Preemptive administration of mesenchymal stem cells-derived conditioned medium can attenuate the development of neuropathic pain in rats via downregulation of proinflammatory cytokines.

Neuropathic pain (NP) is a chronic condition characterized by persistent pain following nerve injury. It is a challenging clinical problem to manage due to limited treatment options. Mesenchymal stem cells (MSCs)-derived conditioned medium (CM) is a cell-free product that contains the secretome of MSCs and has been shown to have therapeutic potential in various inflammatory and degenerative disorders. Several animal studies have examined the antinociceptive effects of MSCs-CM on established neuropathic pain, but none have investigated the early prevention of neuropathic pain using MSCs-CM. Therefore, in this study, we tested whether preemptive administration of MSCs-CM could attenuate the development of NP in rats. To this end, NP was induced in Wistar rats using a chronic constriction injury (CCI) model (day 0), and then the animals were divided into four groups: Sham, CCI, CCI-Dulbecco's Modified Eagle Medium (DMEM), and CCI-CM. The CCI-CM group received 1 ml intraperitoneal administration of MSCs-CM on days - 1, 1, and 2, while the Sham, CCI, and CCI-DMEM groups received vehicle only (normal saline or DMEM). Mechanical withdrawal threshold and thermal withdrawal latency were assessed to evaluate pain sensitivities. In addition, the expression levels of proinflammatory cytokines (TNF-α and IL-1ß) in the spinal cord tissues were measured using quantitative real-time PCR (qRT-PCR). The results demonstrated that preemptive treatment with MSCs-CM can significantly attenuate the development of NP, as evidenced by improved mechanical withdrawal threshold and thermal withdrawal latency in the CCI-CM group compared to the CCI and CCI-DMEM groups. Furthermore, the relative gene expression of proinflammatory cytokines TNF-α and IL-1ß were significantly decreased in the spinal cord tissues of the CCI-CM group compared to the control groups. These findings suggest that preemptive administration of MSCs-CM can attenuate the development of NP in rats, partly due to the downregulation of proinflammatory cytokines.

Relationship between blood-based inflammatory indices and clinical score of schizophrenia patients: A cross-sectional study.

Schizophrenia is a severe mental disorder that may involve inflammation. Inflammatory indices, such as the neutrophil to lymphocyte ratio (NLR), the monocyte to lymphocyte ratio (MLR), the platelet to lymphocyte ratio (PLR), and the systemic inflammation index (SII), are simple and inexpensive measures of inflammation that have been associated with various diseases. However, few studies have compared these indices and their relationships with clinical symptoms in schizophrenia. We conducted a cross-sectional study of 121 schizophrenia patients (101 males, 20 females). We measured the blood-based inflammatory indices (NLR, MLR, PLR, and SII) and assessed the clinical symptoms of schizophrenia using the Positive and Negative Syndrome Scale (PANSS). Statistical analyses were performed to examine the correlations and effects of the inflammatory indices on PANSS scores. We found that NLR, MLR, PLR, and SII were positively correlated with PANSS total score, PANSS positive score, PANSS negative score, and general psychopathology score (adjusted P < 0.02 for all correlations). Subgroup analysis showed that correlations between inflammatory indices and the clinical scores differed by gender. In males, all inflammatory indices were positively correlated with all clinical scores. On the other hand, in females, only NLR and SII were positively correlated with all clinical scores. After adjusting for confounders, we also found that NLR was a predictor of PANSS total score (ß = 23, adjusted P < 0.02), PANSS positive score (ß = 2.6, adjusted P = 0.03), PANSS negative score (ß = 6.8, adjusted P < 0.02), and PANSS general psychopathology score (ß = 13.6, adjusted P < 0.02), while SII was only a predictor for PANSS total score (ß = -0.00003, adjusted P = 0.01) and general psychopathology scores (ß = -0.00002, adjusted P < 0.02). These findings suggest that inflammation is involved in the pathophysiology and clinical manifestations of schizophrenia, and that blood-based inflammatory indices may serve as screening tools or indicators for the inflammatory status and severity of symptoms of schizophrenia patients.

Caffeine modulates apoptosis, oxidative stress, and inflammation damage induced by tramadol in cerebellum of male rats.

Tramadol, an opioid used as analgesic, can induce neurotoxic effects associated to cognitive dysfunction. Moreover, caffeine has been reported to have neuroprotective effects. In this regard, we hypothesized that administration of caffeine can modulate tramadol-induced damages in cerebellum. For this study, forty male Wistar rats were divided into four groups: the control group, the tramadol group (50 mg/kg), the caffeine group (37.5 mg/kg), and the tramadol+caffeine group (50 mg/kg tramadol+37.5 mg/kg caffeine). At the end of study (day 21), after performing rotarod behavioral test, cerebellum tissue samples were removed and prepared for further evaluations including biochemical profile markers (MDA, GPx, and SOD), immunohistochemistry for Caspase-3, as well as the expression of genes involved in cellular processes such as inflammation markers (IL-1ß, HMGB1, IL-6, and TNF), apoptosis markers (Caspase-3, Caspase-8, Bax, and P21), and autophagy markers (LAMP2, ATG5, BECN1, and ATG12). Stereological evaluations were performed to determine the total volume of granular and molecular layers and white matter of cerebellum tissue and numerical density of the Purkinje cells. Our results showed that the stereological parameters, biochemical profiles (except MDA) and behavioral function were significantly higher in the tramadol+caffeine group compared to the tramadol group. Autophagy-related genes were significantly upregulated in tramadol+caffeine group compared to the tramadol group. While the expression of inflammatory and apoptosis genes, MDA level, as well as density of apoptosis cells were significantly lower in the tramadol+caffeine group compared to the tramadol group. Briefly, it can be concluded that administration of caffeine has neuroprotective effects in cerebellar damages induced by tramadol.

COVID-19 Vaccination in Patients With Malignancy; A Systematic Review and Meta-Analysis of the Efficacy and Safety.

Background: Data on the efficacy and safety of COVID-19 vaccines in patients with malignancy are immature. In this paper, we assessed the literature involving the use of COVID-19 vaccines in cancer patients and reported the seroconversion rates as the main outcome and severity of COVID-19 infection and side effects following COVID-19 vaccination as the secondary outcomes. Methods: A systematic review with meta-analysis was performed. Searches were conducted in electronic websites, databases, and journals, including Scopus, PubMed, Embase, and Web of Science from January 01, 2019, to November 30, 2021. Studies reporting data on the safety and efficacy of COVID vaccine in cancer patients using any human samples were included. The risk of bias was assessed using the NEWCASTLE-OTTAWA scale in the included studies. Results: A total of 724 articles were identified from databases, out of which 201 articles were duplicates and were discarded. Subsequently, 454 articles were excluded through initial screening of the titles and abstracts. Moreover, 41 studies did not report the precise seroconversion rate either based on the type of cancer or after injection of a second dose of COVID vaccine. Finally, 28 articles met all the inclusion criteria and were included in this systematic review. The overall seroconversion rates after receiving a second dose of COVID-19 vaccine, based on type of cancer were 88% (95% CI, 81%-92%) and 70% (95% CI, 60%-79%) in patients with solid tumors and hematologic malignancies, respectively. Conclusion: Overall, we conclude that vaccination against COVID-19 in patients with active malignancies using activated and inactivated vaccines is a safe and tolerable procedure that is also accompanied by a high efficacy.

Anti-SARS-CoV-2 spike IgG following injection of the third dose vaccine: A systematic review with meta-analysis of heterologous versus homologous vaccination.

Background: The mass vaccination is a key strategy to prevent and control the coronavirus disease 2019 (COVID-19) pandemic. Today, several different types of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been developed worldwide. These vaccines are usually administered in a two-dose schedule, and the third dose is currently being administered in most countries. This study aimed to systematically review and meta-analyze the immunogenicity of heterologous vs. homologous vaccination after administration of the third dose of COVID-19 vaccines. Methods: Electronic databases and websites including Scopus, PubMed, Web of Science, and Google scholar were searched for relevant randomized clinical trial (RCT) studies. After applying the inclusion and exclusion criteria, a total of three RCTs were included in the study. These RCTs were included 2,613 healthy adults (18 years or older and without a history of laboratory-confirmed COVID-19) with 15 heterologous and five homologous prime-boost vaccination regimens. Anti-SARS-CoV-2-spike IgG levels at day 28 after administration of the third dose, were compared between the heterologous and homologous regimens. Results: The highest antibody responses had been reported for the homologous vaccination regimen of m1273/m1273/m1273 (Moderna), followed by the heterologous regimen of BNT/BNT/m1273. In addition, the immunogenicity of viral vector and inactivated vaccines was remarkably enhanced when they had been boosted by a heterologous vaccine, especially mRNA vaccines. Conclusion: This systematic review suggests that mRNA vaccines in a homologous regimen induce strong antibody responses to SARS-CoV-2 compared to other vaccine platforms. In contrast, viral vector and inactivated vaccines show a satisfactory immunogenicity in a heterologous regimen, especially in combination with mRNA vaccines.

Identification of Leishmania species by high-resolution melting analysis in newly emerged foci in Sabzevar, northeast of Iran.

Cutaneous leishmaniasis (CL) is a zoonotic disease with 1 to 1.5 million annual incidences. Microscopic examination of the Giemsa stained slides is the most common diagnostic method for CL. However, this method cannot distinguish leishmania species. Hence the present study was conducted to identify leishmania species by high-resolution melting (HRM) analysis in the newly emerged foci of CL in Sabzevar, northeast of Iran. In this cross-sectional study, fifty patients with suspicious cutaneous lesions referring to the designated health center for diagnosis and treatment of CL in Sabzevar during 2017-2018, were recruited. All collected samples and prepared slides were stained for microscopic examination and then undergone HRM real-time PCR (HRM-PCR) assay to identify species of Leishmania parasites. The results of HRM-PCR technique showed that Leishmania major (L. major) was the dominant causative parasite in the newly emerged foci whereas L. tropica (L. tropica) was positive only in two patients. This was the first time that 7SL RNA-HRM-PCR assay was performed to precisely identify leishmania parasites in the northeast of Iran. We proved the newfound foci in which both L. major and L. tropica were present. In contrast to the recent studies which identified only L. major in the region, we showed that L. tropica was still present.

Effect of the conditioned medium of mesenchymal stem cells on the expression levels of P2X4 and P2X7 purinergic receptors in the spinal cord of rats with neuropathic pain.

Recent studies have shown that mesenchymal stem cells (MSCs) and their conditioned medium (CM) have potential therapeutic effects in animal models of neuropathic pain (NP). However, the mechanisms underlying these effects are not fully understood. Because of the leading involvement of purinergic receptors in the pathogenesis of NP, this study aimed to investigate the effect of MSCs-CM on the expression levels of P2X4 and P2X7 receptors in a rat model of NP induced by chronic constriction injury (CCI) of the sciatic nerve. CM was prepared from the rats' bone marrow-derived MSCs culture. After that, NP rats were treated by intraperitoneal injection of CM, or Dulbecco's modified Eagle's medium (DMEM) 1 day before and 7 and 11 days after CCI surgery. The NP status was assessed in the treated animals using behavioral tests, including mechanical allodynia and thermal hyperalgesia, on days - 1, 3, 6, 9, 12, and 15 of the study. At the end of the study (Day 15), the animals were sacrificed, and the relative gene expression of P2X4 and P2X7 receptors were measured in the spinal cord using quantitative real-time PCR. The results demonstrated that in the CM-treated NP rats, mechanical allodynia and thermal hyperalgesia were significantly reduced compared with the DMEM-treated group. In addition, the expression levels of P2X4 and P2X7 receptors were noticeably prevented in the CM-treated group than the control group. These findings indicate that the antinociceptive effects of CM in the NP rats are partly mediated through preventing the upregulation of P2X4 and P2X7 receptors in the spinal cord.

Effects of curcumin nanoparticle on the histological changes and apoptotic factors expression in testis tissue after methylphenidate administration in rats.

The present article sought to evaluate the impact of curcumin-loaded superparamagnetic iron oxide (Fe3O4) nanoparticles (NPs) on the histological variables and apoptotic agents in adult male rats after 3-weeks of methylphenidate (MPH) oral administration (20 mg/kg) versus vehicle therapy on the testis. Twenty-four male rats have been categorized randomly into four groups, in which Group 1 has been chosen as the controls, and Group 2 has been a vehicle and taken the sesame oil as curcumin carrier. Moreover, Group 3 has been taken MPH (20 mg/kg by gavage for 21 consecutive days). Group 4 received MPH plus Curcumin nanoparticles (5.4 mg/100 g) for twenty-one consecutive days. Then, testis histology, apoptosis as well as stereology have been examined. According to the examinations, curcumin nanoparticles are significantly capable of improving the sperms and stereological variables; for example, round spermatid and Leydig cells by enhancing the level of the serum testosterone in comparison with the MPH and vehicle groups. Besides, it was found that the gene expression in inflammation pathways and apoptosis genes largely diminished in the treatment group by curcumin nanoparticles in comparison with the MPH and vehicle groups, also we observed considerable differences for the weight of testes between the examined groups. Therefore, Curcumin effectively inhibited the testis damages and MPH-induced apoptosis, indicating possible protecting features of the Curcumin nanoparticles in opposition to MPH.

Toxicology of long-term and high-dose administration of methylphenidate on the kidney tissue - a histopathology and molecular study.

The present study aims to assess the influences of oral methylphenidate on kidney function and structure versus vehicle treatment in adult male rats. In this study, thirty adult male rats equally into two treatment groups divided randomly, and among them, MPH has been administered for 21 days, at doses of 20 mg/kg, and the control group has received salin. In renal, under the effect of MPH applying quantitative real-time PCR, we analyzed nephrotoxicity-related molecular pathways like autophagy, inflammation, and apoptosis. Moreover, the levels of GSH, CAT, and SOD were investigated as antioxidant enzymes. Afterward, stereological analysis in MPH-treated rats has been performed. Analysis of qPCR displayed inflammation, impaired autophagy, and enhanced apoptosis with histological changes in the kidney's tissue, also an important rise in the antioxidant enzymes' level. Besides, 20 mg/kg of MPH led to a decline in the mean of Bowman's space thickness and renal corpuscle's volume in comparison to the control rats. Collectively, our histological and molecular data implicit that in the kidney region, administrating of MPH evoked discriminative expression alterations in nephrotoxicity-associated signaling cascades, specifically autophagy, inflammation, and apoptosis paired with important damage to kidney tissue.

Effect of hydroalcoholic extract of Anethum graveolens leaves on the dentate gyrus of the hippocampus in the epileptic mice: a histopathological and immunohistochemical study.

Anethum graveolens or Dill (local name: Shevid) belongs to the family of Apiaceae (Umbelliferae) and is used traditionally for the treatment of convulsion and diabetes in Iran. This study aimed to investigate the effect of hydroalcoholic extract of A. graveolens leaves on the histology of the dentate gyrus of the hippocampus in the epileptic mice kindled by Pentylenetetrazole (PTZ). In this experimental study, the epileptic BALB/c mice kindled by PTZ were randomly divided into four groups of 10 animals each. Three experimental groups received 250, 500 and 750 mg/kg/day of A. graveolens extract for 21 days. The control group received phosphate-buffered saline (PBS). After the treatment period, the mice were anesthetized, and their hippocampi were dissected for the histopathological analysis, and immunohistochemical analysis for caspase-3 activity. Histopathological examinations showed that the mean numbers of the healthy neuronal cells in the dentate gyrus of the mice received 500 mg/kg/day of A. graveolens extracts were significantly higher than those of the mice received 250 and 750 mg/kg/day of the extracts as well as the control group (P < 0.05 and P < 0.001, respectively). In addition, the results of immunohistochemical analysis revealed that in mice treated with 500 mg/kg/day of A. graveolens; the numbers of caspase-3-positive cells in the dentate gyrus were significantly lower than those of the two other test and the control groups. The findings of this study suggest that 500 mg/kg/day of the A. graveolens extract could have protective effect on the dentate gyrus of the hippocampus in the epileptic mice.