JAK-STAT signaling in inflammation and stress-related diseases: implications for therapeutic interventions

Molecular Biomedicine, Journal Year: 2023, Volume and Issue: 4(1)

Published: Nov. 8, 2023

Abstract The Janus kinase-signal transducer and transcription activator pathway (JAK-STAT) serves as a cornerstone in cellular signaling, regulating physiological pathological processes such inflammation stress. Dysregulation this can lead to severe immunodeficiencies malignancies, its role extends neurotransduction pro-inflammatory signaling mechanisms. Although JAK inhibitors (Jakinibs) have successfully treated immunological inflammatory disorders, their application has generally been limited diseases with similar pathogenic features. Despite the modest expression of JAK-STAT CNS, it is crucial for functions cortex, hippocampus, cerebellum, making relevant conditions like Parkinson's disease other neuroinflammatory disorders. Furthermore, influence on serotonin receptors phospholipase C implications stress mood This review expands understanding JAK-STAT, moving beyond traditional contexts explore stress-related disorders CNS function. Recent findings, effectiveness Jakinibs chronic rheumatoid arthritis, expand therapeutic applicability. Advances isoform-specific inhibitors, including filgotinib upadacitinib, promise greater specificity fewer off-target effects. Combination therapies, involving monoclonal antibodies, aiming enhance efficacy also give great hope. Overall, bridges gap between basic science clinical application, elucidating complex human health guiding future interventions. Graphical

Language: Английский

---

Exploring Novel Therapeutic Targets in the Common Pathogenic Factors in Migraine and Neuropathic Pain

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(4), P. 4114 - 4114

Published: Feb. 18, 2023

Migraine and neuropathic pain (NP) are both painful, disabling, chronic conditions which exhibit some symptom similarities thus considered to share a common etiology. The calcitonin gene-related peptide (CGRP) has gained credit as target for migraine management; nevertheless, the efficacy applicability of CGRP modifiers warrant search more effective therapeutic targets management. This scoping review focuses on human studies pathogenic factors in NP, with reference available preclinical evidence explore potential novel targets. inhibitors monoclonal antibodies alleviate inflammation meninges; targeting transient receptor (TRP) ion channels may help prevent release nociceptive substances, modifying endocannabinoid system open path toward discovery analgesics. There exist tryptophan-kynurenine (KYN) metabolic system, is closely linked glutamate-induced hyperexcitability; alleviating neuroinflammation complement pain-relieving armamentarium, microglial excitation, observed conditions, be possible approach. Those several analgesic deserve explored analgesics; however, much remains missing. highlights need subtypes, TRP modulators, knowledge status KYN metabolites, consensus cytokines sampling, biomarkers function, innovative management methods NP.

Language: Английский

---

The Tryptophan-Kynurenine Metabolic System Is Suppressed in Cuprizone-Induced Model of Demyelination Simulating Progressive Multiple Sclerosis

Biomedicines, Journal Year: 2023, Volume and Issue: 11(3), P. 945 - 945

Published: March 20, 2023

Progressive multiple sclerosis (MS) is a chronic disease with unique pattern, which histologically classified into the subpial type 3 lesions in autopsy. The lesion also homologous to that of cuprizone (CPZ) toxin-induced animal models demyelination. Aberration tryptophan (TRP)-kynurenine (KYN) metabolic system has been observed patients MS; nevertheless, KYN metabolite profile progressive MS remains inconclusive. In this study, C57Bl/6J male mice were treated 0.2% CPZ toxin for 5 weeks and then underwent 4 recovery. We measured levels serotonin, TRP, metabolites plasma brain samples at 1, 3, demyelination, 7 9 remyelination periods by ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) after body weight measurement immunohistochemical analysis confirm development UHPLC-MS/MS measurements demonstrated significant reduction kynurenic acid, 3-hydoxykynurenine (3-HK), xanthurenic acid 3-HK, anthranilic week 5. Here, we show CPZ-induced mouse model Thus, potentially serves as biomarker thus opens new path toward planning personalized treatment, frequently obscured immunologic components deterioration.

Language: Английский

---

Chemokine Dysregulation and Neuroinflammation in Schizophrenia: A Systematic Review

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(3), P. 2215 - 2215

Published: Jan. 22, 2023

Chemokines are known to be immunoregulatory proteins involved not only in lymphocyte chemotaxis the site of inflammation, but also neuromodulation, neurogenesis, and neurotransmission. Multiple lines evidence suggest a peripheral proinflammatory state neuroinflammation at least third patients with schizophrenia. Therefore, chemokines can active players these processes. In this systematic review, we analyzed available data on chemokine dysregulation schizophrenia association neuroinflammation. It has been shown that there is genetic receptor gene polymorphisms Besides, most reliable confirmed by results meta-analyses showed an increase CXCL8/IL-8, CCL2/MCP-1, CCL4/MIP-1β, CCL11/eotaxin-1 blood An CXCL8 found cerebrospinal fluid, other have less well studied. Increased/decreased expression genes their receptors different areas brain immune cells. The may influence since regulated pro- anti-inflammatory cytokines. Mouse models CX3CL1-CX3CR1 CXCL12-CXCR4 axes. Altogether, contribute conclusion, indicates involvement neurobiological processes associated

Language: Английский

---

Investigating the Neuroprotective and Cognitive-Enhancing Effects of Bacopa monnieri: A Systematic Review Focused on Inflammation, Oxidative Stress, Mitochondrial Dysfunction, and Apoptosis

Antioxidants, Journal Year: 2024, Volume and Issue: 13(4), P. 393 - 393

Published: March 25, 2024

The aging of the global population has increased prevalence neurodegenerative conditions. Bacopa monnieri (BM), an herb with active compounds, such as bacosides A and B, betulinic acid, loliolide, asiatic quercetin, demonstrates potential for brain health. Limited research been conducted on therapeutic applications BM in This systematic review aims to project BM’s beneficial role disorders. anti-apoptotic antioxidant actions can repair damaged neurons, stimulate kinase activity, restore synaptic function, improve nerve transmission, increase neuroprotection. included twenty-two clinical trials demonstrated that reduce Nuclear Factor-κB phosphorylation, emotional cognitive functions, anhedonia, hyperactivity, sleep routine, depression, attention deficit, learning problems, memory retention, impulsivity, psychiatric problems. Moreover, levels pro-inflammatory biomarkers oxidative stress. Here, we highlight provides notable benefits serve a complementary approach care patients conditions associated adds growing interest natural products their by improving our understanding mechanisms underlying function neurodegeneration informing development new strategies diseases.

Language: Английский

---

Neurodegenerative disorders: Mechanisms of degeneration and therapeutic approaches with their clinical relevance

Ageing Research Reviews, Journal Year: 2024, Volume and Issue: 99, P. 102357 - 102357

Published: June 1, 2024

Neurodegenerative disorders (NDs) are expected to pose a significant challenge for both medicine and public health in the upcoming years due global demographic changes. NDs mainly represented by degeneration/loss of neurons, which is primarily accountable severe mental illness. This neuronal degeneration leads many neuropsychiatric problems permanent disability an individual. Moreover, tight junction brain, blood-brain barrier (BBB)has protective feature, functioning as biological that can prevent medicines, toxins, foreign substances from entering brain. However, delivering any medicinal agent brain (i.e., Multiple sclerosis, Alzheimer's, Parkinson's, etc.) enormously challenging. There approved therapies address NDs, but most them only help treat associated manifestations. The available have failed control progression certain factors, i.e., BBB drug-associated undesirable effects. extremely complex pathology, with pathogenic mechanisms involved initiation progression; thereby, limited survival rate has been observed ND patients. Hence, understanding exact mechanism behind crucial developing alternative approaches improving patients' rates. Thus, present review sheds light on different cellular novel therapeutic their clinical relevance, will assist researchers alternate strategies limitations conventional therapies. current work offers scope into near future improve approach NDs.

Language: Английский

---

Induction of Tolerance and Immunity by Dendritic Cells: Mechanisms and Clinical Applications

Frontiers in Immunology, Journal Year: 2019, Volume and Issue: 10

Published: Oct. 29, 2019

Dendritic cells (DCs) are key regulators of immune responses that operate at the interface between innate and adaptive immunity, defects in DC functions contribute to pathogenesis a variety disorders. For instance, cancer evolves context limited activity, some autoimmune diseases initiated by DC-dependent antigen presentation. Thus, correcting aberrant stands out as promising therapeutic paradigm for diseases, demonstrated an abundant preclinical clinical literature accumulating over past two decades. However, potential DC-targeting approaches remains be fully exploited clinic. Here, we discuss unique features DCs underlie high strategies critically analyze obstacles have prevented full realization this paradigm.

Language: Английский

---

Searching for Peripheral Biomarkers in Neurodegenerative Diseases: The Tryptophan-Kynurenine Metabolic Pathway

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(24), P. 9338 - 9338

Published: Dec. 8, 2020

Neurodegenerative diseases are multifactorial, initiated by a series of the causative complex which develops into certain clinical picture. The pathogenesis and disease course vary from patient to patient. Thus, it should be likewise treatment. Peripheral biomarkers play central role for tailoring personalized therapeutic plan patients who suffered neurodegenerative such as Alzheimer's disease, Parkinson's multiple sclerosis, among others. Nevertheless, use in practice is still underappreciated data presented biomarker research uncompelling, compared abundant available drug development. So case with kynurenines (KYNs) kynurenine pathway (KP) enzymes, have been associated wide range including cancer, autoimmune diseases, inflammatory neurologic psychiatric disorders. This review article discusses current knowledge KP alterations observed nervous system well periphery, its involvement progression, emerging evidence roles microbiota gut-brain axis, searching practical peripheral ensure treatment plans diseases.

Language: Английский

---

Immune Influencers in Action: Metabolites and Enzymes of the Tryptophan-Kynurenine Metabolic Pathway

Published: June 14, 2021

The tryptophan (TRP)-kynurenine (KYN) metabolic pathway is a main player of TRP metabolism through which more than 95% catabolized. activated by acute and chronic immune responses leading to wide range illnesses including cancer, diseases, neurodegenerative psychiatric disorders. TRP-KYN synthesizes multifarious metabolites oxidants, antioxidants, neurotoxins, neuroprotectants, immunomodulators. immunomodulators are known facilitate the system towards tolerogenic state, resulting in low-grade inflammation (LGI) that commonly present obesity, poor nutrition, exposer chemicals or allergens, prodromal stage various illnesses, diseases. KYN, kynurenic acid, xanthurenic cinnabarinic acid aryl hydrocarbon receptor ligands serve as Furthermore, enzymes be stress hormone cortisol inflammatory cytokines, genotypic variants were observed contribute thus 2,3-dioxygenase, indoleamine 2, 3-oxygenases, kynurenine-3-monooxygenase pathway. This review article discusses with special emphasis on its interaction shift LGI overviews major symptoms, pro- anti-inflammatory toxic protective KYNs explore linkage between LGI, KYNs, psychiatric, depressive disorder, bipolar substance use post-traumatic schizophrenia, autism spectrum disorder.

Language: Английский

---

Monitoring the Redox Status in Multiple Sclerosis

Biomedicines, Journal Year: 2020, Volume and Issue: 8(10), P. 406 - 406

Published: Oct. 12, 2020

Worldwide, over 2.2 million people suffer from multiple sclerosis (MS), a multifactorial demyelinating disease of the central nervous system. MS is characterized by wide range motor, autonomic, and psychobehavioral symptoms, including depression, anxiety, dementia. The blood, cerebrospinal fluid, postmortem brain samples patients provide evidence on disturbance reduction-oxidation (redox) homeostasis, such as alterations oxidative antioxidative enzyme activities presence degradation products. This review article discusses components redox reactive chemical species, enzymes, species cover frequently discussed oxygen/nitrogen infrequently featured chemicals sulfur, carbonyl, halogen, selenium, nucleophilic that potentially act reductive, well pro-oxidative stressors. systems nuclear factor erythroid-2-related 2 (NRF2)-Kelch-like ECH-associated protein 1 (KEAP1) signaling pathway. NRF2 other transcriptional factors become biomarker sensitive to initial phase stress. Altered homeostasis in were search diagnostic, prognostic, predictive, and/or therapeutic biomarker. Finally, monitoring battery products helps evaluate status expedite building personalized treatment plans for sake better quality life.

Language: Английский

---