RESUMEN
Hypertrophic scar (HS) tends to raised above skin level with high inflammatory microenvironment and excessive proliferation of myofibroblasts. The HS therapy remains challenging due to dense scar tissue which makes it hard to penetrate, and the side effects resulting from intralesional corticosteroid injection which is the mainstay treatment in clinic. Herein, bilayer microneedle patches combined with dexamethasone and colchicine (DC-MNs) with differential dual-release pattern is designed. Two drugs loaded in commercially available materials HA and PLGA, respectively. Specifically, after administration, outer layer rapidly releases the anti-inflammatory drug dexamethasone, which inhibits macrophage polarization to pro-inflammatory phenotype in scar tissue. Subsequently, inner layer degrades sustainedly, releasing antimicrotubular agent colchicine, which suppresses the overproliferation of myofibroblasts with extremely narrow therapeutic window, and inhibits the overexpression of collagen, as well as promotes the regular arrangement of collagen. Only applied once, DC-MNs directly delivered drugs to the scar tissue. Compared to traditional treatment regimen, DC-MNs significantly suppressed HS at lower dosage and frequency by differential dual-release design. Therefore, this study put forward the idea of integrated DC-MNs accompany the development of HS, providing a non-invasive, self-applicable, more efficient and secure strategy for treatment of HS.
Asunto(s)
Antiinflamatorios , Cicatriz Hipertrófica , Colchicina , Dexametasona , Miofibroblastos , Agujas , Cicatriz Hipertrófica/tratamiento farmacológico , Cicatriz Hipertrófica/patología , Animales , Miofibroblastos/efectos de los fármacos , Miofibroblastos/metabolismo , Dexametasona/farmacología , Dexametasona/administración & dosificación , Dexametasona/uso terapéutico , Antiinflamatorios/uso terapéutico , Antiinflamatorios/administración & dosificación , Antiinflamatorios/farmacología , Colchicina/farmacología , Colchicina/administración & dosificación , Ratones , Sistemas de Liberación de Medicamentos , Humanos , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/químicaRESUMEN
Inflammation-resident cells within arthritic sites undergo a metabolic shift towards glycolysis, which greatly aggravates rheumatoid arthritis (RA). Reprogramming glucose metabolism can suppress abnormal proliferation and activation of inflammation-related cells without affecting normal cells, holding potential for RA therapy. Single 2-deoxy-d-glucose (2-DG, glycolysis inhibitor) treatment often cause elevated ROS, which is detrimental to RA remission. The rational combination of glycolysis inhibition with anti-inflammatory intervention might cooperatively achieve favorable RA therapy. To improve drug bioavailability and exert synergetic effect, stable co-encapsulation of drugs in long circulation and timely drug release in inflamed milieu is highly desirable. Herein, we designed a stimulus-responsive hyaluronic acid-triglycerol monostearate polymersomes (HTDD) co-delivering 2-DG and dexamethasone (Dex) to arthritic sites. After intravenous injection, HTDD polymersomes facilitated prolonged circulation and preferential distribution in inflamed sites, where overexpressed matrix metalloproteinases and acidic pH triggered drug release. Results indicated 2-DG can inhibit the excessive cell proliferation and activation, and improve Dex bioavailability by reducing Dex efflux. Dex can suppress inflammatory signaling and prevent 2-DG-induced oxidative stress. Thus, the combinational strategy ultimately mitigated RA by inhibiting glycolysis and hindering inflammatory signaling. Our study demonstrated the great potential in RA therapy by reprogramming glucose metabolism in arthritic sites.
Asunto(s)
Artritis Reumatoide , Desoxiglucosa , Dexametasona , Glucosa , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/metabolismo , Animales , Glucosa/metabolismo , Dexametasona/farmacología , Dexametasona/uso terapéutico , Ratones , Desoxiglucosa/farmacología , Inflamación/tratamiento farmacológico , Glucólisis/efectos de los fármacos , Polímeros/química , Ácido Hialurónico/química , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Masculino , Humanos , Proliferación Celular/efectos de los fármacosRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Acute lung injury (ALI) can lead to respiratory failure and even death. KAT2A is a key target to suppress the development of inflammation. A herb, perilla frutescens, is an effective treatment for pulmonary inflammatory diseases with anti-inflammatory effects; however, its mechanism of action remains unclear. AIM OF THE STUDY: The purpose of this study was to investigate the therapeutic effect and underlying mechanism of perilla frutescens leaf extracts (PLE), in the treatment of ALI by focusing on its ability to treat inflammation. MATERIALS AND METHODS: In vivo and in vitro models of ALI induced by LPS. Respiratory function, histopathological changes of lung, and BEAS-2B cells damage were assessed upon PLE. This effect is also tested under conditions of KAT2A over expression and KAT2A silencing. RESULTS: PLE significantly attenuated LPS-induced histopathological changes in the lungs, improved respiratory function, and increased survival rate from LPS stimuation background in mice. PLE remarkably suppressed the phosphorylation of STAT3, AKT, ERK (1/2) and the release of cytokines (IL-6, TNF-α, and IL-1ß) induced by LPS via inhibiting the expression of KAT2A. CONCLUSIONS: PLE has a dose-dependent anti-inflammatory effect by inhibiting KAT2A expression to suppress LPS-induced ALI n mice. Our study expands the clinical indications of the traditional medicine PLE and provide a theoretical basis for clinical use of acute lung injury.
Asunto(s)
Lesión Pulmonar Aguda , Lipopolisacáridos , Perilla frutescens , Extractos Vegetales , Hojas de la Planta , Animales , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/patología , Lesión Pulmonar Aguda/inducido químicamente , Perilla frutescens/química , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Hojas de la Planta/química , Masculino , Ratones , Humanos , Antiinflamatorios/farmacología , Antiinflamatorios/aislamiento & purificación , Antiinflamatorios/uso terapéutico , Citocinas/metabolismo , Línea Celular , Ratones Endogámicos C57BL , Pulmón/efectos de los fármacos , Pulmón/patología , Pulmón/metabolismo , Modelos Animales de EnfermedadRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Shuangdan Jiedu Decoction (SJD) is a formula composed of six Chinese herbs with heat-removing and detoxifying, antibacterial, and anti-inflammatory effects, which is clinically used in the therapy of various inflammatory diseases of the lungs including COVID-19, but the therapeutic material basis of its action as well as its molecular mechanism are still unclear. AIM OF THE STUDY: The study attempted to determine the therapeutic effect of SJD on LPS-induced acute lung injury (ALI), as well as to investigate its mechanism of action and assess its therapeutic potential for the cure of inflammation-related diseases in the clinical setting. MATERIALS AND METHODS: We established an ALI model by tracheal drip LPS, and after the administration of SJD, we collected the bronchoalveolar lavage fluid (BALF) and lung tissues of mice and examined the expression of inflammatory factors in them. In addition, we evaluated the effects of SJD on the cyclic guanosine monophosphate-adenosine monophosphate synthase -stimulator of interferon genes (cGAS-STING) and inflammasome by immunoblotting and real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS: We demonstrated that SJD was effective in alleviating LPS-induced ALI by suppressing the levels of pro-inflammatory cytokines in the BALF, improving the level of lung histopathology and the number of neutrophils, as well as decreasing the inflammatory factor-associated gene expression. Importantly, we found that SJD could inhibit multiple stimulus-driven activation of cGAS-STING and inflammasome. Further studies showed that the Chinese herbal medicines in SJD had no influence on the cGAS-STING pathway and inflammasome alone at the formulated dose. By increasing the concentration of these herbs, we observed inhibitory effects on the cGAS-STING pathway and inflammasome, and the effect exerted was maximal when the six herbs were combined, indicating that the synergistic effects among these herbs plays a crucial role in the anti-inflammatory effects of SJD. CONCLUSIONS: Our research demonstrated that SJD has a favorable protective effect against ALI, and its mechanism of effect may be associated with the synergistic effect exerted between six Chinese medicines to inhibit the cGAS-STING and inflammasome abnormal activation. These results are favorable for the wide application of SJD in the clinic as well as for the development of drugs for ALI from herbal formulas.
Asunto(s)
Lesión Pulmonar Aguda , Medicamentos Herbarios Chinos , Inflamasomas , Lipopolisacáridos , Proteínas de la Membrana , Nucleotidiltransferasas , Transducción de Señal , Animales , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/metabolismo , Lipopolisacáridos/toxicidad , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Nucleotidiltransferasas/metabolismo , Inflamasomas/metabolismo , Inflamasomas/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Ratones , Masculino , Transducción de Señal/efectos de los fármacos , Ratones Endogámicos C57BL , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Modelos Animales de Enfermedad , Pulmón/efectos de los fármacos , Pulmón/patología , Pulmón/metabolismo , Líquido del Lavado Bronquioalveolar/citologíaRESUMEN
The present study identified the protective effects of garlic oligo/poly-saccharides of different chain lengths against dextran sulfate sodium (DSS)-induced colitis in mice and elucidated the structure-function relationships. The results showed that oral intake of garlic oligo/poly-saccharides decreased disease activity index, reduced colon shortening and spleen enlargement, and ameliorated pathological damage in the mouse colon. The dysregulation of colonic pro/anti-inflammatory cytokines was significantly alleviated, accompanied by up-regulated antioxidant enzymes, blocked TLR4-MyD88-NF-κB signaling pathway, enhanced intestinal barrier integrity, and restored SCFA production. Garlic oligo/poly-saccharides also reversed gut microbiota dysbiosis in colitic mice by expanding beneficial bacteria and suppressing the growth of harmful bacteria. High-molecular-weight polysaccharides exhibited stronger alleviating effects on DSS-induced colitic symptoms in mice than low-molecular-weight oligo/poly-saccharides did, probably due to their greater ability to be fermented in the colon. Taken together, this study demonstrated the anti-inflammatory effects of garlic oligo/poly-saccharides and revealed that high-molecular-weight polysaccharide fractions were more effective in alleviating DSS-induced colitis.
Asunto(s)
Antiinflamatorios , Colitis , Sulfato de Dextran , Fructanos , Ajo , Microbioma Gastrointestinal , Animales , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colitis/patología , Ajo/química , Ratones , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/uso terapéutico , Masculino , Microbioma Gastrointestinal/efectos de los fármacos , Fructanos/farmacología , Fructanos/química , Colon/efectos de los fármacos , Colon/patología , Colon/metabolismo , Relación Estructura-Actividad , Citocinas/metabolismo , Ratones Endogámicos C57BL , Peso Molecular , FN-kappa B/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
The natural process of skin aging is influenced by a variety of factors, including oxidative stress, inflammation, collagen degradation, and UV radiation exposure. The potential of polyphenols in controlling skin aging has been the subject of much investigation throughout the years. Due to their complex molecular pathways, polyphenols, a broad class of bioactive substances present in large quantities in plants, have emerged as attractive candidates for skin anti-aging therapies. This review aims to provide a comprehensive overview of the molecular mechanisms through which polyphenols exert their anti-aging effects on the skin. Various chemical mechanisms contribute to reducing skin aging signs and maintaining a vibrant appearance. These mechanisms include UV protection, moisturization, hydration, stimulation of collagen synthesis, antioxidant activity, and anti-inflammatory actions. These mechanisms work together to reduce signs of aging and keep the skin looking youthful. Polyphenols, with their antioxidant properties, are particularly noteworthy. They can neutralize free radicals, lessening oxidative stress that might otherwise cause collagen breakdown and DNA damage. The anti-inflammatory effects of polyphenols are explored, focusing on their ability to suppress pro-inflammatory cytokines and enzymes, thereby alleviating inflammation and its detrimental effects on the skin. Understanding these mechanisms can guide future research and development, leading to the development of innovative polyphenol-based strategies for maintaining healthy skin.
Asunto(s)
Antiinflamatorios , Antioxidantes , Estrés Oxidativo , Polifenoles , Envejecimiento de la Piel , Piel , Envejecimiento de la Piel/efectos de los fármacos , Polifenoles/farmacología , Polifenoles/uso terapéutico , Humanos , Piel/efectos de los fármacos , Piel/metabolismo , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Rayos Ultravioleta/efectos adversos , Mediadores de Inflamación/metabolismoRESUMEN
Burns are the fourth most common type of civilian trauma worldwide, and the management of severe irregular scald wounds remains a significant challenge. Herein, crocin-1 laden hydroxybutyl chitosan (CRO-HBC) thermosensitive hydrogel with smart anti-inflammatory performance was developed for accelerating full-thickness burn healing. The injectable and shape adaptability of the CRO-HBC gel make it a promising candidate for effectively filling scald wounds with irregular shapes, while simultaneously providing protection against external pathogens. The CRO-HBC gel network formed by hydrophobic interactions exhibited an initial burst release of crocin-1, followed by a gradual and sustained release over time. The excessive release of ROS and pro-inflammatory cytokines should be effectively regulated in the early stage of wound healing. The controlled release of crocin-1 from the CRO-HBC gel adequately addresses this requirement for wound healing. The CRO-HBC hydrogel also exhibited an excellent biocompatibility, an appropriate biodegradability, keratinocyte migration facilitation properties, and a reactive oxygen species scavenging capability. The composite CRO-HBC hydrogel intelligently mitigated inflammatory responses, promoted angiogenesis, and exhibited a commendable efficacy for tissue regeneration in a full-thickness scalding model. Overall, this innovative temperature-sensitive CRO-HBC injectable hydrogel dressing with smart anti-inflammatory performance has enormous potential for managing severe scald wounds.
Asunto(s)
Antiinflamatorios , Quemaduras , Carotenoides , Quitosano , Hidrogeles , Cicatrización de Heridas , Quitosano/química , Quitosano/farmacología , Quitosano/análogos & derivados , Quemaduras/tratamiento farmacológico , Cicatrización de Heridas/efectos de los fármacos , Carotenoides/farmacología , Carotenoides/química , Carotenoides/uso terapéutico , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/uso terapéutico , Hidrogeles/química , Hidrogeles/farmacología , Animales , Humanos , Ratones , Temperatura , Masculino , Especies Reactivas de Oxígeno/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
Siweixizangmaoru decoction (SXD) is widely used as an anti-rheumatoid arthritis (RA) in Tibet, however, the specific anti-inflammatory mechanism of SXD is still unclear. This research attempts to examine the efficacy and possible mechanisms of SXD in treating RA. The primary chemical components of SXD were identified using UHPLC-Q-Exactive Orbitrap MS. We established a lipopolysaccharide (LPS)-induced RAW264.7 macrophage inflammatory injury model to explore the anti-inflammatory mechanism of SXD and validated it through in vivo experiments. According to our research in vitro as well as in vivo, SXD exhibits anti-inflammatory qualities. SXD can suppress nitric oxide (NO) and pro-inflammatory factor production in RAW264.7 cells activated by LPS. The mechanism underlying this effect might be connected to the janus tyrosine kinase 2-signal transducer and activator of transcription 3 (JAK2/STAT3) and nuclear factor-κB (NF-κB) signaling pathways. In vivo, SXD alleviates joint swelling, decreases the generation of inflammatory factors in the serum, lowers oxidative stress, and improves joint damage. In short, SXD improves joint degeneration and lowers symptoms associated with RA by regulating inflammation via the suppression of NF-κB and JAK2/STAT3 signaling pathway activation.
Asunto(s)
Antiinflamatorios , Artritis Experimental , Medicamentos Herbarios Chinos , Janus Quinasa 2 , FN-kappa B , Factor de Transcripción STAT3 , Transducción de Señal , Animales , Janus Quinasa 2/metabolismo , FN-kappa B/metabolismo , Factor de Transcripción STAT3/metabolismo , Células RAW 264.7 , Ratones , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/patología , Artritis Experimental/metabolismo , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Transducción de Señal/efectos de los fármacos , Masculino , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Ratas , Ratas Sprague-Dawley , Colágeno Tipo II/metabolismo , Lipopolisacáridos , Óxido Nítrico/metabolismo , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/metabolismo , Estrés Oxidativo/efectos de los fármacos , Medicina Tradicional Tibetana/métodosRESUMEN
Anti-tumor necrosis factor alpha (anti-TNF-α) comprises a group of drugs that inhibit the action of cytokine TNF-α, and are used to treat diseases mainly caused by this cytokine. An increase in cutaneous adverse events has been observed with similar anti-TNF biologic treatments frequently used in clinical practice.
Asunto(s)
Adalimumab , Esclerodermia Localizada , Factor de Necrosis Tumoral alfa , Humanos , Adalimumab/efectos adversos , Adalimumab/uso terapéutico , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Esclerodermia Localizada/inducido químicamente , Fibrosis/inducido químicamente , Antiinflamatorios/efectos adversos , Antiinflamatorios/uso terapéuticoRESUMEN
Maintaining peripheral immune tolerance and preventing harmful autoimmune reactions is a fundamental task of the immune system. However, these essential functions are significantly compromised during autoimmune disorders, creating a major challenge in treating these conditions. In this context, we provide an overview of research on small spleen polypeptides (SSPs) that naturally regulate peripheral immune tolerance. Alongside outlining the observed effects of SSPs, we summarize here the findings on the cellular and molecular mechanisms that underlie their regulatory impact. Specifically, SSPs have demonstrated remarkable effectiveness in halting the progression of developing or established autoimmune disorders like psoriasis or arthritis in animal models. They primarily target dendritic cells (DCs), swiftly prompting the production of extracellular ATP, which is then degraded and sensed by adenosine receptors. This process triggers the mTOR signaling cascade, similar to powerful immune triggers, but instead of a rapid and intense reaction, it leads to a moderate yet significant activation of the mTOR signaling cascade. This induces a tolerogenic state in dendritic cells, ultimately leading to the generation of Foxp3+ immunosuppressor Treg cells. In addition, SSPs may indirectly attenuate the autoimmune response by reducing extracellular ATP synthesis in non-immune cells, such as endothelial cells, when exposed to elevated levels of proinflammatory cytokines. SSPs thus have the potential to contribute to the restoration of peripheral immune tolerance and may offer valuable therapeutic benefits in treating autoimmune diseases.
Asunto(s)
Tolerancia Inmunológica , Bazo , Humanos , Animales , Bazo/inmunología , Bazo/metabolismo , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/tratamiento farmacológico , Células Dendríticas/inmunología , Péptidos/inmunología , Péptidos/farmacología , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Linfocitos T Reguladores/inmunologíaRESUMEN
ABSTRACT: Unhealthy lifestyles have placed a significant burden on individuals' cardiovascular health. Anthocyanins are water-soluble flavonoid pigments found in a wide array of common foods and fruits. Anthocyanins have the potential to contribute to the prevention and treatment of cardiovascular disease by improving lipid profiles and vascular function, reducing blood glucose levels and blood pressure, and inhibiting inflammation. These actions have been demonstrated in numerous clinical and preclinical studies. At the cellular and molecular level, anthocyanins and their metabolites could protect endothelial cells from senescence, apoptosis, and inflammation by activating the phosphoinositide 3-kinase/protein kinase B/endothelial nitric oxide synthases, silent information regulator 1 (SIRT1), or nuclear factor erythroid2-related factor 2 pathways and inhibiting the nuclear factor kappa B, Bax, or P38 mitogen-activated protein kinase pathways. Furthermore, anthocyanins prevent vascular smooth muscle cell from platelet-derived growth factor -induced or tumor necrosis factor-α-induced proliferation and migration by inhibiting the focal adhesion kinase and extracellular regulated protein kinases signaling pathways. Anthocyanins could also attenuate vascular inflammation by reducing the formation of oxidized lipids, preventing leukocyte adhesion and infiltration of the vessel wall, and macrophage phagocytosis of deposited lipids through reducing the expression of cluster of differentiation 36 and increasing the expression of ATP-binding cassette subfamily A member 1 and ATP-binding cassette subfamily G member 1. At the same time, anthocyanins could lower the risk of thrombosis by inhibiting platelet activation and aggregation through down-regulating P-selectin, transforming growth factor-1, and CD40L. Thus, the development of anthocyanin-based supplements or derivative drugs could provide new therapeutic approaches to the prevention and treatment of vascular diseases.
Asunto(s)
Antocianinas , Antiinflamatorios , Enfermedades Cardiovasculares , Transducción de Señal , Humanos , Antocianinas/farmacología , Antocianinas/uso terapéutico , Animales , Enfermedades Cardiovasculares/prevención & control , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/metabolismo , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Fármacos Cardiovasculares/uso terapéutico , Fármacos Cardiovasculares/farmacologíaRESUMEN
PURPOSE: Lipopolysaccharides is well-known in the acute renal injury process. It causes widespread activation of inflammatory cascades. Tumor necrosis factor (TNF)-α and interleukin (Il)-6 are essential proinflammatory cytokines that can induce the production of other cytokines in host response. Adalimumab suppresses TNF-α, IL-1ß, and IL-6. We aimed to evaluate whether adalimumab would prevent the toxicity of lipopolysaccharide on the rat renal tissue. METHODS: Adult female Wistar rats were divided into four groups. To the control group, only intraperitoneal saline injection procedure was carried out. For adalimumab group, adalimumab was injected at a dose for two days. For lipopolysaccharide group, animals were injected with lipopolysaccharide (a dose). For lipopolysaccharide-adalimumab group, animals were given adalimumab treatment before the injection of lipopolysaccharide. Histopathological changes and immunohistochemical analysis for TNF-α and IL-6 were determined. RESULTS: The pathological changes and immunohistochemical staining for TNF-α or IL-6 were similar for control and adalimumab groups (p > 0.05). The lipopolysaccharide group had significantly higher distorted features in the renal tissues (p < 0.001), and also significantly prominent immunohistochemical staining for TNF-α or IL-6 (0.003), compared to the control group. No severe pathological feature was detected in the lipopolysaccharide-adalimumab group, but moderate necrosis was found in all cases (p = 0.003). TNF-α staining and IL-6 staining in the lipopolysaccharide group was found to significantly prominent compared to lipopolysaccharide-adalimumab group (p = 0.013). CONCLUSIONS: Because of its anti-inflammatory property, adalimumab pretreatment may have protective effects on experimental kidney injury. Adalimumab could be considered as a protective agent to acute effects of lipopolysaccharide induced renal injury.
Asunto(s)
Lesión Renal Aguda , Adalimumab , Interleucina-6 , Lipopolisacáridos , Ratas Wistar , Factor de Necrosis Tumoral alfa , Animales , Adalimumab/farmacología , Adalimumab/uso terapéutico , Femenino , Factor de Necrosis Tumoral alfa/análisis , Lesión Renal Aguda/prevención & control , Lesión Renal Aguda/inducido químicamente , Interleucina-6/análisis , Riñón/efectos de los fármacos , Riñón/patología , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Inmunohistoquímica , Ratas , Modelos Animales de Enfermedad , Reproducibilidad de los ResultadosRESUMEN
Inflammatory bowel diseases (IBDs) are chronic, relapsing, and inflammatory disorders of the gastrointestinal tract characterized by abnormal immune responses. Recently, STING has emerged as a promising therapeutic target for various autoinflammatory diseases. However, few STING-selective small molecules have been investigated as novel strategies for IBD. In this study, we sought to examine the effects of PROTAC-based STING degrader SP23 on acute colitis and explore its underlying mechanism. SP23 treatment notably alleviates dextran sulfate sodium (DSS)-induced colitis. Pharmacological degradation of STING significantly reduced the production of inflammatory cytokines, such as TNF-α, IL-1ß, and IL-6, and inhibited macrophage polarization towards the M1 type. Furthermore, SP23 administration decreased the loss of tight junction proteins, including ZO-1, occludin, and claudin-1, and downregulated STING and NLRP3 signaling pathways in intestinal inflammation. In vitro, STING activated NLRP3 inflammasome-mediated pyroptosis in intestinal epithelial cells, which could be abrogated by SP23 and STING siRNA intervention. In conclusion, these findings provide new evidence for STING as a novel therapeutic target for IBD, and reveal that hyperactivation of STING could exaggerate colitis by inducing NLRP3/Caspase-1/GSDMD axis mediated intestinal epithelial cells pyroptosis.
Asunto(s)
Colitis , Sulfato de Dextran , Macrófagos , Proteínas de la Membrana , Ratones Endogámicos C57BL , Proteína con Dominio Pirina 3 de la Familia NLR , Piroptosis , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Animales , Piroptosis/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Colitis/tratamiento farmacológico , Colitis/inducido químicamente , Colitis/inmunología , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/patología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/inmunología , Transducción de Señal/efectos de los fármacos , Inflamasomas/metabolismo , Citocinas/metabolismo , Masculino , Humanos , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Células Epiteliales/inmunología , Modelos Animales de Enfermedad , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéuticoRESUMEN
Plumbagin (PLB) is a naphthoquinone extracted from Plumbago indica. In recent times, there has been a growing body of evidence suggesting the potential importance of naphthoquinones, both natural and artificial, in the pharmacological world. Numerous studies have indicated that PLB plays a vital role in combating cancers and other disorders. There is substantial evidence indicating that PLB may have a significant role in the treatment of breast cancer, brain tumours, lung cancer, hepatocellular carcinoma, and other conditions. Moreover, its potent anti-oxidant and anti-inflammatory properties offer promising avenues for the treatment of neurodegenerative and cardiovascular diseases. A number of studies have identified various pathways that may be responsible for the therapeutic efficacy of PLB. These include cell cycle regulation, apoptotic pathways, ROS induction pathways, inflammatory pathways, and signal transduction pathways such as PI3K/AKT/mTOR, STAT3/PLK1/AKT, and others. This review aims to provide a comprehensive analysis of the diverse pharmacological roles of PLB, examining the mechanisms through which it operates and exploring its potential applications in various medical conditions. In addition, we have conducted a review of the various formulations that have been reported in the literature with the objective of enhancing the efficacy of the compound. However, the majority of the reviewed data are based on in vitro and in vivo studies. To gain a comprehensive understanding of the safety and efficacy of PLB in humans and to ascertain its potential integration into therapeutic regimens for cancer and chronic diseases, rigorous clinical trials are essential. Finally, by synthesizing current research and identifying gaps in knowledge, this review seeks to enhance our understanding of PLB and its therapeutic prospects, paving the way for future studies and clinical applications.
Asunto(s)
Enfermedades Metabólicas , Naftoquinonas , Neoplasias , Naftoquinonas/farmacología , Naftoquinonas/uso terapéutico , Humanos , Neoplasias/tratamiento farmacológico , Enfermedades Metabólicas/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Animales , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/uso terapéutico , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéuticoRESUMEN
The α-Klotho protein (hereafter Klotho) is an obligate coreceptor for fibroblast growth factor 23 (FGF23). It is produced in the kidneys, brain and other sites. Klotho insufficiency causes hyperphosphatemia and other anomalies. Importantly, it is associated with chronic pathologies (often age-related) that have an inflammatory component. This includes atherosclerosis, diabetes and Alzheimer's disease. Its mode of action in these diseases is not well understood, but it inhibits or regulates multiple major pathways. Klotho has a membrane form and a soluble form (s-Klotho). Cytosolic Klotho is postulated but not well characterized. s-Klotho has endocrine properties that are incompletely elucidated. It binds to the FGF receptor 1c (FGFR1c) that is widely expressed (including endothelial cells). It also attaches to soluble FGF23, and FGF23/Klotho binds to FGFRs. Thus, s-Klotho might be a roaming FGF23 coreceptor, but it has other functions. Notably, Klotho (cell-bound or soluble) counteracts inflammation and appears to mitigate related aging (inflammaging). It inhibits NF-κB and the NLRP3 inflammasome. This inflammasome requires priming by NF-κB and produces active IL-1ß, membrane pores and cell death (pyroptosis). In accord, Klotho countered inflammation and cell injury induced by toxins, damage-associated molecular patterns (DAMPs), cytokines, and reactive oxygen species (ROS). s-Klotho also blocks the TGF-ß receptor and Wnt ligands, which lessens fibrotic disease. Low Klotho is associated with loss of muscle mass (sarcopenia), as occurs in aging and chronic diseases. s-Klotho counters the inhibitory effects of myostatin and TGF-ß on muscle, reduces inflammation, and improves muscle repair following injury. The inhibition of TGF-ß and other factors may also be protective in diabetic retinopathy and age-related macular degeneration (AMD). This review examines Klotho functions especially as related to inflammation and potential applications.
Asunto(s)
Envejecimiento , Factor-23 de Crecimiento de Fibroblastos , Glucuronidasa , Proteínas Klotho , Humanos , Envejecimiento/metabolismo , Factor-23 de Crecimiento de Fibroblastos/metabolismo , Animales , Glucuronidasa/metabolismo , Inflamación/metabolismo , Inflamación/patología , Antiinflamatorios/metabolismo , Antiinflamatorios/uso terapéuticoRESUMEN
Arsenic trioxide (ATO) is now part of the standard regimen for the treatment of newly diagnosed and relapsed acute promyelocytic leukemia. The availability of an oral form of ATO has greatly reduced the incidence of cardiotoxicity as compared to intravenous (IV) administration. Increasing evidence suggests that ATO has anti-inflammatory properties that may be useful for the treatment of autoimmune diseases. These include the modulation of Treg cell activation, Th1/Th2 and Th17/Treg balance, depletion of activated T cells and plasmacytoid dendritic cells, and influence of B-cell differentiation, leading to reduced autoantibody and cytokine production. ATO has also been shown to induce apoptosis of activated fibroblast-like synoviocytes through the generation of reactive oxygen species and alter the gut microbiota in collagen-induced arthritis. Despite the emergence of newer treatment modalities, the treatment of systemic lupus erythematosus (SLE), especially refractory manifestations, remains a challenge, owing to the paucity of effective biological and targeted therapies that are devoid of adverse effects. Oral ATO is an attractive option for the treatment of SLE because of the lower cost of production, convenience of administration, and reduced cardiotoxicity. This article summarizes the anti-inflammatory mechanisms of ATO and its potential application in the treatment of SLE and other rheumatic diseases.
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Trióxido de Arsénico , Lupus Eritematoso Sistémico , Humanos , Trióxido de Arsénico/uso terapéutico , Trióxido de Arsénico/farmacología , Lupus Eritematoso Sistémico/tratamiento farmacológico , Animales , Antiinflamatorios/uso terapéutico , Antiinflamatorios/farmacologíaRESUMEN
Osteoarthritis (OA) is an age-related disease characterized by inflammation, pain, articular cartilage damage, synovitis, and irreversible disability. Gynostemma pentaphyllum (Thunb.) Makino (GP), a herbal medicine traditionally used in East Asia for its anti-inflammatory properties, was investigated for its potential to modulate OA pathology and symptoms. This study evaluated GP's efficacy in inhibiting pain, functional decline, and cartilage destruction in monosodium iodoacetate-induced OA and acetic acid-induced writhing models. Additionally, the effects of GP on OA-related inflammatory targets were assessed via mRNA and protein expression in rat knee cartilage and lipopolysaccharide-induced RAW 264.7 cells. The GP group demonstrated significant pain relief, functional improvement, and cartilage protection. Notably, GP inhibited key inflammatory mediators, including interleukin (IL)-1ß, IL-6, matrix metalloproteinases (MMP)-3 and MMP-13, cyclooxygenase-2, and prostaglandin E receptor 2, surpassing the effects of active controls. These findings suggest that GP is a promising candidate for disease-modifying OA drugs and warrants further comprehensive studies.
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Analgésicos , Antiinflamatorios , Gynostemma , Osteoartritis , Extractos Vegetales , Animales , Gynostemma/química , Ratones , Osteoartritis/tratamiento farmacológico , Osteoartritis/patología , Osteoartritis/inducido químicamente , Osteoartritis/metabolismo , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Células RAW 264.7 , Ratas , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Analgésicos/farmacología , Analgésicos/uso terapéutico , Masculino , Cartílago Articular/efectos de los fármacos , Cartílago Articular/patología , Cartílago Articular/metabolismo , Modelos Animales de Enfermedad , Ratas Sprague-Dawley , Dolor/tratamiento farmacológicoRESUMEN
Chalcones have been utilized for centuries as foods and medicines across various cultures and traditions worldwide. This paper concisely overviews their biosynthesis as specialized metabolites in plants and their significance, potential, efficacy, and possibility as future medicines. This is followed by a more in-depth exploration of naturally occurring chalcones and their corresponding mechanisms of action in human bodies. Based on their mechanisms of action, chalcones exhibit many pharmacological properties, including antioxidant, anti-inflammatory, anticancer, antimalarial, antiviral, and antibacterial properties. Novel naturally occurring chalcones are also recognized as potential antidiabetic drugs, and their effect on the GLUT-4 transporter is investigated. In addition, they are examined for their anti-inflammatory effects, focusing on chalcones used for future pharmaceutical utilization. Chalcones also bind to specific receptors and toxins that prevent bacterial and viral infections. Chalcones exhibit physiological protective effects on the biological degradation of different systems, including demyelinating neurodegenerative diseases and preventing hypertension or hyperlipidemia. Chalcones that are/were in clinical trials have been included as a separate section. By revealing the many biological roles of chalcones and their impact on medicine, this paper underlines the significance of naturally occurring chalcones and their extension to patient care, providing the audience with an index of topic-relevant information.
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Chalconas , Chalconas/farmacología , Chalconas/química , Humanos , Ensayos Clínicos como Asunto , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/uso terapéutico , Antioxidantes/farmacología , Antioxidantes/química , Hipoglucemiantes/farmacología , Hipoglucemiantes/química , Hipoglucemiantes/uso terapéutico , Productos Biológicos/farmacología , Productos Biológicos/química , Productos Biológicos/uso terapéuticoRESUMEN
Pomegranate is a notable source of nutrients, containing a considerable proportion of organic acids, polysaccharides, vitamins, fatty acids, and polyphenols such as flavonoids, phenolic acids, and tannins. It is also rich in nutritionally important minerals and chemical elements such as K, P, Na, Ca, Mg, and N. The presence of several bioactive compounds and metabolites in pomegranate has led to its incorporation into the functional food category, where it is used for its numerous therapeutic properties. Pomegranate's bioactive compounds have shown antioxidant, anti-inflammatory, and anticancer effects. Aging is a process characterized by the chronic accumulation of damages, progressively compromising cells, tissues, and organs over time. Inflammaging is a chronic, subclinical, low-grade inflammation that occurs during the aging process and is linked to many age-related diseases. This review aims to summarize and discuss the evidence of the benefits of pomegranate extract and its compounds to slow the aging processes by intervening in the mechanisms underlying inflammaging. These studies mainly concern neurodegenerative and skin diseases, while studies in other fields of application need to be more practical. Furthermore, no human studies have demonstrated the anti-inflammaging effects of pomegranate. In the future, supplementation with pomegranate extracts, polyphenols, or urolithins could represent a valuable low-risk complementary therapy for patients with difficult-to-manage diseases, as well as a valid therapeutic alternative for the topical or systemic treatment of skin pathologies.
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Antiinflamatorios , Inflamación , Extractos Vegetales , Granada (Fruta) , Granada (Fruta)/química , Humanos , Extractos Vegetales/farmacología , Extractos Vegetales/química , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/uso terapéutico , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Envejecimiento/efectos de los fármacos , Antioxidantes/farmacología , Antioxidantes/química , Animales , Polifenoles/farmacología , Polifenoles/química , Polifenoles/uso terapéutico , Lythraceae/químicaRESUMEN
BACKGROUND: Diabetes mellitus has emerged as a pressing global concern, with a notable increase in recent years. Despite advancements in treatment, existing medications struggle to halt the progression of diabetes and its associated complications. Increasing evidence underscores inflammation as a significant driver in the onset of diabetes mellitus. Therefore, perspectives on new therapies must consider shifting focus from metabolic stress to inflammation. High mobility group box (HMGB-1), a nuclear protein regulating gene expression, gained attention as an endogenous danger signal capable of sparking inflammatory responses upon release into the extracellular environment in the late 1990s. PURPOSE: Given the parallels between inflammatory responses and type 2 diabetes (T2D) development, this review paper explores HMGB-1's potential involvement in onset and progression of diabetes complications. Specifically, we will review and update the understanding of HMGB-1 and its inflammatory pathways in insulin resistance, diabetic nephropathy, diabetic neuropathy, and diabetic retinopathy. CONCLUSIONS: HMGB-1 and its receptors i.e. receptor for advanced glycation end-products (RAGE) and toll-like receptors (TLRs) present promising targets for antidiabetic interventions. Ongoing and future projects in this realm hold promise for innovative approaches targeting HMGB-1-mediated inflammation to ameliorate diabetes and its complications.