Inflammopharmacology最新文献

The use of glucocorticoids in systemic sclerosis (SSc) is restricted due to adverse effects. Despite this, a large proportion of patients still use these medications. Their pharmacological effects on the disease are not completely known; few studies have explored them, and the results are controversial. Thus, the present study aimed to investigate the immunomodulatory and antifibrotic activity of Dexamethasone (Dex) in SSc. The effects were evaluated in CD4 + T lymphocytes and macrophages from 20 SSc patients and 10 healthy volunteers and in a murine model of SSc. Cytokines (IL-4, IL-6, IL-13, IL-17A, and TNF) and chemokines (RANTES, IL-8, MIG, and IP-10) were quantified by sandwich enzyme-linked immunosorbent assay (ELISA) or cytometric bead array (CBA) in cell culture supernatant. Balb/c mice received intradermal injections of hypochlorous acid (HOCl) and treatment with Dex (1 mg/kg) by intraperitoneal injections for 6 weeks. RT-qPCR and histological analysis assessed dermal and pulmonary fibrosis. In the supernatant of CD4 + T lymphocytes, Dex reduced the secretion of IL-4 and IL-13 (p < 0.0001 for both), IL-6 (p = 0.0023) and TNF (p = 0.0005), in addition to the chemokines IP-10, MIG, RANTES, IL-8 (p < 0.0001 for all). Furthermore, Dex treatment SSc mice significantly reduced dermal thickening (p < 0.0001), mRNA expression of Col1a1 (p = 0.002), Tgfβ1 (p < 0.0001) and Acta2 (p < 0.0001) in the skin, and Tgfβ1 (p = 0.005) in the lungs. Furthermore, it reduced IL-4 secretion (p = 0.02) in the splenocyte culture supernatant. In summary, Dex showed immunomodulatory and antifibrotic effects in SSc, evidencing its actions in treating the disease.

Acorus calamus L. is a traditional remedy for inflammatory, neurological, and gastrointestinal disorders. Herein, we explored the anti-inflammatory, antioxidative, and anti-arthritic activities of A. calamus rhizome's extracts using an adjuvant-induced rheumatoid arthritis (AIA) rat model. The maceration method was used to prepare methanol (MEAC) and n-hexane (HEAC) extracts of A. calamus rhizomes, and high-performance liquid chromatography (HPLC) analysis was performed for the quantification of polyphenols. In vivo, 100 µL of Complete Freund's adjuvant (CFA) was injected into the right hind paw to develop AIA in rats. Fifty-four female Wistar rats were divided into nine groups (n = 6) and orally treated with meloxicam (MEL; 3 mg/kg) and three doses (125, 250, and 500 mg/kg/day) of MEAC and HEAC for 28 days. Then, physical, hematological, biochemical, radiological, histopathological, and gene expression analyses were performed. Results indicated that each extract exhibited dose-dependent mitigation of arthritis in AIA rats compared to the standard drug. MEAC and HEAC decreased paw swelling and arthritic scores in a dose-dependent manner, restored body and immune organ weights, normalized hematological indicators (RBCs, Hb, WBCs, and platelets), and significantly reduced serum inflammatory (RF, CRP, TNF-α, and PGE2) and oxidative stress (SOD, CAT, and MDA) markers. Additionally, radiological and histological examinations of MEAC and HEAC administered AIA rats revealed fewer degenerative changes. In particular, both plant extracts (500 mg/kg) persuasively downregulated the expression levels of TNF-α, IL-1β, IL-6, and IL-17 A, upregulated IL-4 and IL-10, and modulated OPG, RANKL, and OPG/RANKL ratio in paw tissues. Moreover, MEAC demonstrated promising pharmacological activity in AIA rats compared to HEAC. Our findings suggest that A. calamus exerts anti-arthritic activity by inhibiting inflammation, potentiating antioxidant defense mechanisms, and subsequently modulating the OPG/RANKL pathway. Thus, A. calamus rhizomes may be a potential natural alternative for the treatment of inflammatory and autoimmune diseases.

Background: Diabetic foot ulcers (DFUs), a debilitating manifestation of diabetes mellitus, involve persistent inflammation, oxidative stress, and impaired wound healing, largely driven by NF-κB overactivation. Amlexanox (ALX), a synthetic anti-inflammatory and antioxidant agent, was evaluated for its therapeutic potential in DFUs.

Methods: In-silico molecular docking and pharmacokinetic studies were conducted to predict ALX's interactions with major DFU targets and to assess its topical suitability. STZ-induced diabetic rats with full-thickness foot ulcers (5 mm) received topical ALX (2.5% and 5%) or silver sulfadiazine ointments for 14 days. Wound closure, antioxidant enzymes, oxidative stress markers, connective tissue markers, pro-inflammatory markers and NF-κB expression were assessed in the wound tissue.

Results: ALX demonstrated strong binding to the pathological targets (NF-κB, MMP-9, MPO, and COX-2) and displayed a favourable PK profile. Moreover, ALX topical treatment did not normalise diabetic metabolic alterations, but it dose-dependently promoted wound healing. Indeed, ALX 5% significantly accelerated wound closure (p < 0.0001) and led to marked suppression of NF-κB and MMP-9 expression (p < 0.0001). It also enhanced the levels of connective tissue markers, including hexosamine (p < 0.001), hydroxyproline, and hexuronic acid (p < 0.0001). Robust anti-inflammatory effects were also observed, as ALX reduced IL-1β, IL-6, TNF-α levels and COX-2 activity (p < 0.0001). Furthermore, ALX 5% diminished oxidative stress by lowering LPO, PCO, and MPO levels (p < 0.0001), and restoring GSH levels and SOD and CAT (p < 0.001) activities indicating its anti-oxidant properties.

Conclusion: Taken together, the present work highlights the mechanisms associated with ALX mediated wound healing in diabetic rats thereby demonstrating its potential as a promising strategy for DFU management.

Melatonin, primarily produced by the pineal gland, is also synthesized in significant amounts within the gastrointestinal (GI) tract, where its presence surpasses that in the brain. While the pineal gland secretes melatonin to regulate circadian rhythms and promote sleep, gut-derived melatonin plays a crucial role in regulating motility, protecting the mucosa from oxidative stress, and modulating immune function. The interaction between melatonin and gut microbiota is gaining significant attention, as melatonin can influence specific gut microbes and functions, potentially altering the intestinal microbiota, which is essential for maintaining overall health. This review explores the bidirectional relationship between melatonin and gut microbiota, highlighting its influence on microbial composition, intestinal barrier function, microbial metabolism, and immune modulation. Additionally, melatonin indirectly affects the gut microbiota through circadian regulation, further reinforcing its critical role in gut homeostasis. The presence of melatonin receptors in the gut and its interaction with microbial biofilms underline its importance in maintaining a balanced gut environment. Given these multifaceted roles, melatonin emerges as a promising therapeutic candidate for managing gut-related disorders such as irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and metabolic dysregulation. Despite its promising therapeutic potential, several aspects of melatonin-gut microbiome interactions remain unexplored, necessitating further research into its molecular mechanisms and clinical applications. This review provides an in-depth exploration of melatonin's role in gut microbiome regulation, its therapeutic implications, and future research directions.

Neuroinflammation is a multifaceted and carefully regulated process within the central nervous system (CNS) that serves a dual function in both protecting neurons and contributing to neurodegenerative processes. This process is mainly driven by activated microglia, astrocytes, and immune cells that infiltrate in response to neuronal damage, infections, or toxic exposures. This review emphasizes the key molecular pathways involved in neuroinflammatory reactions, such as the JAK/STAT, NF-κB, NLRP3 inflammasome, and MAPK signaling pathways. Each of these pathways plays a role in the generation and release of pro-inflammatory substances that maintain and increase inflammation in the CNS. Furthermore, the review examines the significance of crucial pro-inflammatory cytokines interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) as well as the chemokines CCL2 and CXCL10, which coordinate the recruitment of immune cells and contribute to neuronal injury. Gaining an understanding of the interactions among these signaling pathways and mediators sheds light on the molecular mechanisms connected to various neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Targeting these inflammatory signaling networks may provide valuable therapeutic approaches to manage neuroinflammation and avert its long-lasting neurotoxic effects.

Protein Kinase C (PKC), a zinc-dependent signaling enzyme pivotal for neuronal survival and synaptic plasticity, has emerged as a central player in the pathogenesis of Alzheimer's disease (AD). Dysregulated PKC activity contributes to amyloid-β accumulation, tau-driven neurofibrillary tangles, and chronic neuroinflammation, mediated through key molecular cascades such as NF-κB, GSK-3β, and MAPK. Notably, conditions such as osteoporosis and rheumatoid arthritis further illustrate how chronic cytokine release can link systemic inflammation to PKC dysregulation and subsequent neurodegeneration. Although mechanistic insights into these pathways have expanded, AD remains a therapeutic enigma with no disease-modifying interventions available. Interestingly, traditional Indian medical texts like the Charaka-Samhita documented herbal and metallic remedies, including gold-based formulations such as Swarna Prashana, reputed for enhancing cognition. Translating this ancient wisdom into modern medicine, aurothioglucose, an FDA-approved agent for rheumatoid arthritis, has demonstrated potent anti-inflammatory properties through PKC modulation. Emerging preclinical evidence now positions aurothioglucose as a promising neuroprotective candidate, capable of mitigating oxidative stress, dampening neuroinflammation, and preserving synaptic integrity via PKC-linked pathways. This review underscores the evolving role of aurothioglucose in AD, highlighting its potential to bridge traditional knowledge with contemporary therapeutics, while emphasizing the pressing need for translational studies to confirm its disease-modifying efficacy, as supported by evidences from current state of art.

Reactive oxygen species (ROS) and nitrogen-derived oxidants, such as nitric oxide (NO), are produced by immune cells through the activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs) and nitric oxide synthases (NOS), respectively. These pro-oxidants disrupt physiological homeostasis, contributing to hyperalgesia, the excessive release of inflammatory markers and oxidative stress during ulcerative colitis (UC). Consequently, diphenyleneiodonium chloride (DPI), an inhibitor of NOXs and NOS, could be effective in alleviating visceral pain and UC. This study examines the antioxidant and analgesic properties of DPI, as well as its ability to modulate oxidative stress and pro-inflammatory responses in UC. The antioxidant properties of DPI and its ability to bind free iron were determined using ABTS and DPPH tests, as well as a ferrous iron chelating capacity assay. DPI's analgesic activity was investigated using a 0.6% acetic acid (AA) mouse model of hyperalgesia, and its preventive effects against UC were determined using a 3% AA rat model of UC. Our results demonstrate that DPI limits free radicals, chelates ferrous iron and reduces writhing number (Wn) by p < 0.001, confirming its analgesic activity. Furthermore, intraperitoneal administration of DPI (100 ng/kg) protected rats from UC by repairing large-scale colonic damage, lowering oxidative stress by decreasing NO levels and restoring antioxidant enzymatic activities in colonic tissue. DPI also lowers plasmatic C-reactive protein (C-RP), NO content, lactate dehydrogenase (LDH) and γ-glutamyl transferase (γ-GT) activity during colitis. Therefore, targeting NOXs and NOS with DPI could be a promising strategy for treating inflammatory diseases such as colitis.

Background: Traumatic brain injury (TBI) is a complex neurological condition, with accumulating evidence highlighting the critical roles of neuroinflammation and oxidative stress in its pathogenesis. In this context, the present study has been designed to evaluate the neuroprotective mechanism of syringic acid, both individually and in combination with minocycline, against trauma-induced behavioural and biochemical impairments in a rat model of experimental brain injury.

Material and methods: Male Sprague-Dawley (SD) rats were undergone traumatic brain injury by the weight dropped method. Following the induction of traumatic brain injury and a subsequent two-week recovery period with syringic acid and minocycline administered either individually or in combination, for an additional two weeks. During the treatment phase, a series of behavioural assessments, including body weight monitoring, evaluation of locomotor activity, motor coordination, anxiety-like behaviour (via the elevated plus maze), and memory performance at different time intervals, were conducted to assess functional recovery. These were followed by biochemical evaluations of oxidative and antioxidant markers, mitochondrial enzyme complexes activities, acetylcholinesterase (AChE) levels, and TNF-α were evaluated in specific brain regions.

Results: TBI significantly reduced body weight and caused marked impairment in locomotor, motor coordination, memory performance, and anxiety-like behaviour. While also inducing blood-brain barrier disruption, cerebral edema, elevated TNF-α and AchE levels, and attenuating oxidative defence mechanisms and mitochondrial enzyme complex activities in discrete areas (cortex and hippocampus) of the brain, compared to the sham group. Treatment with syringic acid (25, 50, and 100 mg/kg) and minocycline (25 mg/kg) for 14 days significantly improved the behavioural and reversed biochemical impairments as compared to control group (TBI), which was comparable to that of salicylic acid (150 mg/kg). Further, the combination of syringic acid (25 mg/kg) with minocycline (25 mg/kg) treatment for 14 days demonstrated a significant neuroprotective effect as compared to their effect per se, suggesting a potential synergistic effect.

Conclusion: The current study demonstrates the involvement of microglial inhibitory mechanisms in the neuroprotective effect of syringic acid in an experimental model of TBI. The study highlights that the syringic acid in combination with minocycline could be used effectively against traumatic brain damage.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), leading to global effects. COVID-19 causes pulmonary and extra-pulmonary manifestations. One of the most common extra-pulmonary manifestations is gastrointestinal (GI) manifestation. Enteric COVID-19 triggers changes in the diversity of gut microbiota (dysbiosis). Dysbiosis of gut flora increases gut permeability, resulting in secondary bacterial infections, systemic inflammation, and injury of the peripheral organs. Dysbiosis may affect the immune system and pulmonary response to the SARS-CoV-2 invasion, suggesting a link between the lungs and gut through the gut-lung axis. Intestinal inflammation caused by SARS-CoV-2 infection induces leaky gut with subsequent transmission of toxins and antigens to the systemic circulation, causing further worsening of the septic condition in COVID-19 patients. Therefore, the anti-inflammatory agents' interruption of the gut-lung axis may reduce respiratory complications due to intestinal inflammation in COVID-19. Rifaximin (RXM) is a semi-synthetic antibacterial drug derived from natural rifamycin that acts locally within GI by inhibiting bacterial RNA polymerase and reducing the bacterial population and associated intestinal inflammation. RXM inhibits bacterial adherence to the intestinal epithelial lining and translocation across this GI lining. RXM has anti-inflammatory effects by inhibiting the release of pro-inflammatory cytokines and modulating the gut pregnane X receptor (PXR). RXM acts as a prebiotic in maintaining the growth of gut microbiota and may prevent the development of COVID-19-induced dysbiosis. Therefore, RXM could be effective in managing COVID-19 and associated inflammatory complications. Therefore, this review aims to discuss the potential role of RXM in managing COVID-19.

Gasdermin D (GSDMD) is currently considered the major effector of pyroptosis, a lytic proinflammatory programmed cell death, which mediates pathogenesis in numerous inflammatory lung diseases, such as acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), asthma, and pulmonary fibrosis. When the N-terminal fragment of GSDMD is cleaved by both canonical (caspase-1) and noncanonical (caspase-4/5/11) inflammasome pathways, membrane pores of the protein are formed, which in turn facilitate cell lysis and the release of IL-18 and IL-1B. These events culminate in immune cell infiltration, epithelial endothelial barrier disruption, and tissue remodelling. This is a critical review of GSDMD-mediated pyroptosis as a convergent pathological mediator in a variety of inflammatory pulmonary diseases and synthesizes the findings from the to 2000-2024 literature databases. We also analyzed the mechanism by which GSDMD activation mediates immune cell recruitment, cytokine storm syndrome, and fibrotic remodelling in preclinical disease models. In addition, we performed a systematic evaluation of emerging therapeutic interventions such as direct pore formation inhibitors (disulfiram and necrosulfonamide), upstream caspase inhibitors (VX-765), and anti-inflammatory phytochemicals (andrographolide, emodin, and baicalin). In our analysis, GSDMD was the chosen therapeutic target, allowing precise regulation of terminal pyroptotic signalling without compromising upstream recognition by the immune system. This is a major advantage compared to traditional general immunosuppressants. This review reports that GSDMD is a promising therapeutic target for acute and chronic inflammatory lung disease. This study provides new mechanistic contributions and translational approaches to augment targeted anti-inflammatory interventions in respiratory care by precise pyroptosis modulation.