• Larynx
• antioxidants
• curcumin
• inflammation
• radiation protection
• radiotherapy
• tumor necrosis factor-alpha

• Chronic pain
• Curcumin
• Nano-curcumin
• Visual Analogue Scale (VAS)
• Von Frey test

• Curcumin/administration & dosage
• Curcumin/pharmacology
• Curcumin/therapeutic use
• Animals
• Analgesics/administration & dosage
• Analgesics/pharmacology
• Humans
• Chronic Pain/drug therapy
• Nanoparticles

• benefits and limiting effects
• bioavailability
• cerebrovascular diseases
• curcumin
• formulations blood–brain barrier

• Curcumin/therapeutic use
• Curcumin/pharmacology
• Humans
• Neurodegenerative Diseases/drug therapy
• Neurodegenerative Diseases/metabolism
• Cerebrovascular Disorders/drug therapy
• Cerebrovascular Disorders/metabolism
• Neuroinflammatory Diseases/drug therapy
• Neuroinflammatory Diseases/metabolism
• Animals
• Blood-Brain Barrier/metabolism
• Blood-Brain Barrier/drug effects
• Biological Availability

• CNCS/CCCDI-UEFISCDI, PN-III-P4-ID-PCE-2020-1910 no 186 Ministerul Cercetării și Inovării

• Anti-apoptosis
• Bioinformatics
• Curcumin
• Diabetic peripheral neuropathy
• Heme oxygenase 1
• Schwann cells

• Curcumin/pharmacology
• Animals
• Diabetic Neuropathies/drug therapy
• Diabetic Neuropathies/metabolism
• Rats
• Computational Biology
• Schwann Cells/drug effects
• Schwann Cells/metabolism
• Apoptosis/drug effects
• Cell Line
• Molecular Docking Simulation
• PTEN Phosphohydrolase/metabolism
• PTEN Phosphohydrolase/genetics
• Glucose/metabolism
• Vascular Endothelial Growth Factor A/metabolism
• Vascular Endothelial Growth Factor A/genetics
• Cell Survival/drug effects
• Neuroprotective Agents/pharmacology

• Chemotherapy-induced peripheral neuropathy (CIPN)
• Diet
• Intervention
• Nutrition
• Phytochemical
• Phytocompound

• Humans
• Peripheral Nervous System Diseases/chemically induced
• Peripheral Nervous System Diseases/prevention & control
• Antineoplastic Agents/adverse effects
• Phytochemicals/therapeutic use
• Phytochemicals/pharmacology
• Nutrients
• Neoplasms/drug therapy
• Dietary Supplements
• Female
• Male

• Curcumin
• Cyclooxygenase
• Diclofenac
• Muscle pain
• Prostaglandin E2

• diabetes complications
• inflammation
• molecular mechanisms
• therapeutic interventions

• National Natural Science Foundation of China
• Natural Science Foundation of Zhejiang Province

• Dysbiosis
• Gut
• Inflammation
• Microbiome
• Neuropathy
• Pain

• Animals
• Humans
• Gastrointestinal Microbiome/physiology
• Chronic Pain/therapy
• Central Nervous System
• Inflammation
• Visceral Pain/therapy
• Brain

• Diabetic neuropathy
• Pentoxifylline
• Prevention
• Rat
• Streptozotocin

• Rats
• Animals
• Diabetic Neuropathies/drug therapy
• Pentoxifylline/therapeutic use
• Neuroprotective Agents/therapeutic use
• Streptozocin
• Vascular Endothelial Growth Factor A
• Diabetes Mellitus, Experimental/drug therapy
• Hyperalgesia/drug therapy
• Tumor Necrosis Factor-alpha

• Diabetes
• alkaloids.
• flavonoids
• inflammation
• neuropathy
• phytochemicals

• Humans
• Diabetic Neuropathies/drug therapy
• Diabetic Neuropathies/metabolism
• Phytochemicals/therapeutic use
• Phytochemicals/pharmacology
• Animals
• Signal Transduction/drug effects
• Oxidative Stress/drug effects
• Oxidative Stress/physiology
• Phytotherapy/methods

• Antinociceptive effects
• Curcuma longa
• Curcumin
• Nano curcumin

• Curcumin-Piperine
• Diabetes mellitus
• Diabetic retinopathy
• OCTA

• functional food
• inflammation
• mitochondria
• nervous system
• pain

• Analgesics, Opioid
• Animals
• Antioxidants/therapeutic use
• Humans
• Hyperalgesia/metabolism
• Neuralgia/drug therapy
• Neuralgia/metabolism
• Pain Management

• astrocyte
• chronic pain
• curcumin
• microglia
• neuroinflammation

• Curcuma longa
• anti-inflammatory
• antinociceptive
• curcumin
• pain
• turmeric

Lesion or disease of the somatosensory system leads to the development of neuropathic pain. Peripheral neuropathic pain encompasses damage or injury of the peripheral nervous system. On the other hand, 10–15% of individuals suffer from acute postoperative pain followed by persistent pain after undergoing surgeries. Antidepressants, anticonvulsants, baclofen, and clonidine are used to treat peripheral neuropathy, whereas opioids are used to treat postoperative pain. The negative effects associated with these drugs emphasize the search for alternative therapeutics with better efficacy and fewer side effects. Curcumin, a polyphenol isolated from the roots of Curcuma longa, possesses antibacterial, antioxidant, and anti-inflammatory properties. Furthermore, the low bioavailability and fast metabolism of curcumin have led to the advent of various curcumin formulations. The present review provides a comprehensive analysis on the effects of curcumin and its formulations in preclinical and clinical studies of neuropathic and postoperative pain. Based on the positive outcomes from both preclinical and clinical studies, curcumin holds the promise of mitigating or preventing neuropathic and postoperative pain conditions. However, more clinical studies with improved curcumin formulations are required to involve its use as adjuvant to neuropathic and postoperative drugs.

• curcumin
• curcumin formulations
• diabetes
• peripheral neuropathy
• postoperative pain
• preemptive analgesia

• Diabetes
• anti-diabetic drugs
• bioactive compounds
• drug discovery
• medicinal plants

• Curcuma longa
• Curcumin
• inflammation
• multi-target pharmacology
• pain
• phytoconstituents

• Arthritis
• Curcumin
• DAS-28
• Rheumatoid arthritis
• Systematic review

• Diabetic Neuropathy
• drug Delivery
• nanomedicines
• polyphenols

Peripheral neuropathies (PN) can be triggered after metabolic diseases, traumatic peripheral nerve injury, genetic mutations, toxic substances, and/or inflammation. PN is a major clinical problem, affecting many patients and with few effective therapeutics. Recently, interest in natural dietary compounds, such as polyphenols, in human health has led to a great deal of research, especially in PN. Curcumin is a polyphenol extracted from the root of Curcuma longa. This molecule has long been used in Asian medicine for its anti-inflammatory, antibacterial, and antioxidant properties. However, like numerous polyphenols, curcumin has a very low bioavailability and a very fast metabolism. This review addresses multiple aspects of curcumin in PN, including bioavailability issues, new formulations, observations in animal behavioral tests, electrophysiological, histological, and molecular aspects, and clinical trials published to date. The, review covers in vitro and in vivo studies, with a special focus on the molecular mechanisms of curcumin (anti-inflammatory, antioxidant, anti-endoplasmic reticulum stress (anti-ER-stress), neuroprotection, and glial protection). This review provides for the first time an overview of curcumin in the treatment of PN. Finally, because PN are associated with numerous pathologies (e.g., cancers, diabetes, addiction, inflammatory disease...), this review is likely to interest a large audience.

• anti-ER-stress
• anti-inflammatory
• antioxidant
• clinical trial
• curcumin
• peripheral neuropathy

• R25 GM090084 NIGMS NIH HHS

New evidence suggests an important role for spinal glial cells in the development of opioid dependence. Curcumin, a component of the Curcuma Longa, has shown to act as a suppressor of microglial cells. The main goal of this study was to explore the attenuating effects of curcumin on morphine dependence with a focus on spinal microglial cells and inflammatory cytokines. In order to induce morphine dependence in male Wistar rats, morphine was administered intraperitoneally (i.p.) once daily for 9 days in an increasing dose of 10, 20, and 40 mg/kg. Curcumin (2.5, 5, and 10 mg/kg, i.p.) was given from the days 10th to 18th. Naloxone-precipitated abstinence syndrome was used to assess the behavioral symptoms of morphine dependence. Immunofluorescence staining of Iba1 and ELISA test were used to measure spinal microglial activity and inflammatory cytokines levels, respectively.

The results showed that curcumin (2.5, 5, and 10 mg/kg) significantly decreased jumping, leaning, and diarrhea in morphine-dependent rats. In addition, the spinal concentration of TNF-α and IL-6 was reduced by curcumin (2.5, 5, and 10 mg/kg) significantly. Moreover, curcumin showed a potent attenuating effect on the number of Iba1 positive cells in rats which were subjected to morphine dependence. The results of this study demonstrated that curcumin exerts a remarkable reducing effect on morphine dependence in rats. The findings showed that the therapeutic effect of curcumin on morphine dependence is mediated through the suppression of activated microglial cells and reduction of inflammatory cytokines levels in the spinal cord.

• Curcumin
• Inflammatory cytokines
• Microglial cells
• Morphine dependence
• Rat
• Spinal cord
• Withdrawal syndrome

Anti-inflammatory proprieties of curcumin were proved to be useful in various diseases, including diabetes mellitus. The aim of this study was to assess the anti-inflammatory comparative effect of curcumin solution with liposomal curcumin formula, regarding the improvement of serum levels of TNF-α (tumor necrosis factor-alpha), IL-6 (interleukin), IL-1α, IL-1β, MCP-1 (monocyte chemoattractant protein-1) and RANTES in experimental diabetes, induced by streptozotocin (STZ), in rats.

Six groups of 7 rats were investigated regarding the effect of i.p. (intraperitoneal) administration of two concentrations of curcumin solution (CC1 and CC2) and two concentrations of liposomal curcumin (LCC1 and LCC2): group 1 – control group with i.p. administration of 1 mL saline solution, group 2 – i.p. STZ administration (60mg/kg bw, bw=body weight), group 3 – STZ+CC1 administration, group 4 – STZ+CC2 administration, group 5 – STZ+ LCC1 administration and group 6 – STZ+ LCC2 administration. The concentrations of curcumin formulas were 1 mg/0.1 kg bw for CC1 and LCC1 and 2 mg/0.1 kg bw for CC2 and LCC2, respectively. Serum levels of C-peptide (as an indicator of pancreatic function) and TNF-α, IL-6, IL-1α, IL-1β, MCP-1, and RANTES (as biomarkers for systemic inflammation) were assessed for each group.

The plasma level of C-peptide showed significant improvements when LCC was administrated, with better results for LCC2 when compared to LCC1 (P<0.003). LCC2 pretreatment proved to be more efficient in reducing the level of TNF-α (P<0.003) and RANTES (P<0.003) than CC2 pretreatment. Upon comparing LCC2 with LCC1 formulas, the differences were significant for TNF-α (P=0.004), IL-1β (P=0.022), and RANTES (P=0.003) levels.

Liposomal curcumin in a dose of 2 mg/0.1 kg bw proved to have an optimum therapeutic effect as a pretreatment in DM induced by STZ. This result can constitute a base for clinical studies for curcumin efficiency as adjuvant therapy in type 1 DM.

• curcumin
• cytokine
• diabetes mellitus
• inflammation

• Myocardial ischemia
• Neuropathic pain
• P2 receptors
• Traditional Chinese medicine

• Bioavailability
• Curcumin
• Depression
• Inflammatory pain
• Neuropathic pain (NP)

• Analgesics/therapeutic use
• Animals
• Curcumin/therapeutic use
• Humans
• Pain/drug therapy
• Pain Measurement

• Herbal medicine
• Hypersensitivity
• Inflammation
• Nociceptive receptors
• Nociceptor

• Curcumin
• transient receptor potential vanilloid 1
• ulcerative colitis
• visceral hyperalgesia

• Arthritis/complications
• Chronic Pain/etiology
• Humans
• Janus Kinases/metabolism
• STAT Transcription Factors/metabolism
• Signal Transduction/physiology

• AMP kinase
• Diabetes
• Inflammation
• J147
• Neuropathy

• AMP-Activated Protein Kinase Kinases
• Animals
• Anti-Inflammatory Agents, Non-Steroidal/therapeutic use
• C-Reactive Protein/metabolism
• Curcumin/chemistry
• Curcumin/therapeutic use
• Diabetic Neuropathies/chemically induced
• Diabetic Neuropathies/drug therapy
• Disease Models, Animal
• Female
• Gene Expression Profiling
• Gene Expression Regulation/drug effects
• Glycated Hemoglobin/metabolism
• Humans
• Insulin/metabolism
• Mice
• Nerve Tissue Proteins/genetics
• Nerve Tissue Proteins/metabolism
• Neural Conduction/drug effects
• Neural Conduction/genetics
• Pain Threshold/drug effects
• Physical Stimulation
• Protein Kinases/genetics
• Protein Kinases/metabolism
• Signal Transduction/drug effects
• Streptozocin/toxicity
• Tumor Necrosis Factor-alpha/genetics
• Tumor Necrosis Factor-alpha/metabolism

• R01 AG046153 NIA NIH HHS
• R01 NS081082 NINDS NIH HHS
• T32 AG000216 NIA NIH HHS

Diabetic peripheral neuropathy results in diabetic neuropathic pain (DNP). Satellite glial cells (SGCs) enwrap the neuronal soma in the dorsal root ganglia (DRG). The purinergic 2 (P2) Y12 receptor is expressed on SGCs in the DRG. SGC activation plays an important role in the pathogenesis of DNP. Curcumin has anti-inflammatory and antioxidant properties. Because curcumin has poor metabolic stability in vivo and low bioavailability, nanoparticle-encapsulated curcumin was used to improve its targeting and bioavailability. In the present study, our aim was to investigate the effects of nanoparticle-encapsulated curcumin on DNP mediated by the P2Y12 receptor on SGCs in the rat DRG. Diabetic peripheral neuropathy increased the expression levels of the P2Y12 receptor on SGCs in the DRG and enhanced mechanical and thermal hyperalgesia in rats with diabetes mellitus (DM). Up-regulation of the P2Y12 receptor in SGCs in the DRG increased the production of pro-inflammatory cytokines. Up-regulation of interleukin-1β (IL-1β) and connexin43 (Cx43) resulted in mechanical and thermal hyperalgesia in rats with DM. The nanoparticle-encapsulated curcumin decreased up-regulated IL-1β and Cx43 expression and reduced levels of phosphorylated-Akt (p-Akt) in the DRG of rats with DM. The up-regulation of P2Y12 on SGCs and the up-regulation of the IL-1β and Cx43 in the DRG indicated the activation of SGCs in the DRG. The nano-curcumin treatment inhibited the activation of SGCs accompanied by its anti-inflammatory effect to decrease the up-regulated CGRP expression in the DRG neurons. Therefore, the nanoparticle-encapsulated curcumin treatment decreased the up-regulation of the P2Y12 receptor on SGCs in the DRG and decreased mechanical and thermal hyperalgesia in rats with DM.

• P2Y12 receptor
• diabetic neuropathic pain
• dorsal root ganglia
• nanoparticle-encapsulated curcumin
• satellite glial cells

Diabetes is a metabolic disorder affecting large percentage of population worldwide. NF-κβ plays key role in pathogenesis of vascular complications of diabetes. Persistent hyperglycemia activates NF-κβ that triggers expression of various cytokines, chemokines and cell adhesion molecules. Over-expression of TNF-α, interleukins, TGF-β, Bcl2 and other pro-inflammatory proteins and pro-apoptotic genes by NF-κβ is key risk factor in vascular dysfunction. NF-κβ over-expression also triggers calcification of endothelial cells leading to endothelial dysfunction and further vascular complications. Inhibition of NF-κβ pro-inflammatory pathway is upcoming novel target for management of vascular complications of diabetes. Various natural and synthetic inhibitors of NF-κβ have been studied in management of diabetic complications. Recent preclinical and clinical studies validate NF-κβ as promising target in the management of vascular complications of diabetes.

• NF-κβ
• NF-κβ inhibitors
• cardiomyopathy
• diabetic complications
• inflammation
• nephropathy
• neuropathy
• retinopathy

• Alcohol neuropathy
• Curcumin
• Oxidative stress
• Sildenafil

• Agarose gel electrophoresis
• Calf thymus DNA
• Curcumin
• Differential Scanning Calorimetry
• Isothermal Titration Calorimetry
• Melting temperature analysis

• Animals
• Calorimetry
• Calorimetry, Differential Scanning
• Cattle
• Curcumin/chemistry
• Curcumin/metabolism
• DNA/chemistry
• DNA/metabolism
• Models, Molecular
• Nucleic Acid Denaturation
• Spectrometry, Fluorescence
• Spectrophotometry, Ultraviolet
• Temperature

• Activities of Daily Living
• Anti-Inflammatory Agents, Non-Steroidal/therapeutic use
• Complementary Therapies/methods
• Curcuma/chemistry
• Humans
• Musculoskeletal Pain/drug therapy
• Pain Measurement

• curcumin
• nanocomposite formulations
• nanocurcumin
• theraputic potential

The reported experimental study was conducted to compare the effects of repeated daily oral doses of curcuminoids (CLE) with metformin as potential antidepressants and analgesics. Effects of a single and ten daily oral doses of CLE (5, 20, 80 mg/kg/day) and of 50 mg/kg/day metformin (MET) were compared in mice hot plate test (HPT) for analgesics. On the 11th treatment day, all animals were subjected to foot shock stress triggered hyperthermia test, and on the 12th treatment day to tail suspension test (TST) for antidepressants. Immediately thereafter, their blood levels of glucose, insulin and cortisol were quantified. Dose dependent analgesic activity of CLE was observed in HPT, whereas the metformin dose tested suppressed only pain hypersensitivity in the test. But statistically significant effects of both of them were observed in TST, and both of them also afforded protections against body weight loss and slight elevation in core temperatures induced by daily handling and repeated testing. CLE or metformin had no significant effects in foot shock stress triggered transient hyperthermic responses or on blood glucose, insulin and cortisol levels. Reported results reveal that curcuminoids as well as metformin are stress response modifiers with antidepressants like activities, but only low dose curcuminoids possess centrally acting analgesics like activities. They suggest that the bio-assay system used in this study is well suited for identifying curcuminoids like plant metabolites with analgesic and anti-stress activities, and that low dose curcuminoids are more effective as analgesics than low dose metformin.

• Curcuma longa
• Curcuminoids
• Foot shock stress
• Hot plate test
• Hyperthermia
• Tail suspension test

• Diabetic peripheral neuropathy
• Meta-analysis
• Tumor necrosis factor-α

IL-1β was considered as an important inflammatory cytokine in diabetic cardiovascular complications. DCM is one of the major manifestations of diabetic cardiovascular complications whose specific mechanisms are still unclear. In this study, we investigated the role of IL-1β in myocytes apoptosis in DCM.

In the in vitro study, high- glucose medium and/or IL-1β were used to incubate the isolated primary myocytes. siRNA was used to knockdown the irak2 gene expression. Apoptosis was evaluated by Hoechst and TUNEL staining. In the in vivo study, DCM in rats was induced by STZ injection and confirmed by cardiac hemodynamic determinations. The IL-1 receptor antagonist, IL-1Ra was also used to treat DCM rats. Myocardial apoptosis was assessed by TUNEL assay. In both in vitro and in vivo studies, expression levels of GRP-78, IRAK-2 and CHOP were analyzed by Western Blotting. ELISA was employed to exam the IL-1β content in serum and cell supernatants.

Myocytes were not identified as the source of IL-1β secretion under high- glucose incubation. High glucose incubation and/or IL-1β incubation elevated ER- stress mediated myocytes apoptosis which was attenuated by irak2 silencing. Dramatically increased circulating and myocardial IL-1β levels were found in DCM rats which stimulated activation of ER stress and lead to elevated myocytes apoptosis. The administration of IL-1Ra, however, attenuated IRAK2/CHOP induced apoptosis without affecting fasting blood glucose concentration.

Elevated circulating IL-1β contributed to promote ER stress- induced myocytes apoptosis by affecting IRAK-2/CHOP pathway in DCM.

Previous study showed that extracts from Croton macrostachyus (Euphorbiaceae) exhibit analgesic effects in acute pain models. The present study evaluates the antinociceptive properties of the methanol/methylene chloride extract (MECM) of the stem bark of this plant using mice models of persistent inflammatory and neuropathic pain, and assesses its mechanism of action.

MECM was tested on Complete Freund adjuvant (CFA)-induced persistent thermal and mechanical pain, neuropathic pain induced by partial sciatic nerve ligation (PSNL), prostaglandin E₂ (PGE₂)-induced acute mechanical hyperalgesia, as well as on nociception induced by capsaicin in mice. Mechanical hyperalgesia was assessed using von Frey hair in awake mice. The mechanism of action of MECM was evaluated by using glibenclamide on PGE₂-induced hyperalgesia or rimonabant on capsaicin-induced pain.

MECM administered orally at the doses of 250 and 500 mg/kg, induced long lasting and significant antihyperalgesic effects on CFA-inflammatory and PSNL-induced neuropathic pain. MECM significantly reduced the mechanical hyperalgesia induced by PGE₂ either when administered preventively or therapeutically. MECM also significantly and time dependently inhibited the capsaicin-induced nociception. These effects were not affected by glibenclamide or by rimonabant.

The present results demonstrate that the oral administration of MECM to mice resulted in long lasting antihyperalgesic activity in inflammatory and neuropathic pain as well as in acute and persistent pain. The mechanism underlying the long lasting MECM antihyperalgesic effect is currently unknown, but might be mediated, at least partially, through the modulation of TRPV1 receptors.

• ACE1
• captopril
• curcumin
• curcumine
• diabetes
• diabète