance. RESULTS: PPI inhibited cell survival, growth, and migration/invasion in both gefitinib-sensitive (PC9) and -resistant (PC9/GR) LUAD cells (IC50 at 2.0 µM). Significantly, treatment with PPI at 1.0 µM resensitized the resistant cells to gefitinib. Moreover, cell-derived xenograft experiments revealed that the combination of PPI and gefitinib overcame gefitinib resistance. The phospho-RTK array and immunoblotting analyses showed PPI significant inhibition of the VEGFR2/p38 pathway. In addition, molecular docking suggested the interaction between PPI and HIF-1α. Mechanistically, PPI reduced the protein expression of HIF-1α in both normoxia and hypoxia conditions by triggering HIF-1α degradation. Moreover, HIF-1α protein but not mRNA level was elevated in gefitinib-resistant LUAD. We further demonstrated that PPI considerably facilitated the binding of HIF-1α to VHL. CONCLUSIONS: We present a novel discovery demonstrating that PPI effectively counteracts gefitinib resistance in LUAD by modulating the VEGF/VEGFR2/p38 pathway. Mechanistic investigations unveil that PPI facilitates the formation of the HIF-1α /VHL complex, leading to the degradation of HIF-1α and subsequent inhibition of angiogenesis. These findings uncover a previously unidentified mechanism governing HIF-1α expression in reaction to PPI, providing a promising method for therapeutic interventions targeting EGFR-TKI resistance in LUAD.

Frailty in the Elderly is Associated with an Increased Risk of Depression: A Systematic Review and Meta-Analysis.

Objective: The aim was to systematically review the association between depression and frailty in the elderly. Methods: Databases such as PubMed, Web of Science, Embase, and Scopus were searched for articles on the link between the risk of depression and frailty since the creation of the databases to September 1, 2023. A pair of investigators collaboratively conducted the screening, collected data, and evaluated the potential for bias in the included studies. R software was utilized for meta-synthesis. Results: Eight cohort studies comprising 13 043 participants and 14 854 senior individuals with depression were included. The meta-analysis showed that there was a significant connection regarding frailty and the incidence of depression among the elderly (Risk Ratio [RR] = 3.26, 95% Confidence Interval [CI]: 1.68-6.32). Subgroup evaluations showed that there was no association between frailty and depression in the community-dwelling elderly (RR = 2.28, 95% CI: 0.644-8.102) and in the elderly patients with depression assessed by Center for Epidemiological Studies Depression Scale (CES-D) (RR = 5.82, 95% CI: 0.481-70.526). Conclusion: Frailty is correlated with the risk of depression in the elderly. Frailty is a contributing factor to depression in the elderly.