Inflammation in diabetes complications: molecular mechanisms and therapeutic interventions

MedComm, Journal Year: 2024, Volume and Issue: 5(4)

Published: April 1, 2024

Abstract At present, diabetes mellitus (DM) has been one of the most endangering healthy diseases. Current therapies contain controlling high blood sugar, reducing risk factors like obesity, hypertension, and so on; however, DM patients inevitably eventually progress into different types complications, resulting in poor quality life. Unfortunately, clear etiology pathogenesis complications have not elucidated owing to intricate whole‐body systems. The immune system was responsible regulate homeostasis by triggering or resolving inflammatory response, indicating it may be necessary complications. In fact, previous studies shown inflammation plays multifunctional roles is attracting attention meaningful therapeutic strategy. To this end, review systematically concluded current over relationships susceptible (e.g., diabetic cardiomyopathy, retinopathy, peripheral neuropathy, nephropathy) inflammation, ranging from cell cytokines interaction pathomechanism organ injury. Besides, we also summarized various strategies improve target special remedies conventional lifestyle changes. This will offer a panoramic insight mechanisms an perspective discuss contemporary clinical interventions.

Language: Английский

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Neuropathic pain; what we know and what we should do about it

Frontiers in Pain Research, Journal Year: 2023, Volume and Issue: 4

Published: Sept. 22, 2023

Neuropathic pain can result from injury to, or disease of the nervous system. It is notoriously difficult to treat. Peripheral nerve promotes Schwann cell activation and invasion immunocompetent cells into site injury, spinal cord higher sensory structures such as thalamus cingulate cortices. Various cytokines, chemokines, growth factors, monoamines neuropeptides effect two-way signalling between neurons, glia immune cells. This sustained hyperexcitability spontaneous activity in primary afferents that crucial for onset persistence well misprocessing information supraspinal structures. Much current understanding aetiology identification drug targets derives studies consequences peripheral rodent models. Although a vast amount has been forthcoming, translation this clinical arena minimal. Few, if any, major therapeutic approaches have appeared since mid 1990's. may reflect failure recognise differences processing males vs. females, cellular responses different types humans animals. Basic science which seek bridge knowledge gap include better assessment animal models, use models emulate human disease, stratification phenotypes according quantitative signs symptoms disease. lead more personalized effective treatments individual patients. Significance statement: There an urgent need find new neuropathic pain. classical revealed essential features central sensitization some molecular mechanisms involved, they do not adequately model multiplicity states injuries bring forth clinic. review seeks integrate disciplines understand pain; including immunology, biology, electrophysiology biophysics, anatomy, neurology, pharmacology behavioral science. Beyond this, it underlines ongoing refinements basic practice will engender improved management.

Language: Английский

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Cortical Potentiation in Chronic Neuropathic Pain and the Future Treatment

Pharmaceuticals, Journal Year: 2025, Volume and Issue: 18(3), P. 363 - 363

Published: March 4, 2025

Pain, or the ability to feel pain and express unpleasantness caused by peripheral injuries, are functions of central nervous system. From sensory nerve terminals certain cortical regions brain, activation related neural networks underlies process. Recently, our knowledge has been increasing dramatically, due advancement scientific approaches. We no longer see brain as a random matrix for but, rather, we able identify step-by-step selective signaling proteins, neurons, that preferentially contribute process chronic its negative emotions, like anxiety fear. However, there is still lacking effective drugs methods treatment clinically. While first-line acute mental diseases also applied clinical management pain, their prolonged usage always causes serious side effects. In this short review, will update summarize recent progress in field mainly focus on roles synaptic mechanisms neuropathic pain. Furthermore, potential drug targets (such plasticity-related molecules, ionic channels, cytokines, neuropeptides) be discussed well. hope review can provide new, valuable insight into

Language: Английский

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Role of microglia in diabetic neuropathic pain

Frontiers in Cell and Developmental Biology, Journal Year: 2024, Volume and Issue: 12

Published: July 29, 2024

Approximately one-third of the patients with diabetes worldwide suffer from neuropathic pain, mainly categorized by spontaneous and stimulus-induced pain. Microglia are a class immune effector cells residing in central nervous system play pivotal role diabetic pain (DNP). specifically respond to hyperglycemia along inflammatory cytokines adenosine triphosphate produced during hyperglycemic damage nerve fibers. Because presence multiple receptors on microglial surface, microglia dynamically highly responsive their immediate environment. Following peripheral sensitization caused hyperglycemia, affected cascade factors other substances accordingly, resulting change functional state for DNP pathogenesis. Inhibition such as P2X reporters, reducing cytokine expression levels reactivity mechanisms, inhibiting intracellular signaling pathways can effectively alleviate DNP. A variety drugs attenuate aforementioned processes induced reactivity. In this review, we summarize pathological mechanisms which promote maintain DNP, therapeutic techniques available, latest advances field.

Language: Английский

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Targeting Members of the Chemokine Family as a Novel Approach to Treating Neuropathic Pain

Molecules, Journal Year: 2023, Volume and Issue: 28(15), P. 5766 - 5766

Published: July 30, 2023

Neuropathic pain is a debilitating condition that affects millions of people worldwide. Numerous studies indicate this type chronic with complex mechanism tends to worsen over time, leading significant deterioration in patients’ quality life and issues like depression, disability, disturbed sleep. Presently used analgesics are not effective enough neuropathy treatment may cause many side effects due the high doses needed. In recent years, researchers have pointed important role chemokines only development maintenance but also effectiveness analgesic drugs. Currently, approximately 50 known act through 20 different seven-transmembrane G-protein-coupled receptors located on surface neuronal, glial, immune cells. Data from years clearly more than initially thought (CCL1/2/3/5/7/8/9/11, CXCL3/9/10/12/13/14/17; XCL1, CX3CL1) pronociceptive properties; therefore, blocking their action by using neutralizing antibodies, inhibiting synthesis, or brings neuropathic relief. Several them (CCL1/2/3/7/9/XCL1) been shown be able reduce opioid drug neuropathy, antibodies against can restore morphine and/or buprenorphine analgesia. The latest research provides irrefutable evidence chemokine promising targets for pharmacotherapy; receptor antagonists relieve etiologies, most enhance analgesia, example, blockade CCR1 (J113863), CCR2 (RS504393), CCR3 (SB328437), CCR4 (C021), CCR5 (maraviroc/AZD5672/TAK-220), CXCR2 (NVPCXCR220/SB225002), CXCR3 (NBI-74330/AMG487), CXCR4 (AMD3100/AMD3465), XCR1 (vMIP-II). Recent has multitarget receptors, such as CCR2/5 (cenicriviroc), CXCR1/2 (reparixin), CCR2/CCR5/CCR8 (RAP-103), very painkillers. A multidirectional strategy based modulation neuronal–glial–immune interactions changing activity family significantly improve patients suffering pain. However, members still underestimated pharmacological treatment. article, we review literature provide new insights into

Language: Английский

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Microglial activation in the lateral amygdala promotes anxiety‐like behaviors in mice with chronic moderate noise exposure

CNS Neuroscience & Therapeutics, Journal Year: 2024, Volume and Issue: 30(3)

Published: March 1, 2024

Abstract Background Long‐term non‐traumatic noise exposure, such as heavy traffic noise, can elicit emotional disorders in humans. However, the underlying neural substrate is still poorly understood. Methods We exposed mice to moderate white for 28 days induce anxiety‐like behaviors, measured by open‐field, elevated plus maze, and light–dark box tests. In vivo multi‐electrode recordings awake were used examine neuronal activity. Chemogenetics silence specific brain regions. Viral tracing, immunofluorescence, confocal imaging applied define circuit characterize morphology of microglia. Results Exposure at an 85‐dB sound pressure level resulted behaviors tracing revealed that fibers projecting from auditory cortex thalamus terminate lateral amygdala (LA). A noise‐induced increase spontaneous firing rates LA blockade noise‐evoked chemogenetic inhibition glutamatergic neurons together confirmed plays a critical role anxiety. Noise‐exposed animals more vulnerable anxiety induced acute stressors than control mice. addition these behavioral abnormalities, ionized calcium‐binding adaptor molecule 1 (Iba‐1)‐positive microglia underwent corresponding morphological modifications, including reduced process length branching increased soma size following exposure. Treatment with minocycline suppress inhibited noise‐associated changes microglial morphology, electrophysiological activity, changes. Furthermore, microglia‐mediated synaptic phagocytosis favored inhibitory synapses, which cause imbalance between excitation inhibition, leading behaviors. Conclusions Our study identifies activation mediator through selective synapse phagocytosis. results highlight pivotal but previously unrecognized roles chronic

Language: Английский

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Terahertz wave alleviates comorbidity anxiety in pain by reducing the binding capacity of nanostructured glutamate molecules to GluA2

Research, Journal Year: 2024, Volume and Issue: 7

Published: Jan. 1, 2024

Comorbid anxiety in chronic pain is clinically common, with a comorbidity rate of over 50%. The main treatments are based on pharmacological, interventional, and implantable approaches, which have limited efficacy carry risk side effects. Here, we report terahertz (THz, 10 12 Hz) wave stimulation (THS) technique, exerts nonthermal, long-term modulatory effects neuronal activity by reducing the binding between nano-sized glutamate molecules GluA2, leading to relief comorbid anxiety-like behaviors mice. In mice co-occurring induced complete Freund’s adjuvant (CFA) injection, hyperactivity was observed glutamatergic neurons anterior cingulate cortex (ACC Glu ). Using whole-cell recording ACC slices, demonstrated that THS (34 THz) effectively inhibited excitability . Moreover, molecular dynamics simulations showed reduced number hydrogen bonds bound GluA2. Furthermore, target CFA-treatment suppressed and, as result, alleviated behaviors. Consistently, inhibition chemogenetics mimics THS-induced antinociceptive antianxiety behavior. Together, our study provides evidence for an intervention technique modulating viable clinical treatment strategy anxiety.

Language: Английский

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Xiao‐Chai‐Hu‐Tang Ameliorates Depressive Symptoms via Modulating Neuro‐Endocrine Network in Chronic Unpredictable Mild Stress‐Induced Mice

CNS Neuroscience & Therapeutics, Journal Year: 2025, Volume and Issue: 31(2)

Published: Feb. 1, 2025

ABSTRACT Objective Xiao‐Chai‐Hu‐Tang (XCHT) has been demonstrated to exert an antidepressant effect during long‐term clinical practices. However, the potential mechanisms of XCHT remain unknown. This study aims investigate on chronic unpredictable mild stress‐induced mice with depressive‐like behaviors and explore underlying mechanisms. Methods The active compositions related targets in brain were obtained through UPLC‐Q‐TOF‐MS, network pharmacology, bioinformatics analyses, verified by experimental validation. Then, protein–protein interaction (PPI), Gene Ontology (GO), Kyoto Encyclopedia Genes Genomes (KEGG) molecular docking used predict core depression. After being treated standard decoction, based enzyme‐linked immunosorbent assay (ELISA), non‐targeted metabolism, targeted LC–MS RNA‐seq, quantitative RT‐PCR, immunofluorescence, western blotting determined clarify mechanism treatment anxiety depression disorder. Results In total, 166 ingredients 525 detected selected from databases. inflammatory response metabolism neurotransmitters main signaling pathways predicted KEGG enrichment analyses. Behavioral testing shows that effects, untargeted metabolomic studies showed it significantly reduced levels neurotoxic substance quinoline acid. Combining results docking, blot revealed regulated nerve regeneration via BDNF/TrkB/CREB PI3K/AKT pathways. Immunofluorescence analysis downregulated activation microglia astrocytes hippocampus. Conclusion exerts functions modulating neuroinflammation neuroregeneration.

Language: Английский

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Targeting stromal cells in tumor microenvironment as a novel treatment strategy for glioma

Cancer Cell International, Journal Year: 2025, Volume and Issue: 25(1)

Published: Feb. 21, 2025

Glioma is the most common primary malignant tumor of central nervous system in adults, characterized by high mortality, low cure rate and recurrence rate. Among gliomas, glioblastoma multiforme (GBM) subtype. Currently, standard treatment for patients with GBM maximum surgical excision combined radiotherapy chemotherapy. But only a small percentage benefit from this treatment. The microenvironment plays an important role occurrence development tumors. It primarily composed cells, peripheral blood vessels, extracellular matrix, signaling molecules, stromal immune cells. cells has emerged as focus current research. interaction among tumor, stromal, within can influence development. Traditional research drug therapy glioma mainly on themselves, but recent studies have found that targeting also modulate progression GBM. Here, we review its related mechanism, well molecular targets pathways, providing new ideas prognosis

Language: Английский

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Spinal neuron-glial crosstalk and ion channel dysregulation in diabetic neuropathic pain

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: April 8, 2025

Diabetic neuropathic pain (DNP) is one of the most prevalent complications diabetes, characterized by a high global prevalence and substantial affected population with limited effective therapeutic options. Although DNP closely associated hyperglycemia, an increasing body research suggests that elevated blood glucose levels are not sole inducers DNP. The pathogenesis intricate, involving release inflammatory mediators, alterations in synaptic plasticity, demyelination nerve fibers, ectopic impulse generation, yet precise mechanisms remain to be elucidated. spinal dorsal horn coordinates dynamic interactions between peripheral central pathways, wherein neurons, microglia, astrocytes synergize Schwann cell-derived signals process nociceptive information flow. Abnormally activated neurons can alter signal transduction modifying local microenvironment, compromising myelin integrity, diminishing trophic support, leading neuronal sensitization amplifying effect on signals, which turn triggers pain. Ion channels play pivotal role conduction, modulation sodium, potassium, calcium being particularly crucial for regulation signals. In light rising incidence diabetes current scarcity treatments, thorough investigation into glial cells, especially ion channel function DNP, imperative identifying potential drug targets, developing novel strategies, thereby enhancing prospects management.

Language: Английский

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