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The effects of chickpea protein (CP) modified by heating and/or high-pressure homogenization (HPH) on the gelling properties of myofibrillar protein under reduced phosphate conditions (5 mM sodium triphosphate, STPP) were investigated. The results showed that heating and HPH dual-modified CP could decrease the cooking loss by 29.57 %, elevate the water holding capacity by 17.08 %, and increase the gel strength by 126.88 %, which conferred myofibrillar protein with gelation performance comparable with, or even surpassing, that of the high-phosphate (10 mM STPP) control. This gelation behavior improvement could be attributed to enhanced myosin tail-tail interactions, decreased myosin thermal stability, elevated trans-gauche-trans disulfide conformation, strengthened hydrophobic interactions and hydrogen bonding, the uncoiling of α-helical structures, the formation of well-networked myofibrillar protein gel, and the disulfide linkages between the myosin heavy chain, actin, and CP subunits. Therefore, the dual-modified CP could be a promising phosphate alternative to develop healthier meat products.

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Radical cascade cyclizations of N-cyanamide alkenes have been developed for the divergent synthesis of pyrroloquinazolinones bearing azido, alkenyl, and nitro groups by controlling the reaction conditions. The reaction temperature and the loading of the base play important roles in the different reaction pathways. These reactions are characterized by wide functional group compatibility and mild conditions.

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Introduction: Goose astrovirus (GAstV) is a newly emerging pathogen that is currently widespread among geese, causing visceral gout and leading to substantial gosling mortalities, posing a severe threat to the waterfowl industry. GAstV II is the predominant epidemic strain, characterized by its high morbidity and mortality rate. Consequently, there is an urgent necessity to develop an effective diagnostic approach to control the dissemination of GAstV II, particularly in clinical farms with limited laboratory resources. Methods: In this study, a novel multi-enzyme isothermal rapid amplification (MIRA) and lateral flow dipstick (LFD) combined assay was developed. Different primers designed specific targeting a highly conserved region within the viral RdRp gene for the detection of GAstV II. Primers optimized and MIRA-LFD assay analyzed its performance regarding limits of detection, specificity, and efficiency of detection. Results: The developed MIRA amplification is conducted at a constant temperature and accomplished within 10 minutes. Subsequent naked-eye observation of the LFD strips merely takes 5 minutes. The established MIRA-LFD method exhibits high specificity, with no cross-reaction with other pathogens and attains a detection sensitivity of 1 copy/µl, which is consistent with the reverse transcription quantitative PCR (RT-qPCR) assay. Further evaluation with clinical samples indicates that the accuracy of this MIRA-LFD method correlates well with RT-qPCR for the detection of GAstV II. Conclusion: In summary, the convenience, sensitivity, and rapidity of this newly developed detection method offer a significant advantage for on-site diagnosis of GAstV II.

Asunto(s)

Infecciones por Astroviridae , Gansos , Técnicas de Diagnóstico Molecular , Técnicas de Amplificación de Ácido Nucleico , Enfermedades de las Aves de Corral , Sensibilidad y Especificidad , Animales , Infecciones por Astroviridae/diagnóstico , Infecciones por Astroviridae/veterinaria , Infecciones por Astroviridae/virología , Gansos/virología , Técnicas de Amplificación de Ácido Nucleico/métodos , Técnicas de Diagnóstico Molecular/métodos , Enfermedades de las Aves de Corral/diagnóstico , Enfermedades de las Aves de Corral/virología , Avastrovirus/genética , Avastrovirus/aislamiento & purificación , Cartilla de ADN/genética , ARN Viral/genética

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This case report describes a patient in their 40s with hypertension who exhibited presyncopal symptoms following an exercise test.

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Targeting cellular senescence and Senescence Associated Secretory Phenotype (SASP) through autophagy has emerged as a promising intervertebral disc (IVD) degeneration (IDD) treatment strategy in recent years. This study aimed to clarify the role and mechanism of autophagy in preventing IVD SASP. Methods involved in vitro experiments with nucleus pulposus (NP) tissues from normal and IDD patients, as well as an in vivo IDD animal model. GATA4's regulatory role in SASP was validated both in vitro and in vivo, while autophagy modulators were employed to assess their impact on GATA4 and SASP. Transcriptomic sequencing identified Oxidized low-density lipoprotein receptor 1 (OLR1) as a key regulator of autophagy and GATA4. A series of experiments manipulated OLR1 expression to investigate associated effects. Results demonstrated significantly increased senescent NP cells (NPCs) and compromised autophagy in IDD patients and animal models, with SASP closely linked to IDD progression. The aged disc milieu impeded autophagic GATA4 degradation, leading to elevated SASP expression in senescent NPCs. Restoring autophagy reversed senescence by degrading GATA4, hence disrupting the SASP cascade. Moreover, OLR1 was identified for its regulation of autophagy and GATA4 in senescent NPCs. Silencing OLR1 enhanced autophagic activity, suppressing GATA4-induced senescence and SASP expression in senescent NPCs. In conclusion, OLR1 was found to control autophagy-GATA4 and SASP, with targeted OLR1 inhibition holding promise in alleviating GATA4-induced senescence and SASP expression while delaying extracellular matrix degradation, offering a novel therapeutic approach for IDD management.

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BACKGROUND: Depression is a significant global health concern, projected to become the leading disease burden. Vascular burden has been implicated in the pathogenesis of depression. Conversely, whether depression independently influences the process of vascular aging is unknown. This study aims to investigate the mutual relationship between vascular age and depression. METHODS: Utilizing data from the National Health and Nutrition Examination Survey (NHANES), the study included 27,764 participants after exclusions. Depression was assessed using the Patient Health Questionnaire (PHQ-9). Vascular aging was assessed by estimated pulse wave velocity (ePWV) and the heart age/vascular age (HVA) based on Framingham Risk Score (FRS). The study employed weighted logistic regression and Cox proportional hazards models to analyze the association between vascular age and depression as well as its mortality risk. Mendelian randomization was utilized to explore the causal associations. RESULTS: Individuals with depression exhibited a higher risk of an advanced vascular age over their chronological age. Mendelian randomization analysis indicated a causal relationship between depression and arterial stiffness. A significant association was found between vascular age and depression incidence with odds ratios ranging from 1.10 to 1.38. As vascular age increased, the risk of mortality in individuals with depression increased by 22 % and 46 %, respectively. LIMITATIONS: The study design limits the exploration of the dynamic relationship between changes in vascular age and depression due to the single timepoint measurement. CONCLUSION: This study highlights the bidirectional relationship between depression and vascular age. Vascular age is a significant biomarker for the risk and prognosis of depression, while depression may contribute to vascular aging, which underscores the importance of integrated strategies for managing both vascular health and depression.

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This study employs an optimized and environmentally friendly method to extract and purify chondroitin sulfate (CS) from bovine nasal cartilage using enzymatic hydrolysis, ethanol precipitation, and DEAE Sepharose Fast Flow column chromatography. The extracted CS, representing 44.67 % ± 0.0016 of the cartilage, has a molecular weight of 7.62 kDa. Characterization through UV, FT-IR, NMR spectroscopy, and 2-aminoacridone derivatization HPLC revealed a high content of sulfated disaccharides, particularly ΔDi4S (73.59 %) and ΔDi6S (20.61 %). Interaction studies with bovine serum albumin (BSA) using fluorescence spectroscopy and molecular docking confirmed a high-affinity, static quenching interaction with a single binding site, primarily mediated by van der Waals forces and hydrogen bonding. The interaction did not significantly alter the polarity or hydrophobicity of BSA aromatic amino acids. These findings provide a strong foundation for exploring the application of CS in tissue engineering and drug delivery systems, leveraging its unique interaction with BSA for targeted delivery and enhanced efficacy.

Asunto(s)

Sulfatos de Condroitina , Cartílagos Nasales , Albúmina Sérica Bovina , Animales , Bovinos , Sulfatos de Condroitina/química , Simulación del Acoplamiento Molecular , Peso Molecular , Cartílagos Nasales/química , Cartílagos Nasales/metabolismo , Unión Proteica , Albúmina Sérica Bovina/química

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Pulmonary hypertension is a pathophysiologic manifestation of a heterogeneous group of diseases, with the main pathophysiologic mechanisms being persistent pulmonary vasoconstriction and irreversible vascular remodeling. The impact significantly affects the prognosis of patients with pulmonary hypertension. If it is not treated and intervened in time, it may lead to right ventricular failure and further endanger the patient's life. Within the past decade or so, nebulized inhalation therapy is considered to have advantages in the treatment of pulmonary hypertension as a safe, limited, and rapid therapy, for example, inhaled vasodilators (prostate analogs, nitroglycerin, carbon monoxide analogs sildenafil, and nitroprusside), inhaled anti-inflammatory and antiproliferative agents (simvastatin, and selatinib), and inhaled peroxides (levocetirizine) have been recognized as emerging therapeutic approaches in the treatment of pulmonary hypertension as emerging therapeutic approaches. Therefore, this article provides a brief review of recent advances in the potential of nebulized inhaled vasodilators, anti-inflammatory and antiproliferative agents, and anti-peroxides for the treatment of pulmonary hypertension, with the aim of providing different therapeutic options for the treatment of pulmonary hypertension, enhancing the quality of survival, alleviating symptoms, and improving the prognosis of patients with this condition.

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Nebulizadores y Vaporizadores , Vasodilatadores , Humanos , Administración por Inhalación , Vasodilatadores/administración & dosificación , Antiinflamatorios/administración & dosificación , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/fisiopatología , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Hipertensión Arterial Pulmonar/fisiopatología

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A photocatalyst-free and EDA complex-enabled radical cascade cyclization reaction of inactive alkenes with bromodifluoroacetamides was reported for the divergent synthesis of fluorine-containing tetralones and quinazolinones. In this transformation, persulfates as electron donors and difluoro bromamide as electron acceptors generate the EDA complex. This is a promising photochemical method with advantages such as mild reaction conditions, simple operation, being metal-free, and excellent functional group tolerance.

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Bio-cement is a green and energy-saving building material that has attracted much attention in the field of ecological environment and geotechnical engineering in recent years. The aim of this study is to investigate the use of bio-cement (enzyme-induced calcium carbonate precipitation-EICP) in combination with admixtures for the improvement of desert sands, which can effectively improve the mechanical properties of desert sands and is particularly suitable for sand-rich countries. In addition, the suitability of tap water in bio-cement was elucidated and the optimum ratio of each influencing factor when tap water is used as a solvent was derived. The results showed that peak values of unconfined compressive strength (maximum increase of about 130 times), shear strength (increase of 27.09%), calcium carbonate precipitation value (increase of about 4.39 times), and permeability (decrease of about 93.72 times) were obtained in the specimens modified by EICP combined with admixture as compared to the specimens modified by EICP only. The incorporation of skimmed milk powder, though significantly increasing the strength, is not conducive to cost control. The microscopic tests show that the incorporation of admixtures can provide nucleation sites for EICP, thus improving the properties of desert sand. This work can provide new research ideas for cross-fertilization between the disciplines of bio-engineering, ecology, and civil engineering.

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Carbonato de Calcio , Arena , Arena/química , Carbonato de Calcio/química , Materiales de Construcción , Clima Desértico , Fuerza Compresiva

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Detailed data on safety associated with drug-drug interactions (DDIs) between Linezolid (LZD) and other antibiotics are limited. The aim of this study was to investigate the safety signals related to these DDIs and to provide a reference for clinically related adverse drug event monitoring. Adverse event (AE) information from 1 January 2004 to 16 June 2022 of the target antibiotics including LZD using alone or in combination with LZD was extracted from the OpenVigil FDA data platform for safety signal analysis. The combined risk ratio model, reporting ratio method, Ω shrinkage measure model, and chi-square statistics model were used to analyze the safety signals related to DDIs. Meanwhile, we evaluated the correlation and the influence of sex and age between the drug(s) and the target AE detected. There were 18991 AEs related to LZD. There were 2293, 1726, 4449, 821, 2431, 1053, and 463 AE reports when LZD was combined with amikacin, voriconazole, meropenem, clarithromycin, levofloxacin, piperacillin-tazobactam, and azithromycin, respectively. Except for azithromycin, there were positive safety signals related to DDIs between LZD and these antibiotics. These DDIs might influence the incidence of 13, 16, 7, 7, 6, and 15 types of AEs, respectively, and is associated with higher reporting rates of AEs compared with use alone. Moreover, sex and age might influence the occurrence of AEs. We found that the combinations of LZD and other antibiotics are related to multiple AEs, such as hepatotoxicity, drug resistance and electrocardiogram QT prolonged, but further research is still required to investigate their underlying mechanisms. This study can provide a new reference for the safety monitoring of LZD combined with other antibiotics in clinical practice.

Asunto(s)

Sistemas de Registro de Reacción Adversa a Medicamentos , Antibacterianos , Interacciones Farmacológicas , Linezolid , Humanos , Linezolid/efectos adversos , Masculino , Antibacterianos/efectos adversos , Femenino , Persona de Mediana Edad , Adulto , Anciano , Sistemas de Registro de Reacción Adversa a Medicamentos/estadística & datos numéricos , Adolescente , Adulto Joven , Niño , Preescolar , Lactante , Anciano de 80 o más Años , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Monitoreo de Drogas/métodos , Factores de Edad , Recién Nacido , Factores Sexuales

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Intervertebral disc degeneration (IDD) is a common musculoskeletal system disease, which is one of the most important causes of low back pain. Despite the high prevalence of IDD, current treatments are limited to relieving symptoms, and there are no effective therapeutic agents that can block or reverse the progression of IDD. Oxidative stress, the result of an imbalance between the production of reactive oxygen species (ROS) and clearance by the antioxidant defense system, plays an important role in the progression of IDD. Polyphenols are antioxidant compounds that can inhibit ROS production, which can scavenge free radicals, reduce hydrogen peroxide production, and inhibit lipid oxidation in nucleus pulposus (NP) cells and IDD animal models. In this review, we discussed the antioxidant effects of polyphenols and their regulatory role in different molecular pathways associated with the pathogenesis of IDD, as well as the limitations and future prospects of polyphenols as a potential treatment of IDD.

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This article investigates a laser-directed energy deposition additive manufacturing (AM) method, based on coaxial powder feeding, for preparing quartz glass. Through synergistic optimization of line deposition and plane deposition experiments, key parameters of laser coaxial powder feeding AM were identified. The corresponding mechanical properties, thermal properties, and microstructure of the bulk parts were analyzed. The maximum mechanical strength of the obtained quartz glass element reached 72.36 ± 5.98 MPa, which is ca. 95% that of quartz glass prepared by traditional methods. The thermal properties of the obtained quartz glass element were also close to those prepared by traditional methods. The present research indicates that one can use laser AM technology that is based on coaxial powder feeding to form quartz glass with high density and good thermodynamic properties. Such quartz glass has substantial potential in, for example, optics and biomedicine.

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BACKGROUND: Intervertebral disc degeneration (IVDD) is a multifaceted condition characterized by heterogeneity, wherein the balance between catabolism and anabolism in the extracellular matrix of nucleus pulposus (NP) cells plays a central role. Presently, the available treatments primarily focus on relieving symptoms associated with IVDD without offering an effective cure targeting its underlying pathophysiological processes. D-mannose (referred to as mannose) has demonstrated anti-catabolic properties in various diseases. Nevertheless, its therapeutic potential in IVDD has yet to be explored. METHODS: The study began with optimizing the mannose concentration for restoring NP cells. Transcriptomic analyses were employed to identify the mediators influenced by mannose, with the thioredoxin-interacting protein (Txnip) gene showing the most significant differences. Subsequently, small interfering RNA (siRNA) technology was used to demonstrate that Txnip is the key gene through which mannose exerts its effects. Techniques such as colocalization analysis, molecular docking, and overexpression assays further confirmed the direct regulatory relationship between mannose and TXNIP. To elucidate the mechanism of action of mannose, metabolomics techniques were employed to pinpoint glutamine as a core metabolite affected by mannose. Next, various methods, including integrated omics data and the Gene Expression Omnibus (GEO) database, were used to validate the one-way pathway through which TXNIP regulates glutamine. Finally, the therapeutic effect of mannose on IVDD was validated, elucidating the mechanistic role of TXNIP in glutamine metabolism in both intradiscal and orally treated rats. RESULTS: In both in vivo and in vitro experiments, it was discovered that mannose has potent efficacy in alleviating IVDD by inhibiting catabolism. From a mechanistic standpoint, it was shown that mannose exerts its anti-catabolic effects by directly targeting the transcription factor max-like protein X-interacting protein (MondoA), resulting in the upregulation of TXNIP. This upregulation, in turn, inhibits glutamine metabolism, ultimately accomplishing its anti-catabolic effects by suppressing the mitogen-activated protein kinase (MAPK) pathway. More importantly, in vivo experiments have further demonstrated that compared with intradiscal injections, oral administration of mannose at safe concentrations can achieve effective therapeutic outcomes. CONCLUSIONS: In summary, through integrated multiomics analysis, including both in vivo and in vitro experiments, this study demonstrated that mannose primarily exerts its anti-catabolic effects on IVDD through the TXNIP-glutamine axis. These findings provide strong evidence supporting the potential of the use of mannose in clinical applications for alleviating IVDD. Compared to existing clinically invasive or pain-relieving therapies for IVDD, the oral administration of mannose has characteristics that are more advantageous for clinical IVDD treatment.

Asunto(s)

Proteínas de Ciclo Celular , Glutamina , Degeneración del Disco Intervertebral , Manosa , Degeneración del Disco Intervertebral/tratamiento farmacológico , Manosa/farmacología , Manosa/uso terapéutico , Animales , Ratas , Glutamina/farmacología , Glutamina/metabolismo , Masculino , Ratas Sprague-Dawley , Humanos , Núcleo Pulposo/efectos de los fármacos , Núcleo Pulposo/metabolismo

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Seven new meroterpenoids, paraphaeones A-G (1-7), and two new polyketides, paraphaeones H-I (8-9), along with eight known compounds (10-17), were isolated from the endophytic fungus Paraphaeosphaeria sp. C-XB-J-1. The structures of 1-9 were identified through the analysis of 1H, 13C, and 2D NMR spectra, assisted by HR-ESI-MS data. Compounds 1 and 7 exhibited a dose-dependent decrease in lactate dehydrogenase levels, with IC50 values of 1.78 µM and 1.54 µM, respectively. Moreover, they inhibited the secretion of IL-1ß and CASP-1, resulting in a reduction in the activity levels of NLRP3 inflammasomes. Fluorescence microscopy results indicated that compound 7 concentration-dependently attenuated cell pyroptosis. Additionally, compounds 4 and 7 showed potential inhibitory effects on the severe acute respiratory syndrome coronavirus-2 main protease (SARS-CoV-2 Mpro), with IC50 values of 10.8 ± 0.9 µM and 12.9 ± 0.7 µM, respectively.

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Ascomicetos , Proteasas 3C de Coronavirus , Policétidos , SARS-CoV-2 , Terpenos , Policétidos/química , Policétidos/farmacología , Policétidos/aislamiento & purificación , Ascomicetos/química , Humanos , Terpenos/química , Terpenos/farmacología , Terpenos/aislamiento & purificación , SARS-CoV-2/efectos de los fármacos , Proteasas 3C de Coronavirus/antagonistas & inhibidores , Proteasas 3C de Coronavirus/metabolismo , Proteasas 3C de Coronavirus/química , Estructura Molecular , Antivirales/farmacología , Antivirales/química , Antivirales/aislamiento & purificación , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/aislamiento & purificación , Relación Dosis-Respuesta a Droga , Relación Estructura-Actividad , Tratamiento Farmacológico de COVID-19 , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/aislamiento & purificación

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While advances in single-particle cryoEM have enabled the structural determination of macromolecular complexes at atomic resolution, particle orientation bias (the so-called "preferred" orientation problem) remains a complication for most specimens. Existing solutions have relied on biochemical and physical strategies applied to the specimen and are often complex and challenging. Here, we develop spIsoNet, an end-to-end self-supervised deep-learning-based software to address the preferred orientation problem. Using preferred-orientation views to recover molecular information in under-sampled views, spIsoNet improves both angular isotropy and particle alignment accuracy during 3D reconstruction. We demonstrate spIsoNet's capability of generating near-isotropic reconstructions from representative biological systems with limited views, including ribosomes, ß-galactosidases, and a previously intractable hemagglutinin trimer dataset. spIsoNet can also be generalized to improve map isotropy and particle alignment of preferentially oriented molecules in subtomogram averaging. Therefore, without additional specimen-preparation procedures, spIsoNet provides a general computational solution to the preferred orientation problem.

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BACKGROUND: Peste des petits ruminants (PPR) is a contagious and fatal disease of sheep and goats. PPR virus (PPRV) infection induces endoplasmic reticulum (ER) stress-mediated unfolded protein response (UPR). The activation of UPR signaling pathways and their impact on apoptosis and virus replication remains controversial. OBJECTIVES: To investigate the role of PPRV-induced ER stress and the IRE1-XBP1 and IRE1-JNK pathways and their impact on apoptosis and virus replication. METHODS: The cell viability and virus replication were assessed by 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay, immunofluorescence assay, and Western blot. The expression of ER stress biomarker GRP78, IRE1, and its downstream molecules, PPRV-N protein, and apoptosis-related proteins was detected by Western blot and quantitative reverse transcription-polymerase chain reaction, respectively. 4-Phenylbutyric acid (4-PBA) and STF-083010 were respectively used to inhibit ER stress and IRE1 signaling pathway. RESULTS: The expression of GRP78, IRE1α, p-IRE1α, XBP1s, JNK, p-JNK, caspase-3, caspase-9, Bax and PPRV-N were significantly up-regulated in PPRV-infected cells, the expression of Bcl-2 was significantly down-regulated. Due to 4-PBA treatment, the expression of GRP78, p-IRE1α, XBP1s, p-JNK, caspase-3, caspase-9, Bax, and PPRV-N were significantly down-regulated, the expression of Bcl-2 was significantly up-regulated. Moreover, in PPRV-infected cells, the expression of p-IRE1α, p-JNK, Bax, and PPRV-N was significantly decreased, and the expression of Bcl-2 was increased in the presence of STF-083010. CONCLUSIONS: PPRV infection induces ER stress and IRE1 activation, resulting in apoptosis and enhancement of virus replication through IRE1-XBP1s and IRE1-JNK pathways.

Asunto(s)

Butilaminas , Enfermedades de las Cabras , Peste de los Pequeños Rumiantes , Virus de la Peste de los Pequeños Rumiantes , Enfermedades de las Ovejas , Sulfonamidas , Tiofenos , Ovinos , Animales , Sistema de Señalización de MAP Quinasas , Caspasa 3/metabolismo , Caspasa 9/metabolismo , Chaperón BiP del Retículo Endoplásmico , Endorribonucleasas/metabolismo , Proteína X Asociada a bcl-2/metabolismo , Proteínas Serina-Treonina Quinasas , Cabras/metabolismo , Apoptosis , Estrés del Retículo Endoplásmico

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The rapid development of 5G communication technology has increased public concern about the potential adverse effects on human health. Till now, the impacts of radiofrequency radiation (RFR) from 5G communication on the central nervous system and gut-brain axis are still unclear. Therefore, we investigated the effects of 3.5 GHz (a frequency commonly used in 5G communication) RFR on neurobehavior, gut microbiota, and gut-brain axis metabolites in mice. The results showed that exposure to 3.5 GHz RFR at 50 W/m2 for 1 h over 35 d induced anxiety-like behaviour in mice, accompanied by NLRP3-dependent neuronal pyroptosis in CA3 region of the dorsal hippocampus. In addition, the microbial composition was widely divergent between the sham and RFR groups. 3.5 GHz RFR also caused changes in metabolites of feces, serum, and brain. The differential metabolites were mainly enriched in glycerophospholipid metabolism, tryptophan metabolism, and arginine biosynthesis. Further correlation analysis showed that gut microbiota dysbiosis was associated with differential metabolites. Based on the above results, we speculate that dysfunctional intestinal flora and metabolites may be involved in RFR-induced anxiety-like behaviour in mice through neuronal pyroptosis in the brain. The findings provide novel insights into the mechanism of 5G RFR-induced neurotoxicity.

Asunto(s)

Ansiedad , Microbioma Gastrointestinal , Proteína con Dominio Pirina 3 de la Familia NLR , Piroptosis , Animales , Microbioma Gastrointestinal/fisiología , Ratones , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Ondas de Radio/efectos adversos , Inflamasomas/metabolismo , Neuronas , Masculino , Conducta Animal/efectos de la radiación

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The inflammation-related tumor microenvironment (TME) is one of the major driving forces of hepatocarcinogenesis. We aimed to investigate cell-to-cell communication among Hepatocellular Carcinoma (HCC) through re-analyzing HCC single-cell RNA-seq data, and to confirm such cellular interaction through in vitro and in vivo study. We found a subset of Regulatory B cells with PD-L1 expression (PD-L1+ Bregs), mainly located in adjacent HCC tissues. In co-localization with PD-L1+ Bregs, a subset of Tumor Associated Macrophages with high expression of CXCL12 (CXCL12+ TAMs) was also mainly located in adjacent HCC tissues. Moreover, CXCL12+ TAMs can be stimulated in vitro using an HCC conditional medium. Using CellChat analysis and Multiplex Immunohistochemistry staining (mIHC), CXCL12+ TAMs were found to be first recruited by Cancer-Associated Fibroblasts (CAFs) through a CD74/macrophage migration inhibitory factor (MIF) pattern, and further differentiated into TGF-ß-enriched tissues. Furthermore, CXCL12+ TAMs recruited PD-L1+ Bregs via the CXCL12/CXCR4 axis, and CXCR4 expression was significantly positively correlated to PD-L1 expression in PD-L1+ Bregs. At last, we confirmed the communications among CAFs, Macrophages and B cells and their tumor-promoting effects by using an orthotopic mouse model of HCC. Immunosuppressive HCC TME involving cell-to-cell communications comprised MIF-secreting CAFs, CXCL12-secreting TAMs, and PD-L1-producing Bregs, and their regulation could be promising therapeutic targets in future immunotherapy for human HCC.

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Efforts on developing transient receptor potential vanilloid 1 (TRPV1) drugs for pain management have been hampered by deleterious hypo- or hyperthermia caused by TRPV1 agonists/antagonists. Here, we compared the effects of four antagonists on TRPV1 polymodal gating and core body temperature (CBT) in Trpv1+/+, Trpv1-/-, and Trpv1T634A/T634A. Neither the effect on proton gating nor drug administration route, hair coverage, CBT rhythmic fluctuations, or inflammation had any influence on the differential actions of TRPV1 drugs on CBT. We identified the S4-S5 linker region exposed to the vanilloid pocket of TRPV1 to be critical for hyperthermia associated with certain TRPV1 antagonists. PSFL2874, a TRPV1 antagonist we discovered, is effective against inflammatory pain but devoid of binding to the S4-S5 linker and inducing CBT changes. These findings implicate that biased allosteric mechanisms exist for TRPV1 coupling to nociception and CBT regulation, opening avenues for the development of non-opioid analgesics without affecting CBT.

Asunto(s)

Temperatura Corporal , Nocicepción , Canales Catiónicos TRPV , Canales Catiónicos TRPV/metabolismo , Canales Catiónicos TRPV/genética , Animales , Ratones , Regulación Alostérica/efectos de los fármacos , Nocicepción/efectos de los fármacos , Nocicepción/fisiología , Temperatura Corporal/efectos de los fármacos , Analgésicos/farmacología , Masculino , Humanos , Ratones Endogámicos C57BL , Ratones Noqueados , Dolor/metabolismo , Dolor/tratamiento farmacológico