Neurological recovery and neurogenesis by curcumin sustained-release system cross-linked with an acellular spinal cord scaffold in rat spinal cord injury: Targeting NLRP3 inflammasome pathway.

In the context of treating spinal cord injury (SCI), the modulation of inflammatory responses, and the creation of a suitable region for tissue regeneration may present a promising approach. This study aimed to evaluate the effects of curcumin (Cur)-loaded bovine serum albumin nanoparticles (Cur-BSA NPs) cross-linked with an acellular spinal cord scaffold (ASCS) on the functional recovery in a rat model of SCI. We developed an ASCS using chemical and physical methods. Cur-BSA, and blank (B-BSA) NPs were fabricated and cross-linked with ASCS via EDC-NHS, resulting in the production of Cur-ASCS and B-ASCS. We assessed the properties of scaffolds and NPs as well as their cross-links. Finally, using a male rat hemisection model of SCI, we investigated the consequences of the resulting scaffolds. The inflammatory markers, neuroregeneration, and functional recovery were evaluated. Our results showed that Cur was efficiently entrapped at the rate of 42% ± 1.3 in the NPs. Compared to B-ASCS, Cur-ASCS showed greater effectiveness in the promotion of motor recovery. The implantation of both scaffolds could increase the migration of neural stem cells (Nestin- and GFAP-positive cells) following SCI with the superiority of Cur-ASCS. Cur-ASCS was successful to regulate the gene expression and protein levels of NLRP3, ASC, and Casp1in the spinal cord lesion. Our results indicate that using ASCS can lead to the entrance of cells into the scaffold and promote neurogenesis. However, Cur-ASCS had greater effects in terms of inflammation relief and enhanced neurogenesis.

Acellular spinal cord scaffold containing quercetin-encapsulated nanoparticles plays an anti-inflammatory role in functional recovery from spinal cord injury in rats.

Inflammatory responses play a crucial role in the pathophysiology of spinal cord injury (SCI) and developing new approaches to establish an anti-inflammatory environment for the promotion of neuroregeneration holds promise as a potential approach. In this study, our aim was to investigate the potential of combining an acellular spinal cord scaffold (ASCS) with quercetin-loaded bovine serum albumin (Qu/BSA) nanoparticles (NPs) for the treatment of SCI. The ASCS was prepared using physical and chemical methods, while the Qu/BSA NPs were prepared through a desolvation technique. The NPs exhibited favorable characteristics, including a mean size of 203 nm, a zeta potential of -38, and an encapsulation efficiency of 96%. Microscopic evaluation confirmed the successful distribution of NPs on the walls of ASCS. Animal studies revealed that Qu/BSA NPs group exhibited a significant decrease in NLRP3, ASC, and Casp1 gene expression compared to the SCI group (p < 0.0001). The findings indicated a significant decrease in the NLRP3, ASC, and Casp1 protein level between the Qu/BSA/ASCS group and the SCI group (p < 0.0001). Moreover, treatment with ASCS containing either blank BSA (B/BSA) NPs or Qu/BSA NPs effectively promoted functional recovery via increasing the amount of nestin- and glial fibrillary acidic protein (GFAP)-positive cells in the site of injury. Notably, Qu/BSA/ASCS exhibited superior outcomes compared to B/BSA/ASCS. Overall, the combination of ASCS with the Qu delivery system presents a promising therapeutic approach for SCI by inhibiting inflammatory responses and promoting neuroregeneration, leading to the restoration of motor function in animals. This study demonstrates the potential of utilizing biomaterials and NPs to enhance the effectiveness of SCI treatment.

Targeting autophagy and neuroinflammation pathways with plant-derived natural compounds as potential antidepressant agents.

Major depressive disorder (MDD) is a life-threatening disease that presents several characteristics. The pathogenesis of depression still remains poorly understood. Moreover, the mechanistic interactions of natural components in treating depression to target autophagy and neuroinflammation are yet to be evaluated. This study overviewed the effects of plant-derived natural components in regulating critical pathways, particularly neuroinflammation and autophagy, associated with depression. A list of natural components, including luteolin, apigenin, hyperforin, resveratrol, salvianolic acid b, isoliquiritin, nobiletin, andrographolide, and oridonin, have been investigated. All peer-reviewed journal articles were searched by Scopus, MEDLINE, PubMed, Web of Science, and Google Scholar using the appropriated keywords, including depression, neuroinflammation, autophagy, plant, natural components, etc. The neuroinflammation and autophagy dysfunction are critically associated with the pathophysiology of depression. Natural components with higher efficiency and lower complications can be used for targeting neuroinflammation and autophagy. These components with different doses showed the beneficial antidepressant properties in rodents. These can modulate autophagy markers, mainly AMPK, LC3II/LC3I ratio, Beclin-1. Moreover, they can regulate the NLRP3 inflammasome, resulting in the suppression of proinflammatory cytokines (e.g., IL-1ß and IL-18). Future in vitro and in vivo studies are required to develop novel therapeutic approaches based on plant-derived active components to treat MDD.

The Distinct Functions of Dopaminergic Receptors on Pain Modulation: A Narrative Review.

Chronic pain is considered an economic burden on society as it often results in disability, job loss, and early retirement. Opioids are the most common analgesics prescribed for the management of moderate to severe pain. However, chronic exposure to these drugs can result in opioid tolerance and opioid-induced hyperalgesia. On pain modulation strategies, exploiting the multitarget drugs with the ability of the superadditive or synergistic interactions attracts more attention. In the present report, we have reviewed the analgesic effects of different dopamine receptors, particularly D1 and D2 receptors, in different regions of the central nervous system, including the spinal cord, striatum, nucleus accumbens (NAc), and periaqueductal gray (PAG). According to the evidence, these regions are not only involved in pain modulation but also express a high density of DA receptors. The findings can be categorized as follows: (1) D2-like receptors may exert a higher analgesic potency, but D1-like receptors act in different manners across several mechanisms in the mentioned regions; (2) in the spinal cord and striatum, antinociception of DA is mainly mediated by D2-like receptors, while in the NAc and PAG, both D1- and D2-like receptors are involved as analgesic targets; and (3) D2-like receptor agonists can act as adjuvants of µ-opioid receptor agonists to potentiate analgesic effects and provide a better approach to pain relief.

Transcutaneous Electrical Nerve Stimulation in Relieving Neuropathic Pain: Basic Mechanisms and Clinical Applications.

PURPOSE OF REVIEW: Transcutaneous electrical nerve stimulation (TENS) is widely used as a non-pharmacological approach for pain relief in a variety of clinical conditions. This manuscript aimed to review the basic mechanisms and clinical applications regarding the use of TENS for alleviating the peripheral (PNP) and central neuropathic pain (CNP). RECENT FINDINGS: Basic studies on animal models showed that TENS could alleviate pain by modulating neurotransmitters and receptors in the stimulation site and its upper levels, including the spinal cord, brainstem, and brain. Besides, many clinical studies have investigated the efficacy of TENS in patients with CNP (caused by spinal cord injury, stroke, or multiple sclerosis) and PNP (induced by diabetes, cancer, or herpes zoster). Most clinical trials have demonstrated the efficacy of TENS in attenuating neuropathic pain and suggested that appropriate stimulation parameters (e.g., stimulation frequency and intensity) were critical to improving the analgesic effects of TENS. However, there are some conflicting findings related to the efficacy of TENS in relieving neuropathic pain. With optimized stimulation parameters, TENS would be effective in attenuating neuropathic pain. To obtain sufficient evidence to support the use of TENS in the clinic, researchers recommended performing multicenter clinical trials with optimized TENS protocols for the treatment of various CNP and PNP.

Subventricular zone-derived extracellular vesicles promote functional recovery in rat model of spinal cord injury by inhibition of NLRP3 inflammasome complex formation.

Spinal cord injury (SCI) is the destruction of spinal cord motor and sensory resulted from an attack on the spinal cord, which can cause significant physiological damage. The inflammasome is a multiprotein oligomer resulting in inflammation; the NLRP3 inflammasome composed of NLRP3, apoptosis-associated speck-like protein (ASC), procaspase-1, and cleavage of procaspase-1 into caspase-1 initiates the inflammatory response. Subventricular Zone (SVZ) is the origin of neural stem/progenitor cells (NS/PCs) in the adult brain. Extracellular vesicles (EVs) are tiny lipid membrane bilayer vesicles secreted by different types of cells playing an important role in cell-cell communications. The aim of this study was to investigate the effect of intrathecal transplantation of EVs on the NLRP3 inflammasome formation in SCI rats. Male wistar rats were divided into three groups as following: laminectotomy group, SCI group, and EVs group. EVs was isolated from SVZ, and characterized by western blot and DLS, and then injected into the SCI rats. Real-time PCR and western blot were carried out for gene expression and protein level of NLRP3, ASC, and Caspase-1. H&E and cresyl violet staining were performed for histological analyses, as well as BBB test for motor function. The results indicated high level in mRNA and protein level in SCI group in comparison with laminectomy (p < 0.001), and injection of EVs showed a significant reduction in the mRNA and protein levels in EVs group compared to SCI (p < 0.001). H&E and cresyl violet staining showed recovery in neural cells of spinal cord tissue in EVs group in comparison with SCI group. BBB test showed the promotion of motor function in EVs group compared to SCI in 14 days (p < 0.05). We concluded that the injection of EVs could recover the motor function in rats with SCI and rescue the neural cells of spinal cord tissue by suppressing the formation of the NLRP3 inflammasome complex.

An evaluation of the delayed effect of intra-articular injections of lidocaine (2%) on articular cartilage: an experimental study in rabbits.

Lidocaine is commonly injected into the joints as an analgesic. The aim of the present study was to evaluate the delayed effect of intra-articular injections of lidocaine (2%) on articular cartilage in rabbit knees. Ten rabbits were divided into two groups, each group containing five animals. Two milliliters of normal saline solution was injected into both knee joints of animals in group one (control group), and 2 ml of lidocaine was injected into both knee joints of animals in group two (case group). After 8 weeks, the articular cartilage of the distal femur was harvested and analyzed through confocal microscopy and real-time polymerase chain reaction to evaluate the viability and function of chondrocytes, respectively. Confocal microscopy showed a significant decrease in the number of live cells caused by lidocaine (P ≤ 0.001). The changes in gene expression of collagen types II (COL II) and aggrecan were significant in group two (P = 0.008 and P = 0.002, respectively). According to the results, the delayed in vivo effect of lidocaine on chondrocyte is to reduce live chondrocytes and change in the gene expression of COL II and aggrecan.

Role of NLRP3 Inflammasome in Post-Spinal-Cord-Injury Anxiety and Depression: Molecular Mechanisms and Therapeutic Implications.

The majority of research on the long-term effects of spinal cord injury (SCI) has primarily focused on neuropathic pain (NP), psychological issues, and sensorimotor impairments. Among SCI patients, mood disorders, such as anxiety and depression, have been extensively studied. It has been found that chronic stress and NP have negative consequences and reduce the quality of life for individuals living with SCI. Our review examined both human and experimental evidence to explore the connection between mood changes following SCI and inflammatory pathways, with a specific focus on NLRP3 inflammasome signaling. We observed increased proinflammatory factors in the blood, as well as in the brain and spinal cord tissues of SCI models. The NLRP3 inflammasome plays a crucial role in various diseases by controlling the release of proinflammatory molecules like interleukin 1ß (IL-1ß) and IL-18. Dysregulation of the NLRP3 inflammasome in key brain regions associated with pain processing, such as the prefrontal cortex and hippocampus, contributes to the development of mood disorders following SCI. In this review, we summarized recent research on the expression and regulation of components related to NLRP3 inflammasome signaling in mood disorders following SCI. Finally, we discussed potential therapeutic approaches that target the NLRP3 inflammasome and regulate proinflammatory cytokines as a way to treat mood disorders following SCI.

Stress, pain, anxiety, and depression in endometriosis-Targeting glial activation and inflammation.

Endometriosis (EM) is a gynecological inflammatory disease often accompanied by stress, chronic pelvic pain (CPP), anxiety, and depression, leading to a diminished quality of life. This review aims to discuss the relationship between systemic and local inflammatory responses in the central nervous system (CNS), focusing on glial dysfunctions (astrocytes and microglia) as in critical brain regions involved in emotion, cognition, pain processing, anxiety, and depression. The review presents that EM is connected to increased levels of pro-inflammatory cytokines in the circulation. Additionally, chronic stress and CPP as stressors may contribute to the dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, depleting the production of inflammatory mediators in the circulatory system and the brain. The systemic cytokines cause blood-brain barrier (BBB) breakdown, activate microglia in the brain, and lead to neuroinflammation. Furthermore, CPP may induce neuronal morphological alterations in critical regions through central sensitization and the activation of glial cells. The activation of glial cells, particularly the polarization of microglia, leads to the activation of the NLRP3 inflammasome and the overproduction of inflammatory cytokines. These inflammatory cytokines interact with the signaling pathways involved in neural plasticity. Additionally, persistent inflammatory conditions in the brain lead to neuronal death, which is correlated with a reduced volume of key brain regions such as the hippocampus. This review highlights the involvement of glial cells in the pathogenesis of the mental comorbidities of EM (i.e., pain, anxiety, and depression) and to discuss potential therapeutic approaches for targeting the inflammation and activation of microglia in key brain regions.

Molecular mechanisms of Schisandra chinensis in treating depression-neuropathic pain comorbidity by network pharmacology and molecular docking analysis.

This study utilized network pharmacology and docking analyses to explore a groundbreaking therapeutic approach for managing the neuropathic pain and depressive disorder (NP/DD) comorbidity. Schisandra chinensis (SC), a common Chinese medicine, has demonstrated numerous beneficial effects in treating neuropsychological disorders. The main objective of this study was to identify potential bioactive components of SC and investigate their interactions with relevant target genes associated with NP/DD. To gain insights into the underlying molecular mechanisms, GO and KEGG analyses were conducted. Furthermore, molecular docking analysis was employed to validate the therapeutic relevance of SC's active ingredients. Seven bioactive components of SC, namely Longikaurin A, Deoxyharringtonine, Angeloylgomisin O, Schisandrin B, Gomisin A, Gomisin G, and Gomisin R, exhibited effectiveness in the treatment of NP/DD. From this list, the first five components were selected for further analysis. The analyses revealed a complex network of interactions between the targets of SC and NP/DD, providing valuable information about the molecular mechanisms involved in the treatment of NP/DD with SC. SC components demonstrated the ability to regulate pathways involving tumor necrosis factor (TNF), vascular endothelial growth factor (VEGF), and other growth hormones (GH). Overall, this study contributes to our understanding of the molecular mechanisms underlying the effects of SC in treating NP/DD. Further investigation is necessary to explore the therapeutic potential of SC as a viable strategy for NP/DD comorbidity. These findings lay a solid foundation for future research endeavors in this field, holding potential implications for the development of novel therapeutic interventions targeting NP/DD.

Potential anxiolytic and antidepressant-like effects of luteolin in a chronic constriction injury rat model of neuropathic pain: Role of oxidative stress, neurotrophins, and inflammatory factors.

This study aimed to examine the effects of luteolin (LUT) on chronic neuropathic pain (NP)-induced mood disorders (i.e., anxiety and depression) by regulating oxidative stress, neurotrophic factors (NFs), and neuroinflammation. Chronic constrictive injury (CCI) was used to induce NP in the animals. Animals in the treatment groups received LUT in three doses of 10, 25, and 50 mg/kg for 21 days. The severity of pain and mood disorders were examined. Finally, animals were sacrificed, and their brain tissue was used for molecular and histopathological studies. CCI led to cold allodynia and thermal hyperalgesia. Mood alterations were proven in the CCI group, according to the behavioral tests. Levels of glial cell-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), B-cell lymphoma-2 (Bcl2), superoxide dismutase (SOD), catalase (CAT), and nuclear factor erythroid-2-related factor 2 (Nrf2) were reduced in the hippocampus (HPC) and prefrontal cortex (PFC). Furthermore, the levels of MDA, Bcl-2-associated X protein (Bax), and inflammatory markers, including nuclear factor kappa B (NF-κB), NLR family pyrin domain containing 3 (NLRP3), interleukin-1ß (IL-1ß), IL-18, IL-6, and tumor necrosis factor-α (TNF-α) significantly increased in the HPC and PFC following CCI induction. LUT treatment reversed the behavioral alterations via regulation of oxidative stress, neurotrophines, and inflammatory mediators in the HPC and PFC. Findings confirmed the potency of LUT in the improvement of chronic pain-induced anxiety- and depressive-like symptoms, probably through antioxidant, anti-inflammatory, and neuroprotective properties in the HPC and PFC.

Therapeutic potential of thymoquinone and its nanoformulations in neuropsychological disorders: a comprehensive review on molecular mechanisms in preclinical studies.

Thymoquinone (THQ) and its nanoformulation (NFs) have emerged as promising candidates for the treatment of neurological diseases due to their diverse pharmacological properties, which include anti-inflammatory, antioxidant, and neuroprotective effects. In this study, we conducted an extensive search across reputable scientific websites such as PubMed, ScienceDirect, Scopus, and Google Scholar to gather relevant information. The antioxidant and anti-inflammatory properties of THQ have been observed to enhance the survival of neurons in affected areas of the brain, leading to significant improvements in behavioral and motor dysfunctions. Moreover, THQ and its NFs have demonstrated the capacity to restore antioxidant enzymes and mitigate oxidative stress. The primary mechanism underlying THQ's antioxidant effects involves the regulation of the Nrf2/HO-1 signaling pathway. Furthermore, THQ has been found to modulate key components of inflammatory signaling pathways, including toll-like receptors (TLRs), nuclear factor-κB (NF-κB), interleukin 6 (IL-6), IL-1ß, and tumor necrosis factor alpha (TNFα), thereby exerting anti-inflammatory effects. This comprehensive review explores the various beneficial effects of THQ and its NFs on neurological disorders and provides insights into the underlying mechanisms involved.

Exogenous melatonin alleviates neuropathic pain-induced affective disorders by suppressing NF-κB/ NLRP3 pathway and apoptosis.

In this study, we aimed to evaluate the anti-inflammatory and anti-apoptotic effects of melatonin (MLT) on neuropathic pain (NP)-induced anxiety and depression in a rat model. Adult male rats were separated into four groups, i.e., Sham-VEH: healthy animals received a vehicle, Sham-MLT (10 mg/kg), and chronic constrictive injury (CCI)-VEH: nerve ligation received the vehicle, and CCI-MLT. Next, we used behavioral tests to evaluate pain severity, anxiety, and depression. Finally, rats were sacrificed for molecular and histopathological studies. Behavioral tests showed that NP could induce depressive- and anxiety-like behaviors. NP activated NF-κB/NLRP3 inflammasome pathways by upregulating NF-κB, NLRP3, ASC, active Caspase-1, also enhancing the concentrations of cytokines (IL-1ß and IL-18) in the prefrontal cortex (PFC) and hippocampus (HC). NP upregulated Bax, downregulated Bcl2, and increased cell apoptosis in the HC and PFC. The rats treated with MLT eliminated the effects of NP, as the reduced pain severity, improved anxiety- and depressive-like behaviors, ameliorated NF-κB/NLRP3 inflammasome pathways, and modulated levels of cytokines in the HC and PFC. MLT could promote cell survival from apoptosis by modulating Bax and Bcl2. Therefore, it might be inferred that its anti-inflammatory and anti-apoptotic properties mediate the beneficial effects of MLT in NP-induced affective disorders.

Wharton's jelly mesenchymal stem cells attenuate global hypoxia-induced learning and memory impairment via preventing blood-brain barrier breakdown.

Objectives: Intracerebroventricular (ICV) injections of mesenchymal stem cells (MSCs) may improve the function and structure of blood-brain barrier (BBB), possibly by preserving the BBB integrity. This study examined the impact of Wharton's jelly (WJ)-MSCs on cognitive dysfunction and BBB disruption following a protracted hypoxic state. Materials and Methods: Twenty-four male Wistar rats were randomly studied in four groups: Control (Co): Healthy animals, Sham (Sh): Rats were placed in the cage without hypoxia induction and with ICV injection of vehicle, Hypoxic (Hx)+vehicle: Hypoxic rats with ICV injection of vehicle (5 µl of PBS), and Hx+MSCs: Hypoxic rats with ICV injection of MSCs. Spatial learning and memory were evaluated one week after WJ-MSCs injection, and then animals were sacrificed for molecular research. Results: Hypoxia increased latency and lowered the time and distance required reaching the target quarter, according to the findings. Furthermore, hypoxic rats had lower gene expression and protein levels of hippocampus vascular endothelial (VE)-cadherin, claudin 5, and tricellulin gene expression than Co and Sh animals (P<0.05). Finally, administering WJ-MSCs after long-term hypoxia effectively reversed the cognitive deficits and prevented the BBB breakdown via the upregulation of VE-cadherin, claudin 5, and tricellulin genes (P<0.05). Conclusion: These findings suggest that prolonged hypoxia induces spatial learning and memory dysfunction and increases BBB disruption, the potential mechanism of which might be via reducing VE-cadherin, claudin 5, and tricellulin genes. Hence, appropriate treatment with WJ-MSCs could reverse ischemia adverse effects and protect the BBB integrity following prolonged hypoxia.

Plant-Derived Antioxidants for Management of COVID-19: A Comprehensive Review of Molecular Mechanisms.

We aimed to review the literature to introduce some effective plant-derived antioxidants to prevent and treat COVID-19. Natural products from plants are excellent sources to be used for such discoveries. Among different plant-derived bioactive substances, components including luteolin, quercetin, glycyrrhizin, andrographolide, patchouli alcohol, baicalin, and baicalein were investigated for several viral infections as well as SARS-COV-2. The mechanisms of effects detected for these agents were related to their antiviral activity through inhibition of viral entry and/or suppuration of virus function. Also, the majority of components exert anti-inflammatory effects and reduce the cytokine storm induced by virus infection. The data from different studies confirmed that these agents may play a critical role against SARS-COVID-2 via direct (antiviral activity) and indirect (antioxidant and anti-inflammatory) mechanisms, suggesting that natural products are a potential option for management of patients with COVID-19 due to the lower side effects and high efficiency.

Benzodiazepines related sexual dysfunctions: A critical review on pharmacology and mechanism of action.

INTRODUCTION: Normal sexual functioning of both men and women, being a very complex process, is affected by numerous issues besides aging. Many factors affect the sexual function and lifestyle of the young population. In this article, we tried to review the literature to update the knowledge on benzodiazepine-related (BZD) sexual dysfunction (SD) and involved mechanisms of actions based on animal and human studies. METHODS: Different standard websites such as PubMed were used to review the literature and keywords including benzodiazepines, sexual dysfunction, gammaaminobutyric acid A (GABAA) receptor and erectile dysfunction were used. RESULTS: SD is one of the most common disorders in males and females which has recently been demonstrated to be associated with psychotropic medications such as antihypertensive agents, tranquilizers, antihistamines, appetite suppressants, antidepressants and anxiolytics. BZDs are among the most common psychotropic agents worldwide. SD including decreased libido, erectile dysfunction (ED) and other undesired sexual urges were observed in the patients receiving BZDs. DISCUSSION: The mechanisms of action of BZDs to induce SD mainly relate to enhanced GABAA receptor function which reduces penile erection.

Immunology, immunopathogenesis and immunotherapeutics of COVID-19; an overview.

Coronavirus disease 2019 (COVID-19) infection which is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to a "public health emergency of international concern" (PHEIC). The infection is highly contagious, has a high mortality rate, and its pathophysiology remains poorly understood. Pulmonary inflammation with substantial lung damage together with generalized immune dysregulation are major components of COVID-19 pathogenesis. The former component, lung damage, seems to be at least in part a consequence of immune dysregulation. Indeed, studies have revealed that immune alteration is not merely an association, as it might occur in systemic infections, but, very likely, the core pathogenic element of COVID-19. In addition, precise management of immune response in COVID-19, i.e. enhancing anti-viral immunity while inhibiting systemic inflammation, may be key to successful treatment. Herein, we have reviewed current evidence related to different aspects of COVID-19 immunology, including innate and adaptive immune responses against the virus and mechanisms of virus-induced immune dysregulation. Considering that current antiviral therapies are chiefly experimental, strategies to do immunotherapy for the management of disease have also been reviewed. Understanding immunology of COVID-19 is important in developing effective therapies as well as diagnostic, and prophylactic strategies for this disease.

Intrathecal administration of the extracellular vesicles derived from human Wharton's jelly stem cells inhibit inflammation and attenuate the activity of inflammasome complexes after spinal cord injury in rats.

Activation of inflammasome complexes during spinal cord injury (SCI) lead to conversion of pro-inflammatory cytokines, interleukin-1beta (IL-1ß) and interleukin-18 (IL-18) to their active form to initiates the neuroinflammation. Mesenchymal stem cells (MSCs) showed anti-inflammatory properties through their extracellular vehicles (EVs). We investigated immunomodulatory potential of human Wharton's jelly mesenchymal stem cells derived extracellular vesicles (hWJ-MSC-EVs) on inflammasome activity one week after SCI in rats. The gene expression and protein level of IL-1ß, IL-18, tumor necrosis factor alpha (TNF-α) and caspase1, were assessed by QPCR and western blotting. Immunohistochemistry (IHC) was done to measure the glial fibrillary acidic protein (GFAP) and Nestin expression. Cell death, histological evaluation and hind limb locomotion was studied by TUNEL assay, Nissl staining and Basso, Beattie, Bresnaham (BBB), respectively. Our finding represented that intrathecally administrated of hWJ-MSC-EVs significantly attenuated expression of the examined factors in both mRNA (P < 0.05 and P ≤ 0.01) and protein levels (P < 0.05 and P ≤ 0.01), decreased GFAP and increased Nestin expression (P < 0.05), reduced cell death and revealed the higher number of typical neurons in ventral horn of spinal cord. Consequently, progress in locomotion. We came to the conclusion that hWJ-MSC-EVs has the potential to control the inflammasome activity after SCI in rats. Moreover, EVs stimulated the neural progenitor cells and modulate the astrocyte activity.

Co-administration of Aluminum Sulfate and Propolis Regulates Matrix Metalloproteinases-2/9 Expression and Improves the Uterine Leiomyoma in Adult Rat Model.

The aim of this study was to evaluate the effects of aluminum sulfate (alum) with propolis (PR) on uterine leiomyoma (UL) in rat model. One hundred and four female Wistar rats (180-200 g) were allocated into two main groups of control (Co, n = 8) and experiment (UL model [estradiol benzoate 200 µg/kg/IM twice/week/8 weeks] with/without treatment) defined in 13 subgroups with/without treatment with coil oil (UL + COi), PR (100 or 200 mg/kg) as UL + PR100 or 200, alum (35, 75 or 150 mg/Kg) as UL + AL 35, 75, or 150, and PR (100 mg/kg or 200) with alum (35, 75, or 150 mg/Kg) as UL + PR100 or 200 + AL35, 75, or 150. Subgroups received doses of therapeutics for 14 days (IP). In the end, rats were sacrificed, and the uteri were isolated for molecular and histopathological investigations. The myometrium thickness, collagen contents, and gene expression of MMP-2 and 9 increased significantly in experimental groups with/without treatment (P Ë‚ 0.05). PR administration (100 and 200 mg/kg) alone or with alum (35 and 75 mg/kg) significantly decreased myometrium collagen contents and the gene expression and protein concentration of MMP-2 and 9 compared with UL and UL + Coi subgroups (P Ë‚ 0.05). Alum (75 mg/kg) with PR (200 mg/kg) could improve UL features and reduce MMP-2 and 9 gene expression.

Modulating Pro-inflammatory Cytokines, Tissue Damage Magnitude, and Motor Deficit in Spinal Cord Injury with Subventricular Zone-Derived Extracellular Vesicles.

BACKGROUND: The upregulation of TNF-α, IL-1ß, IL-18, and IL-6 exacerbates the spinal cord injury by amplifying the neuroinflammation. Impeding the release and activation of these cytokines can stop the progression of lesion and promote healing. Modulating the inflammatory response with subventricular zone-derived extracellular vesicles (SVZ-EVs) is one highly promising approach. METHODS AND MATERIALS: SVZ tissue was cultured and EVs were prepared, isolated, and injected intrathecal, in spinal cord-injured (SCI) rats. BBB locomotor scoring, qRT-PCR, Western Blot, H&E, and Nissl staining techniques were applied to record the outcomes. RESULTS: The intracisternally injected SVZ-EVs significantly decreased the gene and protein expression of TNF-α, IL-1ß, IL-18, and IL-6, prevented extensive tissue damage, allowed healing, and improved the hind limb motor function in SCI models. CONCLUSION: The results of the present study showed that SVZ-EVs therapy ameliorate inflammation, tissue damage, and motor deficit in traumatic spinal cord injury.