Novel analgesic peptide derived from Cinobufacini injection suppressing inflammation and pain via ERK1/2/COX-2 pathway.

Inflammatory pain is a chronic pain caused by peripheral tissue inflammation, seriously impacting the patient's life quality. Cinobufacini injection, as a traditional Chinese medicine injection preparation, shows excellent efficacy in anti-inflammatory and analgesic treatment in patients with advanced tumors. In this study, a novel analgesic peptide CI5 with anti-inflammatory and analgesic bio-functions that naturally presents in Cinobufacini injection and its regulatory mechanism are reported. Our results showed that the administration of CI5 significantly relieved the pain of mice in the acetic acid twisting analgesic model and formalin inflammatory pain model. Furthermore, CI5 effectively reduced the inflammatory cytokines (IL-6, TNF-α and IL-1ß) and inflammatory mediator (PGE2) expressions, and prevented the carrageenan-induced paw edema in mice. Further LC-MS/MS results showed the anti-inflammatory and analgesic bio-functions of CI5 depended on its interaction with the Rac-2 protein upstream of ERK1/2 and the inflammatory signaling pathway (ERK1/2/COX-2 axis). In summary, CI5, as a novel natural candidate identified from Cinobufacini injection, showed substantial clinical promise for inflammatory pain treatments.

Adipose-Derived exosome from Diet-Induced-Obese mouse attenuates LPS-Induced acute lung injury by inhibiting inflammation and Apoptosis: In vivo and in silico insight.

BACKGROUND: Acute lung injury (ALI) is a severe clinical condition in the intensive care units, and obesity is a high risk of ALI. Paradoxically, obese ALI patients had better prognosis than non-obese patients, and the mechanism remains largely unknown. METHODS: Mouse models of ALI and diet-induced-obesity (DIO) were used to investigate the effect of exosomes derived from adipose tissue. The adipose-derived exosomes (ADEs) were isolated by ultracentrifugation, and the role of exosomal miRNAs in the ALI was studied. RESULTS: Compared with ADEs of control mice (C-Exo), ADEs of DIO mice (D-Exo) increased survival rate and mitigated pulmonary lesions of ALI mice. GO and KEGG analyses showed that the target genes of 40 differentially expressed miRNAs between D-Exo and C-Exo were mainly involved with inflammation, apoptosis and cell cycle. Furthermore, the D-Exo treatment significantly decreased Ly6G+ cell infiltration, down-regulated levels of pro-inflammatory cytokines (IL-6, IL-12, TNF-α, MCP-1) and chemokines (IL-8 and MIP-2), reduced pulmonary apoptosis and arrest at G0G1 phase (P < 0.01). And the protective effects of D-Exo were better than those of C-Exo (P < 0.05). Compared with the C-Exo mice, the levels of miR-16-5p and miR-335-3p in the D-Exo mice were significantly up-regulated (P < 0.05), and the expressions of IKBKB and TNFSF10, respective target of miR-16-5p and miR-335-3p by bioinformatic analysis, were significantly down-regulated in the D-Exo mice (P < 0.05). CONCLUSIONS: Exosomes derived from adipose tissue of DIO mice are potent to attenuate LPS-induced ALI, which could be contributed by exosome-carried miRNAs. Our data shed light on the interaction between obesity and ALI.

Clinical efficacy and identification of factors confer resistance to afatinib (tyrosine kinase inhibitor) in EGFR-overexpressing esophageal squamous cell carcinoma.

Epidermal growth factor receptor (EGFR) is reportedly overexpressed in most esophageal squamous cell carcinoma (ESCC) patients, but anti-EGFR treatments offer limited survival benefits. Our preclinical data showed the promising antitumor activity of afatinib in EGFR-overexpressing ESCC. This proof-of-concept, phase II trial assessed the efficacy and safety of afatinib in pretreated metastatic ESCC patients (n = 41) with EGFR overexpression (NCT03940976). The study met its primary endpoint, with a confirmed objective response rate (ORR) of 39% in 38 efficacy-evaluable patients and a median overall survival of 7.8 months, with a manageable toxicity profile. Transcriptome analysis of pretreatment tumors revealed that neurotrophic receptor tyrosine kinase 2 (NTRK2) was negatively associated with afatinib sensitivity and might serve as a predictive biomarker, irrespective of EGFR expression. Notably, knocking down or inhibiting NTRK2 sensitized ESCC cells to afatinib treatment. Our study provides novel findings on the molecular factors underlying afatinib resistance and indicates that afatinib has the potential to become an important treatment for metastatic ESCC patients.

Highly Stretchable Double Network Ionogels for Monitoring Physiological Signals and Detecting Sign Language.

At the heart of the non-implantable electronic revolution lies ionogels, which are remarkably conductive, thermally stable, and even antimicrobial materials. Yet, their potential has been hindered by poor mechanical properties. Herein, a double network (DN) ionogel crafted from 1-Ethyl-3-methylimidazolium chloride ([Emim]Cl), acrylamide (AM), and polyvinyl alcohol (PVA) was constructed. Tensile strength, fracture elongation, and conductivity can be adjusted across a wide range, enabling researchers to fabricate the material to meet specific needs. With adjustable mechanical properties, such as tensile strength (0.06-5.30 MPa) and fracture elongation (363-1373%), this ionogel possesses both robustness and flexibility. This ionogel exhibits a bi-modal response to temperature and strain, making it an ideal candidate for strain sensor applications. It also functions as a flexible strain sensor that can detect physiological signals in real time, opening doors to personalized health monitoring and disease management. Moreover, these gels' ability to decode the intricate movements of sign language paves the way for improved communication accessibility for the deaf and hard-of-hearing community. This DN ionogel lays the foundation for a future in which e-skins and wearable sensors will seamlessly integrate into our lives, revolutionizing healthcare, human-machine interaction, and beyond.

Photothermally responsive graphene hybrid dry powders for diabetic wound healing.

The treatment of diabetic wounds remains a significant challenge in the medical field. In this study, we present a novel approach using photothermally responsive graphene hybrid dry powders for the treatment of diabetic wounds. These powders, derived from polyacrylic acid (PAA) and polyethyleneimine (PEI), exhibit rapid water absorption at the interface, leading to thein situformation of physically crosslinked hydrogels due to interactions between polymers. Furthermore, by incorporating graphene into the PAA/PEI powder mixture, we establish a multifunctional platform with capabilities such as photothermal antibacterial effects and drug release. Given the outstanding performance of this hybrid material, we demonstrate its potential in wound healing by incorporating the tumor necrosis factor-alpha (TNF-α) inhibitor Etanercept into the PAA/PEI powder. This intervention resulted in a significant improvement in the wound healing process in diabetic rats, as evidenced by the downregulation of inflammatory factors, promotion of collagen deposition, and enhanced vascularization. These remarkable attributes underscore the enormous potential value of the presented hydrogel patches in the field of biomedicine.

Prognostic and predictive value of angiogenesis-associated serum proteins for immunotherapy in esophageal cancer.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have significantly improved patient survival in multiple cancers. However, therapy response in esophageal cancer is limited to subgroups of patients and clinically useful predictive biomarkers are lacking. METHODS: We collected a series of plasma samples from 91 patients with esophageal cancer before and after ICI treatment. The Olink Immuno-Oncology panel (92 proteins) with proximity extension assays was used to detect the dynamic changes in plasma and potential biomarkers associated with treatment outcomes. We screened all survival-related proteins and established a risk score model to better predict the prognosis and treatment response in patients with esophageal cancer immunotherapy. RESULTS: We found that 47 out of 92 quantified proteins had significant changes in plasma levels during ICI treatment (p<0.050), and these changed proteins were involved in immune-related reactions, such as intercellular adhesion and T-cell activation. Notably, the baseline levels of three angiogenesis-related proteins (IL-8, TIE2, and HGF) were significantly associated with the survival outcomes of patients treated with ICIs (p<0.050). According to these prognostic proteins, we established an angiogenesis-related risk score, which could be a superior biomarker for ICI response prediction. In addition, antiangiogenic therapy combined with ICIs significantly improved overall survival compared with ICI monotherapy (p=0.044). CONCLUSIONS: An angiogenesis-related risk score based on three proteins (IL-8, TIE2, and HGF) could predict ICI response and prognosis in patients with esophageal cancer, which warrants verification in the future. Our study highlights the potential application of combining ICIs and antiangiogenic therapy and supports Olink plasma protein sequencing as a liquid biopsy method for biomarker exploration.

High-efficiency and sustainable sodium humate aerogel evaporator for solar steam generation.

The utilization of solar interface evaporation technology (SIET) for freshwater production from seawater and sewage is a sustainable, green, viable, and promising approach. However, the absorption rate of sunlight, evaporation rates, and high costs still pose large-scale solar steam generation. In this paper, a novel aerogel (named SAS) was prepared by graft copolymerization with sodium alginate (SA), acrylic acid (AA) and sodium humate (SH) in aqueous solution, using N, N'-Methylenebisacrylamide (MBA) as crosslinker and ammonium persulfate (APS) as initiator, which has high light absorption (90 %), high porosity (87.96 %), superhydrophilicity (35 ms), low thermal conductivity (0.23 W m-1 k-1). The evaporation rate of SAS aerogel can reach up to 1.66 kg m-2h-1 under 1 kW m-2 light intensity, and the reusability and reliability of SAS aerogel are verified by 10 cycles of experiments. The utilization of this SAS aerogel holds significant implications for the design and fabrication of cost-effective, high-performance solar steam evaporation systems, thereby offering promising solutions to address global freshwater shortages and enhance wastewater treatment efficiency.

Cadherin-5 facilitated the differentiation of human induced pluripotent stem cells into sinoatrial node-like pacemaker cells by regulating ß-catenin.

Our study was conducted to investigate whether cadherin-5 (CDH5), a vascular endothelial cell adhesion glycoprotein, could facilitate the differentiation of human induced pluripotent stem cells (hiPSCs) into sinoatrial node-like pacemaker cells (SANLPCs), following previous findings of silk-fibroin hydrogel-induced direct conversion of quiescent cardiomyocytes into pacemaker cells in rats through the activation of CDH5. In this study, the differentiating hiPSCs were treated with CDH5 (40 ng/mL) between Day 5 and 7 during cardiomyocytes differentiation. The findings in the present study demonstrated that CDH5 stimulated the expression of pacemaker-specific markers while suppressing markers associated with working cardiomyocytes, resulting in an increased proportion of SANLPCs among hiPSCs-derived cardiomyocytes (hiPSC-CMs) population. Moreover, CDH5 induced typical electrophysiological characteristics resembling cardiac pacemaker cells in hiPSC-CMs. Further mechanistic investigations revealed that the enriched differentiation of hiPSCs into SANLPCs induced by CDH5 was partially reversed by iCRT14, an inhibitor of ß-catenin. Therefore, based on the aforementioned findings, it could be inferred that the regulation of ß-catenin by CDH5 played a crucial role in promoting the enriched differentiation of hiPSCs into SANLPCs, which presents a novel avenue for the construction of biological pacemakers in forthcoming research.

A "Win-Win" Strategy to Modify Co/C Foam with Carbon Microspheres for Enhanced Dielectric Loss and Microwave Absorption Characteristics.

3D carbon foams have demonstrated their superiority in the field of microwave absorption recently, but the preparation processes of traditional graphene foams are complicated, while some novel carbon foams usually suffer from inadequate dielectric property. Herein, a simple "win-win" strategy is demonstrated to synchronously realize the construction of 3D Co/C foam and its surface decoration with carbon microspheres. Therein, the host Co/C foams and guest carbon microspheres interact with each other, resulting in the improvement of the dispersity of carbon microspheres and Co nanoparticles. The bilaterally synergistic effect can effectively enhance the interfacial polarization and conductive loss of these obtained samples. Electromagnetic analysis reveals that the optimized sample with moderate carbon microsphere content (about 33.5 wt%) displays a widened maximum effective absorption bandwidth of 5.2 GHz and a consolidated reflection loss intensity of -67.6 dB. Besides, the microwave absorption enhancement mechanisms are investigated and discussed in detail. It is believed that this work provides valuable ideas for the development of 3D-foam-based microwave absorbing materials for practical applications.

Obesity Paradox in Lung Diseases: What Explains It?

BACKGROUND: Obesity is a globally increasing health problem that impacts multiple organ systems and a potentially modifiable risk factor for many diseases. Obesity has a significant impact on lung function and is strongly linked to the pathophysiology that contributes to lung diseases. On the other hand, reports have emerged that obesity is associated with a better prognosis than for normal weight individuals in some lung diseases, including pneumonia, acute lung injury/acute respiratory distress syndrome, chronic obstructive pulmonary disease, and lung cancer. The lesser mortality and better prognosis in patients with obesity is known as obesity paradox. While obesity paradox is both recognized and disputed in epidemiological studies, recent research has suggested possible mechanisms. SUMMARY: In this review, we attempted to explain and summarize these factors and mechanisms, including immune response, pulmonary fibrosis, lung function, microbiota, fat and muscle reserves, which are significantly altered by obesity and may contribute to the obesity paradox in lung diseases. We also discuss contrary literature that attributes the "obesity paradox" to confounding. KEY MESSAGES: The review will illustrate the possible role of obesity in the prognosis or course of lung diseases, leading to a better understanding of the obesity paradox and provide hints for further basic and clinical research in lung diseases.

Panaxynol ameliorates cardiac ischemia/reperfusion injury by suppressing NLRP3-induced pyroptosis and apoptosis via HMGB1/TLR4/NF-κB axis.

BACKGROUND AND PURPOSE: Panaxynol (PNN) is a common natural minor component in Umbelliferae plants. Many clinical studies have shown that PNN exhibits nutritional value and anti-inflammatory and other pharmacological activities. However, whether PNN can mediate cardiac ischemia/reperfusion injury (IRI) remains unclear. Here, we aimed to determine the potential effects of PNN on myocardial IRI. METHODS: Myocardial IRI was stimulated in a mouse IRI model, and neonatal rat ventricle myocytes (NRVMs) were exposed to hypoxia/reoxygenation to construct in an vitro model. Myocardial infarction size, myocardial tissue injury, myocardial apoptotic index, hemodynamic monitoring, pyroptosis-related proteins, cardiac enzyme activities and inflammatory responses were examined to assess myocardial injury. RESULTS: It was found that PNN administration markedly reduced myocardial infarct size and apoptosis, suppressed myocardial damage and cell pyroptosis, attenuated pro-inflammatory cytokines and neutrophil infiltration via NLRP3 inhibitor. More importantly, PNN treatment remarkably decreased the expression of TLR4/NF-κB pathway-associated proteins and NLRP3-related pyroptosis proteins by HMGB1 inhibitor. PNN also enhanced cell viability, reduced cardiac enzyme activities, suppressed apoptosis and attenuated inflammation in the isolated NRVMs. Furthermore, vitro studies indicated that MCC950 (a NLRP3 inhibitor) increased the anti-inflammatory and anti-apoptotic effects of PNN on NRVMs via HMGB1/TLR4 pathway. CONCLUSION: To sum up, our results demonstrate that PNN exhibits a cardioprotective effect by modulating heart IRI-induced apoptosis and pyroptosis via HMGB1/TLR4/NF-κB pathway, thereby inhibiting NLRP3 inflammasome stimulation.

Living microecological hydrogels for wound healing.

Chronic hard-to-heal wounds draw great attention worldwide, as their treatments are limited by infections and hypoxia. Inspired by the natural oxygen production capacity of algae and the competitive advantage of beneficial bacteria over other microbes, we presented a living microecological hydrogel (LMH) with functionalized Chlorella and Bacillus subtilis encapsulation to realize continuous oxygen delivery and anti-infections for promoting chronic wound healing. As the hydrogel consisted of thermosensitive Pluronic F-127 and wet-adhesive polydopamine, the LMH could keep liquid at a low temperature while quickly solidifying and tightly adhering to the wound bed. It was demonstrated that by optimizing the proportion of the encapsulated microorganism, the Chlorella could continuously produce oxygen to relieve hypoxia and support the proliferation of B. subtilis, while B. subtilis could eliminate the colonized pathogenic bacteria. Thus, the LMH substantially promoted the healing of infected diabetic wounds. These features make the LMH valuable for practical clinical applications.

The method of sinus node-like pacemaker cells from human induced pluripotent stem cells by BMP and Wnt signaling.

The embryonic development of sinus nodes (SAN) is co-regulated by multiple signaling pathways. Among these, the bone morphogenetic protein (BMP) and Wnt signaling pathways are involved in the development of SAN. In this study, the effects of BMP and Wnt signaling on the differentiation of SAN-like pacemaker cells (SANLPCs) were investigated. Human induced pluripotent stem cells (hiPSCs) were divided into four groups: control, BMP4, CHIR-3, and BMP4 + CHIR (CHIR: a Wnt signaling activator). The samples were tested at day (D) 15 of differentiation. The final protocol for the activation of BMP signaling at D0-D3 and reactivation of Wnt signaling at D5-D7 in the differentiation of hiPSCs were determined. The results showed that the mRNA levels of pacemaker markers (TBX18, SHOX2, TBX3, HCN4, and HCN1) were higher in the BMP4 + CHIR group than in the control group, and working myocardial genes were downregulated. The immunofluorescence assay revealed that the expression of SHOX2 and HCN4 increased in the BMP4 + CHIR group compared to that in the other groups. In addition, the results of patch clamps revealed that a funny current of higher density and typical SAN action potentials were recorded, except in the control group, in which the L-type calcium current was higher in the BMP4 + CHIR group than in the other groups. Finally, the proportion of SANLPCs (cTnT+ NKX2.5-) was further enhanced by the combination of BMP4 and CHIR treatment. In summary, the combination of BMP and Wnt signaling promotes the differentiation of SANLPCs from hiPSCs.

Functionalized Cycloolefin Ligand as a Solution to Ortho-Constraint in the Catellani-Type Reaction.

The Catellani reaction, i.e., the Pd/norbornene (NBE) catalysis, has been evolved into a versatile approach to multisubstituted arenes via the ortho-functionalization/ipso-termination process of a haloarene. Despite significant advances over the past 25 years, this reaction still suffered from an intrinsic limitation in the substitution pattern of haloarene, referred to as "ortho-constraint". When an ortho substituent is absent, the substrate often fails to undergo an effective mono ortho-functionalization process, and either ortho-difunctionalization products or NBE-embedded byproducts predominate. To tackle this challenge, structurally modified NBEs (smNBEs) have been developed, which were proved effective for the mono ortho-aminative, -acylative, and -arylative Catellani reactions of ortho-unsubstituted haloarenes. However, this strategy is incompetent for solving the ortho-constraint in Catellani reactions with ortho-alkylation, and to date there lacks a general solution to this challenging but synthetically useful transformation. Recently, our group developed the Pd/olefin catalysis, in which an unstrained cycloolefin ligand served as a covalent catalytic module to enable the ortho-alkylative Catellani reaction without NBE. In this work, we show that this chemistry could afford a new solution to ortho-constraint in the Catellani reaction. A functionalized cycloolefin ligand bearing an amide group as the internal base was designed, which allowed for mono ortho-alkylative Catellani reaction of iodoarenes suffering from ortho-constraint before. Mechanistic study revealed that this ligand is capable of both accelerating the C-H activation and inhibiting side reactions, which accounts for its superior performance. The present work showcased the uniqueness of the Pd/olefin catalysis as well as the power of rational ligand design in metal catalysis.

Tubeimoside I Ameliorates Doxorubicin-Induced Cardiotoxicity by Upregulating SIRT3.

Cardiotoxicity linked to doxorubicin (DOX) is primarily caused by inflammation, oxidative stress, and apoptosis. The role of tubeimoside I (TBM) in DOX-induced cardiotoxicity remains ambiguous, despite growing evidence that it could reduce inflammation, oxidative stress, and apoptosis in various diseases. This study was designed to investigate the role of TBM in DOX-induced cardiotoxicity and uncover the underlying mechanisms. H9c2 cell line and C57BL/6 mice were used to construct an in vitro and in vivo model of DOX-induced myocardial injury, respectively. We observed that DOX treatment provoked inflammation, oxidative stress, and cardiomyocyte apoptosis, which were significantly alleviated by TBM administration. Mechanistically, TBM attenuated DOX-induced downregulation of sirtuin 3 (SIRT3), and SIRT3 inhibition abrogated the beneficial effects of TBM both in vitro and in vivo. In conclusion, TBM eased inflammation, oxidative stress, and apoptosis in DOX-induced cardiotoxicity by increasing the expression of SIRT3, suggesting that it holds great promise for treating DOX-induced cardiac injury.

The paired-related homeobox protein 1 promotes cardiac fibrosis via the Twist1-Prrx1-tenascin-C loop.

Cardiac fibrosis is a common pathology in the advanced stage of cardiovascular diseases, which leads to cardiac systolic and diastolic dysfunction. It is important to prevent cardiac fibrosis during myocardial injury. The transcription factor Prrx1 is involved in cancer-associated fibrosis and other organ fibrosis. However, the role and mechanism of Prrx1 in cardiac fibrosis deserves further exploration. We identified that overexpressed Prrx1 promoted the proliferation and migration of cardiac fibroblasts, and transform cardiac fibroblasts to myofibroblasts in vitro. We demonstrated that the expression of Prrx1 is upregulated in TGF-ß1-treated fibroblasts. And silencing Prrx1 could attenuate cardiac fibrosis induced by TGF-ß1 in vitro. In addition, a Twist1-paired-related homeobox 1 (Prrx1)-tenascin-C (TNC) positive feedback loop (PFL) combined with Twist1, Prrx1, and TNC activated fibroblasts, which was the mechanism the Prrx1 in cardiac fibrosis. In conclusion, our findings showed that the deficiency of Prrx1 attenuated cardiac fibrosis in vitro and reveal a novel Twist1-Prrx1-TNC PFL in the regulation of cardiac fibrosis.

Maresin1 ameliorates ventricular remodelling and arrhythmia in mice models of myocardial infarction via NRF2/HO-1 and TLR4/NF-kB signalling.

Ventricular remodelling and arrhythmias are the main factors that affect the quality of life of patients with myocardial infarction (MI). Maresin 1 (Mar1) is associated with antioxidative and anti-inflammatory effects. However, the mechanisms underlying the effects of Mar1 in MI remain unclear. In this study, we aimed to explore the role and potential mechanisms of Mar1 in a mouse model of MI. The mice were divided into four groups: Sham, Sham + Mar1, MI, and MI + Mar1. In the MI groups, the left anterior descending coronary artery of the mice was ligated for 28 days, while this ligation was not conducted in the Sham groups. Mar1 was injected into mice in the Sham + Mar1 and MI + Mar1 groups. H9c2 cells were cultured in vitro under hypoxic conditions for MI models, and then Mar1 was added to the medium for 24 h. Our data demonstrated that Mar1 activated NRF2/HO-1 signalling and inhibited TLR4/NF-kB signalling in MI. These activities lead to inhibition of the release of inflammatory cytokines, reduction of myocardial apoptosis and interstitial fibrosis, decreased susceptibility to ventricular arrhythmias, and improved cardiac function. Similarly, our in vitro analyses showed that Mar1 inhibited inflammatory signalling by enhancing the antioxidative function of NRF2/HO-1 signalling. Furthermore, Mar1 inhibited hypoxia-activated apoptosis in cardiomyocytes. Taken together, our data demonstrate that Mar1 ameliorates ventricular remodelling and arrhythmias in mice post-MI via the activation of NRF2/HO-1 signalling and inhibition of the TLR4/NF-kB signalling pathways.

Physical and Chemical Cues at the Nano-Bio Interface for Immunomodulation.

Immunomodulation has made remarkable progress in fighting infectious disease and cancer. Conventionally, immunomodulation largely relies on chemical/biochemical agents, which, unfortunately, suffer from sever off-target adverse effects. Recent insights into nano-bio interactions suggest that nanomaterials can directly participate in immunomodulation. A range of physical and chemical cues at the nano-bio interface have been harnessed to regulate diverse immuno-signaling for disease control and treatment. In this Minireview, we summarize recent studies on the physical and chemical cues enabled by intrinsic nanomaterials to trigger immunological signaling. First, we discuss physical cues mediated by surface topography, hydrophobicity, charge, and heat at the nano-bio interface for immunomodulation. Then, various nanomaterials enabled chemical cues, such as metal species and oxidative species are outlined. Finally, our perspectives on challenges and possible future directions are provided.