Protective role of alpha-lipoic acid against rhabdomyolysis-induced acute kidney injury in rats.

Objectives: Rhabdomyolysis, a potentially life-threatening condition, occurs when myoglobin is released from damaged muscle cells, leading to acute kidney injury (AKI). Alpha lipoic acid (ALA), an organosulfur compound known for its anti-oxidant and anti-inflammatory properties, was examined in this study for its potential impact on rhabdomyolysis-induced AKI in rats. Materials and Methods: Six groups of rats were included in the study, with each group consisting of six rats (n=6): Control, rhabdomyolysis, rhabdomyolysis treated with different doses of ALA (5, 10, and 20 mg/kg), and ALA alone (20 mg/kg) groups. Rhabdomyolysis was induced by intramuscular injection of glycerol on the first day of the experiment, while ALA was administered intraperitoneally for four consecutive days. Renal function parameters, oxidative stress markers, and histological changes in the kidneys were evaluated. Western blot analysis was performed to measure the levels of neutrophil gelatinase-associated lipocalin (NGAL) and tumor necrosis factor-alpha (TNF-α) proteins. Results: A significant increase in serum urea, creatinine, renal malondialdehyde, NGAl, and TNF-α protein levels was observed in glycerol-injected rats. In addition, a significant decrease in glutathione was recorded. Compared to the rhabdomyolysis group, treatment with ALA recovered kidney histological and biochemical abnormalities. Conclusion: Results suggest that rhabdomyolysis-induced AKI is associated with increased oxidative stress and inflammation. Treatment with ALA improved kidney histological abnormalities and reduced oxidative stress markers in rats. Therefore, ALA may have a potential protective effect against rhabdomyolysis-induced AKI.

Evaluation of Three Methods for the Treatment of Dentin Hypersensitivity: A Randomised Clinical Trial.

OBJECTIVES: In this study, we aimed to compare the effectiveness of Gluma and high-power 980-nm diode laser, alone or in combination, in the treatment of cervical dentin hypersensitivity. METHODS: A total of 20 patients (5 men and 15 women), aged 25 to 60 years, who met the inclusion criteria, were enrolled in this study. A total of 60 teeth were randomly divided into 4 groups: G1, 980 nm diode laser (in 2 sessions within a 1-week interval); G2, Gluma (in 2 sessions within a 1-week interval); G3, 980 nm diode laser plus Gluma; and G4: control. Thermal (cold spray) and air blast (air syringe of dental unit) stimuli were used to evaluate cervical dentin hypersensitivity in the patients. Their pain response was assessed using a visual analogue scale (VAS) before treatment (baseline), in the first treatment session (15 minutes after treatment), in the second treatment session (after 1 week), and in 2-week, 1-month, and 3-month follow-up sessions. The obtained data were analysed using non-parametric tests, including Kruskal-Wallis test, Friedman test, Mann-Whitney test, and Wilcoxon test, in SPSS Version 22 at a significance level of P < .05. RESULTS: Based on the results, there was a significant difference in the average VAS scores for cold and air blast stimuli between the 4 groups 1 month after the intervention (P < .05). Meanwhile, the laser group had the lowest VAS score for cold and air stimuli. On the contrary, no significant difference was found between the 4 groups 3 months after the intervention (P ˃ .05). CONCLUSION: The present results showed that 980-nm diode laser alone was more effective than the other 2 intervention methods for 1 month. TRIAL REGISTRATION: The study was registered in the Iranian Registry of Clinical Trials (IRCT20120901010703N5).

Renoprotective effect of thymoquinone against rhabdomyolysis-induced acute kidney injury in the rat model.

Objectives: Rhabdomyolysis leads to the release of myoglobin, sarcoplasmic proteins, and electrolytes into the blood circulation causing acute kidney injury (AKI). Thymoquinone, a natural compound found in Nigella sativa seeds, has antioxidant and anti-inflammatory effects. This investigation assessed the renoprotective effect of thymoquinone on rhabdomyolysis-induced AKI in rats. Materials and Methods: Male Wistar rats were categorized into six groups (n = 6): 1. Control: (normal saline), 2. Glycerol (50 ml/kg, single dose, IM), 3-5: Glycerol + thymoquinone (1, 2.5 and 5 mg/kg, 4 days, IP), 6. Thymoquinone (5 mg/kg). On day 5, serum and kidney tissue were isolated and the amounts of serum creatinine and blood urea nitrogen (BUN), renal malondialdehyde (MDA), glutathione (GSH.), tumor necrosis factor-alpha (TNF-α), neutrophil gelatinase-associated lipocalin (NGAL), and pathological changes were evaluated. Results: Glycerol increased creatinine, BUN, MDA, TNF-α, and NGAL levels. It decreased GSH amounts and caused renal tubular necrosis, glomerular atrophy, and myoglobin cast in kidney tissue. Co-administration of glycerol and thymoquinone reduced creatinine, BUN, histopathological alterations, and MDA levels, and enhanced GSH amounts. Administration of glycerol and thymoquinone (5 mg/kg) had no significant effect on TNF-α amount but decreased NGAL protein levels. The administration of thymoquinone (5 mg/kg) alone did not display a significant difference from the control group. Conclusion: Rhabdomyolysis from glycerol injection in rats can cause kidney damage. Thymoquinone may attenuate renal dysfunction and oxidative stress. However, the TNF-α level was not significantly affected. Further studies are needed to explore the potential therapeutic effects of thymoquinone in managing AKI.

Effects of Propolis-Based Herbal Toothpaste on Dentine Hypersensitivity.

INTRODUCTION: The objective of this in vitro study was to compare the effectiveness of a propolis-based herbal toothpaste with 5% sodium fluoride varnishin obstructing human dentinal tubules; Scanning electron microscopy was utilised to obtain quantitative and qulitative data on tubular obstruction. METHODS: Thirty-nine extracted human premolar teeth were collected. The cementum layer was removed using a water-cooled diamond bur and the smear layer using ethylenediaminetetraacetic acid (EDTA) 17%. Then, the samples were randomly divided into 3 groups (n = 13 each), as follows: group 1: dentin discs exposed to the propolis-based herbal toothpaste (Herbex); group 2: dentin discs exposed to 5% sodium fluoride varnish; and group 3: control. Then, all discs were observed and imaged in 4 non-overlapping fields by an electron microscope at 2000× magnification. The topography and number of open, closed, and semi-closed tubules were counted in all images. The data were analysed using Kruskal-Wallis test, Mann-Whitney U test, and Friedman test. The statistical analysis was performed with SPSS statistic 22.0 software, with a significance level of α = 0.05. RESULTS: In pairwise comparisons of the groups considering the percentage of open, closed, and semi-closed tubules, the difference was not statistically significant between the 5% sodium fluoride varnish and propolis groups in the closed and semi-closed tubules, but it was statistically significant with the control group. Additionally, the percentage of open tubules in the propolis-based herbal toothpaste group was significantly lower than in the 5% sodium fluoride varnish and control group. CONCLUSIONS: Both propolis-based herbal toothpaste and 5% sodium fluoride varnish is effective in blocking human dentin tubules to various extents.

Structure of PD1 and its mechanism in the treatment of autoimmune diseases.

PD-1 and CTLA-4 can play an important role in addressing the issue of autoimmune diseases. PD-1 is a transmembrane glycoprotein expressed on T, B, and Dentric cells. This molecule functions as a checkpoint in T cell proliferation. Ligation of PD-1 with its ligands inhibits the production of IL-2, IL-7, IL-10, and IL-12 as well as other cytokines by macrophages, natural killer (NK) cells, and T cells, which can suppress cell proliferation and inflammation. Today, scientists attempt to protect against autoimmune diseases by PD-1 inhibitory signals. In this review, we discuss the structure, expression, and signaling pathway of PD-1. In addition, we discuss the importance of PD-1 in regulating several autoimmune diseases, reflecting how manipulating this molecule can be an effective method in the immunotherapy of some autoimmune diseases.

STA-21, a small molecule STAT3 inhibitor, ameliorates experimental autoimmune encephalomyelitis by altering Th-17/Treg balance.

BACKGROUND: Numerous studies have demonstrated the role of T helper (Th) 17 and T regulatory (reg) cells and pro-inflammatory and anti-inflammatory cytokines related to these cells in the pathogenesis of MS and its animal model, experimental autoimmune encephalomyelitis (EAE). STAT3 is one of the downstream signaling proteins of IL-23, IL-6, and IL-21 that are required for Th17 cells differentiation. STA-21 is a STAT3 inhibitor that functions by inhibiting STAT3 dimerization and binding to DNA impairing the expression of STAT3 target genes including, RORγt, IL-21 and IL-23R that are also required for Th17 cell differentiation. AIM: In this study, we evaluated the effect of STA-21 on EAE Model and investigated how this small molecule can change Th17/Treg balance leading to amelioration of disease. METHODS: After EAE induction and treatment with STA-21, its effects were assessed. Major assays were H&E and LFB staining, Flow cytometric analysis, Reverse transcription-PCR (RT-PCR), and ELISA. RESULTS: STA-21 ameliorated the EAE severity and decreased the EAE inflammation and demyelination. It also decreased STAT3 phosphorylation, the proportion of Th17 cells and the protein level of IL-17. In contrast, the balance of Tregs and the level of anti-inflammatory cytokine, IL-10 increased in STA-21-treated mice. Moreover, STA-21 significantly decreased the expression of Th17 related transcription factors, RORɣt and IL-23R while FOXP3 expression associated with Treg differentiation was increased. CONCLUSION: This study showed that STA-21 has therapeutic effects in EAE by reducing inflammation and shifting inflammatory immune responses to anti-inflammatory and can be used as a suitable treatment strategy for the treatment of EAE. The effectiveness of inhibiting or strengthening the functional cells of the immune system by these small molecules in terms of easy to access, simple construction and inexpensive expansion make them as a suitable tool for the treatment of inflammatory and autoimmune diseases.

Comprehensive comparison of theranostic nanoparticles in breast cancer.

Breast cancer is the most frequently happening cancer and the most typical cancer death among females. Despite the crucial progress in breast cancer therapy by using Chemotherapeutic agents, most anti-tumor drugs are insufficient to destroy exactly the breast cancer cells. The noble method of drug delivery using nanoparticles presents a great promise in treating breast cancer most sufficiently and with the least harm to the patient. Nanoparticles, with their spectacular characteristics, help overcome problems of this kind. Unique features of nanoparticles such as biocompatibility, bioavailability, biodegradability, sustained release, and, most importantly, site-specific targeting enables the Chemotherapeutic agents loaded in nanocarriers to differentiate between healthy tissue and cancer cells, leading to low toxicity and fewer side effects. This review focuses on evaluating and comprehending nanoparticles utilized in breast cancer treatment, including the most recent data related to the drugs they can carry. Also, this review covers all information related to each nanocarrier, such as their significant characteristics, subtypes, advantages, disadvantages, and chemical modification methods with recently published studies. This article discusses over 21 nanoparticles used in breast cancer treatment with possible chemical ligands such as monoclonal antibodies and chemotherapeutic agents binding to these carriers. These different nanoparticles and the unique features of each nanocarrier give the researchers all the data and insight to develop and use the brand-new drug delivery system.

High-Frequency TiO2 Nanotube-Adapted Microwave Coplanar Waveguide Resonator for High-Sensitivity Ultraviolet Detection.

Ultraviolet (UV) sensors are a key component in growing applications such as water quality treatment and environmental monitoring, with considerable interest in their miniaturization and enhanced operation. This work presents a passive gold coplanar waveguide split ring resonator integrated with anodic self-organized TiO2 nanotube (TNT) membranes with a thickness of 20 µm to provide real-time UV detection. The resonator operated as a one-port device to capture the reflection coefficient (S11) signal, with a center frequency of 16 GHz and a notch amplitude of -88 dB. It was experimentally analyzed for its UV sensing capability in the range of 36.5-463 µW/cm2. The high-frequency resonator was improved through design choices including the addition of a tapered input transmission line, wire bonding for practical device design, and an interdigitated capacitive ring gap. The high frequency also helped mitigate noise due to water vapor or environmental contaminants. S11 amplitude variation was found through both experiments and modeling to follow a linear trend with UV illumination intensity. The resonator exhibited over 45 ± 2 dB shift in the resonant amplitude under the highest UV illumination conditions, with a sensitivity of 0.084 dB/µW cm-2 and the potential to sense UV intensity as low as 2.7 µW/cm2. The presented device enabled a repeatable and accurate microwave response under UV illumination with very high sensitivity, entirely through the use of passive circuit elements.

Under hypoxic conditions, MSCs affect the expression and methylation level of survival-related genes in ALL independent of apoptosis pathways in vitro.

Mesenchymal stem cells (MSCs) are one of the most prominent cells in the bone marrow. MSCs can affect acute lymphocytic leukemia (ALL) cells under hypoxic conditions. With this aim, we used MOLT-4 cells as simulators of ALL cells cocultured with bone marrow mesenchymal stem cells (BMMSCs) under hypoxic conditions in vitro. Then, mRNA and protein expression of the MAT2A, PDK1, and HK2 genes were evaluated by real-time PCR and Western blot which was also followed by apoptosis measurement by a flow-cytometric method. Next, the methylation status of the target genes was investigated by MS-qPCR. Additionally, candidate gene expressions were examined after treatment with rapamycin using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. We found that the mRNA expression of the candidate genes was augmented under the hypoxic condition in which MAT2A was upregulated in cocultured cells compared to MOLT-4, while HK2 and PDK1 were downregulated. Moreover, we found an association between gene expression and promoter methylation levels of target genes. Besides, expressions of the candidate genes were decreased, while their methylation levels were promoted following treatment with rapamycin. Our results suggest an important role for the BMMSC in regulating the methylation of genes involved in cell survival in hypoxia conditions; however, we found no evidence to prove the MSCs' effect on directing malignant lymphoblastic cells to apoptosis.

Ruxolitinib attenuates experimental autoimmune encephalomyelitis (EAE) development as animal models of multiple sclerosis (MS).

AIMS: STAT3 signaling is critical for Th17 development that plays an important role in multiple sclerosis pathogenesis. To evaluate the anti-inflammatory and regulatory T cells effects of JAK1/2 and STAT3 inhibition, we assessed the JAK 1/2 inhibitor ruxolitinib effects on Th17 cell/Tregs balance. MAIN METHODS: Ruxolitinib was administered to experimental autoimmune encephalomyelitis (EAE) mice via oral gavage, and its effects were assessed. The expression of pro-inflammatory and anti-inflammatory cytokines, including IL-17A and IL-10, were analyzed by real-time PCR. The frequency of Th17 cells and Tregs were evaluated by flow cytometry. KEY FINDING: Ruxolitinib ameliorated the EAE severity and decreased the proportion of Th17 cells and inflammatory markers levels. In contrast, the balance of Tregs and the level of anti-inflammatory cytokine were increased in ruxolitinib-treated mice. Furthermore, ruxolitinib markedly decreased the expression of Th17 related transcription factor, RORÉ£t, whereas FOXP3 expression associated with Treg differentiation was increased. SIGNIFICANCE: Our results show that ruxolitinib may be a promising therapeutic strategy for multiple sclerosis.

miR-193a-5p as a promising therapeutic candidate in colorectal cancer by reducing 5-FU and Oxaliplatin chemoresistance by targeting CXCR4.

Colorectal cancer (CRC) is one of the most common causes of cancer-related deaths worldwide. The role of microRNAs (miRNAs/miRs) as small (19-25 nucleotides in length) non-coding RNA molecules that modify gene expression has been shown in several types of cancer. 5-Fluorouracil (5-FU) and oxaliplatin (Ox) are two common chemotherapeutic agents used to treat cancer. The present study aimed to evaluate the expression levels of miR-193a-5p in CRC, and its effect on the C-X-C Motif Chemokine Receptor 4 (CXCR4) target gene alone and in combination with chemotherapeutic drugs, to determine its possible role in chemoresistance. CRC tissues and adjacent non-cancerous tissue were obtained from 67 patients who had undergone surgery to determine the expression levels of miR-193a-5p and CXCR4. Subsequently, qPCR and Western blotting were performed to determine the effect of miR-193a-5p and chemotherapy drugs on CXCR4. َAlso, MTT assay, and flow cytometry was performed to determine their role in cell viability and apoptosis. Besides, the relationship between miR-193a-5p and CXCR4 with patients' clinical features was investigated. The results of the present study showed that miR-193a-5p was significantly downregulated, whereas CXCR4 was significantly upregulated in tumor tissues obtained from patients with CRC compared with the adjacent non-tumor healthy controls. In addition, the upregulation of miR-193-5p reduced the expression levels of CXCR4, particularly in combination with 5-FU and OX. Besides, using rescue experiments, the present study showed that miR-193a-5p replacement was able to suppress CXCR4-induced CRC cell proliferation by directly targeting CXCR4. Furthermore, there was a significant association between miR-193a-5p and CXCR4 with certain clinicopathological characteristics, particularly with metastasis-related features. These results suggest that miR-193a-5p serves a tumor-suppressive function in CRC and can directly target CXCR4 and decrease its mRNA and protein expression levels. Additionally, miR-193a-5p in combination with 5-FU and Ox potentiated reducing CXR4 expression, which may reveal its contribution to tumor chemoresistance. In conclusion, miR-193-5p may be applicable as a prognostic and diagnostic marker, and also serve as a therapeutic factor by reducing CXCR4 in combination with chemotherapeutic drugs.

Epigenetic mechanisms shape the underlining expression regulatory mechanisms of the STAT3 in multiple sclerosis disease.

OBJECTIVES: Immunological tolerance is mediated by CD4+CD25+ regulatory T (Treg) cells. Studies have shown that thymic and peripheral generations of Treg cells depend on the CD28 signaling pathway. T helper 17 (Th17) cells are involved in the pathophysiology of various inflammatory diseases. Cytokines, such as interleukin (IL)-6 and TGF-ß, regulate the reciprocal development of Th17 and Treg cells. In CD4+ T cells, signal transducer and activator of transcription 3 (STAT3) play a critical role in the induction of Th17 cell differentiation and inhibition of Treg cell development. RESULTS: In this study, we investigated the STAT3 methylation and gene expression status in patients with MS. Our study demonstrated that the level of STAT3 methylation decreased in relapsing-remitting MS patient compared to control groups, which the decreases were statistically significant. STAT3 gene expression increased in patient group relative to healthy one, and the increases were found to be statistically significant. According to our findings, it can be suggested that DNA hypermethylation of STAT3 affects the gene expression. In addition, there is a strong and significant negative correlation between the methylation status and mRNA level of STAT3.

Innate and adaptive immune responses against coronavirus.

Coronaviruses (CoVs) are a member of the Coronaviridae family with positive-sense single- stranded RNA. In recent years, the CoVs have become a global problem to public health. The immune responses (innate and adaptive immunity) are essential for elimination and clearance of CoVs infections, however, uncontrolled immune responses can result in aggravating acute lung injury and significant immunopathology. Gaining profound understanding about the interaction between CoVs and the innate and adaptive immune systems could be a critical step in the field of treatment. In this review, we present an update on the host innate and adaptive immune responses against SARS-CoV, MERS-CoV and newly appeared SARS-CoV-2.

Targeting STAT3 in cancer and autoimmune diseases.

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that is activated downstream of a broad range of receptors particularly interleukin-6 (IL-6) family. STAT3 is the key regulator of cell proliferation, survival and apoptosis and is constitutively activated in most human cancers, indicating that it can be an important potential therapeutic target for cancer treatment. STAT3 also has important roles in lymphocyte biology, regulation of immune responses and autoimmunity. Considering the vital role of STAT3 in tumor progression and autoimmunity, scientists have focused to develop small molecules that suppress STAT3 function. In this review, we firstly discussed the predominant role of STAT3 in cancer and autoimmune diseases. Subsequently, we discussed the efficacy and therapeutic potential of different STAT3 inhibitors in cancer and autoimmune diseases in preclinical studies and clinical trials offering an insight into novel approaches for development of new STAT3 inhibitors.

The role of B cells in the immunopathogenesis of multiple sclerosis.

There is ongoing debate on how B cells contribute to the pathogenesis of multiple sclerosis (MS). The success of B-cell targeting therapies in MS highlighted the role of B cells, particularly the antibody-independent functions of these cells such as antigen presentation to T cells and modulation of the function of T cells and myeloid cells by secreting pathogenic and/or protective cytokines in the central nervous system. Here, we discuss the role of different antibody-dependent and antibody-independent functions of B cells in MS disease activity and progression proposing new therapeutic strategies for the optimization of B-cell targeting treatments.

Janus kinase inhibitors: A therapeutic strategy for cancer and autoimmune diseases.

Many cytokines are crucial drivers of cancers and autoimmune conditions. These proteins bind to receptors and signal their responses through Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathways. Genetic variations in the JAK-STAT pathway are correlated with the increased risk of cancers, autoimmunity as well as inflammatory diseases. Targeting JAKs and STATs can be a safe and efficacious strategy for treating these diseases. Tofacitinib, as the first JAK inhibitor, is approved for rheumatoid arthritis therapy. Also, many other JAK inhibitors have been proven or are in various phases of clinical trials for various diseases. At present, small-molecule JAK inhibitors are considered as a novel category of drugs in the treatment of cancer and immune-mediated diseases.

CTLA-4: From mechanism to autoimmune therapy.

CD28 and CTLA-4 are both important stimulatory receptors for the regulation of T cell activation. Because receptors share common ligands, B7.1 and B7.2, the expression and biological function of CTLA-4 is important for the negative regulation of T cell responses. Therefore, elimination of CTLA-4 can result in the breakdown of immune tolerance and the development of several diseases such as autoimmunity. Inhibitory signals of CTLA-4 suppress T cell responses and protect against autoimmune diseases in many ways. In this review, we summarize the structure, expression and signaling pathway of CTLA-4. We also highlight how CTLA-4 defends against potentially self-reactive T cells. Finally, we discuss how the CTLA-4 regulates a number of autoimmune diseases that indicate manipulation of this inhibitory molecule is a promise as a strategy for the immunotherapy of autoimmune diseases.

IL-21 and IL-21-producing T cells are involved in multiple sclerosis severity and progression.

Multiple sclerosis is a common neuroinflammatory disease of the central nervous system causing nervous system defects and severe physical disability. IL-21 is a proinflammatory cytokine produced mainly by Th-17 and Tfh cells which its exact role in MS was not yet clearly understood. In the present study we aimed to investigate the possible correlation of IL-21 gene expression, methylation, and its serum levels with MS severity and progression. The results showed that IL-21 mRNA level and serum level were significantly increased in patient group compared with control group (p = 0.02 and p < 0.0001 respectively). Moreover, we found a strong positive correlation between IL-21 mRNA levels and EDSS scores (r = 0.637, P < 0.0001), IL-21 mRNA levels and Progression Index (r = 0.540, P < 0.0001), IL-21 serum levels and EDSS scores (r = 0.617, P < 0.0001), and IL-21 serum levels and Progression Index (r = 0.527, P < 0.0001) in MS patients. Additionally, we found that the methylation level of IL-21 promoter region was decreased in patient group compared with the control group (p < 0.0001). We also found that methylation level of IL-21 gene promoter is negatively correlated with the IL-21 mRNA level (r = -0.263, p = 0.02), serum level (r = -0.249, p = 0.03), EDSS scores (r = -0.276, p = 0.01) and Progression Index (r = -0.430, p = 0.0001). Data showed that the increased percentages of IL-21-producing Tfh-like, Th-17 and Th1 cells in patients are positively correlated with MS severity and progression. The results of our study suggest a pro-inflammatory and booster role for IL-21 in the MS pathogenesis and progression.