Inflammopharmacology最新文献

Parkinson's disease (PD) remains a challenging disease for treatment, which is usually polypharmacological. In addition to motor symptoms, non-motor symptoms such as depression are present in approximately 40% of patients, contributing to the loss of quality of life. In the last two decades, a growing body of evidence has emerged regarding the involvement of the microbiota-gut-brain axis in both PD and depression. Fructooligosaccharides (FOS) and galactooligosaccharides (GOS) are prebiotic fibers that can be fermented by the gut microbiota, which produce metabolites called short-chain fatty acids (SCFAs), whose effects can contribute to improvement in neurodegenerative and psychiatric conditions. This study analyzed the effects of FOS and GOS administration in a rotenone-induced PD model and demonstrated a relief of motor symptoms and depressive-like behavior, followed by an increase of brain serotonin and its respective receptor (SERT). FOS and GOS treatment also led to an increase in SCFAs-producing gut bacteria with significantly higher levels of serum and brain butyrate. Furthermore, in the intestine, prebiotics reduced the accumulation of α-synuclein, decreased inflammation, and improved the expression of zonula occludens and occludin. FOS and GOS also attenuated the loss of dopaminergic neurons and reduced neuroinflammation by decreasing α-synuclein, IBA-1, GFAP, iNOS, p-NFkB, and IL1-β levels in the substantia nigra and prefrontal cortex. In addition, these prebiotics improved neuroplasticity by promoting the expression of butyrate receptors (GPR43 and GPR109), BDNF, p-CREB, and synaptic protein PSD-95. In conclusion, FOS and GOS administration attenuatted depressive-like behavior, neuroinflammation, and synaptic plasticity in Parkinson's disease by modulating butyrate-producing gut bacteria.

A novel series of antioxidant-conjugated mutual prodrugs of ibuprofen (RJ-02-01 to RJ-02-10) was designed and synthesized to address the gastrointestinal (GI) toxicity. Ibuprofen was covalently linked to substituted aniline-based antioxidant moieties through an amide bond. In-vitro hydrolysis results demonstrated the immense stability of the synthesized ibuprofen prodrugs in simulated gastric fluid (pH 1.2) with minimal drug release, indicating reduced potential for gastric irritation. Whereas enhanced hydrolysis was observed in simulated intestinal fluid (pH 7.4). Molecular docking revealed strong binding affinities for selected derivatives, with RJ-02-07 showing the most favorable interaction profile compared with ibuprofen. Biological evaluation identified RJ-02-07 as the lead compound, exhibiting significantly stronger COX-1 and COX-2 inhibitory activity than the parent drug. Cellular assays further demonstrated reduced reactive oxygen species levels, increased superoxide dismutase activity, and downregulation of COX-1/COX-2 protein expression, indicating improved antioxidant and anti-inflammatory potential. Cytotoxicity assessment showed lower toxicity relative to ibuprofen, suggesting a favorable safety profile. These findings suggest that this mutual prodrug strategy may reduce gastric exposure to free ibuprofen while enhancing the therapeutic efficacy; however, further in-vivo pharmacokinetic and gastro-protective studies will be required to confirm these potential benefits.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder defined by progressive cognitive impairment, neuroinflammation, oxidative stress, amyloid-β (Aβ) accumulation, synaptic dysfunction, mitochondrial impairment, and tau hyperphosphorylation. The gut-brain axis (GBA) is a crucial regulatory signaling cascade that links intestinal microbiome composition with both neural health and disease through the vagus nerve. Gut dysbiosis has increasingly been implicated in AD pathogenesis by exacerbating systemic and neuroinflammatory signaling, disrupting intestinal and blood-brain barrier (BBB) structural stability, and promoting microglial activation, thereby facilitating Aβ aggregation and neurodegeneration. Preclinical studies indicate that symbiotic interventions restore microbial balance and improve gut-brain communication, contributing to neuroprotective effects. Additionally, it has been demonstrated that symbiotics can restore synaptic plasticity and cognitive resilience by suppressing pro-inflammatory cytokines, as exemplified by interleukin-1β (IL-1β) and tumour necrosis factor-α (TNF-α), and by upregulating neurotrophic factors, particularly brain-derived neurotrophic factor (BDNF). These effects are associated with normalised glial reactivity, attenuation of oxidative stress, and improved mitochondrial bioenergetics, together contributing to enhanced synaptic function, reduced neuroinflammation, and preservation of cognitive performance. This review highlights a critical assessment of the treatment potential of symbiotic interventions in modulating the GBA in AD, emphasising mechanistic insights into neurodegenerative pathways and evaluating their capacity to mitigate symptoms and delay disease progression, as supported by current preclinical evidence.

Ageing has been recognized as the leading risk factor for Alzheimer's disease (AD), with an intricate interplay of oxidative stress, neuroinflammation, and cellular senescence implicated in its pathogenesis. Mitochondrial dysfunction has been linked to redox imbalance and excessive production of reactive oxygen species (ROS), which disrupt homeostasis and damage both mitochondrial and nuclear DNA, thereby promoting amyloid-β accumulation and cognitive decline. Chronic activation of inflammasome signaling in microglia and astrocytes, characterized by the upregulation of NLRP3 and NF-κB, has been linked to the establishment of a neuroinflammatory environment, leading to synaptic loss and exacerbating tau pathology. Additionally, the accumulation of senescent glial and neuronal cells has been shown to drive the senescence-associated secretory phenotype (SASP), further amplifying inflammation and oxidative damage. Promising therapeutic interventions, including mitochondria-targeted antioxidants and senolytics, have been evaluated; however, translational challenges persist, such as the heterogeneity of biomarker measures and the insufficient delivery of antioxidants. A proposed roadmap emphasizes the importance of monitoring oxidative and inflammatory biomarkers, implementing combinatorial therapies, and personalizing interventions to enhance resilience in the ageing brain and delay the onset of AD.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder linked with oxidative imbalance, cholinergic dysfunction and neuroinflammation, necessitates developing new multitarget natural compounds with potential disease-modifying action. Piperitone was evaluated using in-silico, in-vitro and in-vivo methods. In-silico study identified the pharmacokinetic parameters (PK) and the interaction stability of piperitone with acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-secretase. In-vivo assessment of spatial memory in scopolamine-induced rat model was identified by behavioral assays with donepezil as a reference standard. In-vitro assays identified activity of cholinesterases, oxidative stress markers, levels of antioxidants and neuroinflammatory substrates, quantified with Reverse Transcription Polymerase Chain Reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). Piperitone demonstrated favorable PK properties & docking scores comparable to Donepezil, Tacrine & QUD. Molecular dynamics simulations (MDS) confirmed stable associations with catalytic residues of cholinesterases and beta-secretase. Dose dependent reduction was recorded in cholinesterases, improvement in behavioral outcomes, and supplemented defenses of antioxidants including Glutathione (Reduced Form (GSH), Glutathione S-Transferase (GST), Catalase (CAT), Superoxide Dismutase (SOD), and diminished Lipid Peroxidation (LPO), Nitric Oxide (NO), Tumor Necrosis Factor-alpha (TNF-α), Interleukin (IL)-1β, IL-18, Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB), NOD-like Receptor Family Pyrin Domain Containing 3 (NLRP3) and amyloid-β production, while improving Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling. Piperitone showed significant neuroprotective and cognitive enhancement benefits by modulating cholinergic signaling, oxidative stress, and neuroinflammation. These multitarget actions advocate piperitone as a prospective lead candidate for the development of disease modifying treatments for AD.

Excessive osteoclast-mediated bone resorption is a hallmark of osteolytic disorders, including aseptic prosthetic loosening, osteoporosis, and rheumatoid arthritis. Therefore, the identification of agents that effectively suppress osteoclast differentiation and function is critical for the prevention and treatment of pathological bone loss. PI1840, a non-covalent proteasome inhibitor, has been reported to inhibit the proliferation of multiple tumor cell lines; however, its role in osteoclast-associated bone diseases remains unclear. Here, we demonstrate for the first time that PI1840 markedly suppresses RANKL-induced osteoclastogenesis and bone-resorptive activity by downregulating the master transcription factor NFATc1 and its upstream regulator c-Fos through inhibition of the NF-κB and MAPK (p38 and JNK) signaling pathways. Moreover, in a murine model of lipopolysaccharide-induced calvarial osteolysis, PI1840 administration significantly alleviated bone destruction, as evidenced by micro-computed tomography and histological analyses. Collectively, these findings identify PI1840 as a promising therapeutic candidate for osteolytic diseases driven by aberrant osteoclast activation.