Adjunctive silymarin supplementation and its effects on disease severity, oxidative stress, and inflammation in patients with Alzheimer's disease.

BACKGROUND: Brain tissue in Alzheimer's patients is exposed to oxidative stress. Silymarin is an adjunct drug that has anti-inflammatory and antioxidant properties. OBJECTIVE: This study aimed to evaluate the effect of silymarin on biomarkers of oxidative stress, inflammation, and disease severity in Alzheimer's patients. METHODS: This randomized, single-blind clinical trial study was performed on 33 patients with Alzheimer's disease (AD) whose disease was confirmed by DSM-5 criteria and by brain imaging. Patients in the case group received three 250 mg silymarin capsules daily (each containing 150 mg silymarin), as an adjunctive medication in addition to the routine medication regimen. In the placebo group (control), patients received the same amount of placebo. All patients underwent Mini Mental State Exam (MMSE) and a panel of blood tests including malondialdehyde, neopterin, catalase, paraoxonase-1, total oxidative status, and total antioxidant capacity to reevaluate the changes pre/postintervention at the end of the trimester. RESULTS: The catalase and MDA serum levels after the adjunctive silymarin treatment decreased significantly (Catalasebefore silymarin = 9.29 ± 7.02 vs Catalaseafter silymarin = 5.32 ± 2.97, p = 0.007 and MDAbefore silymarin = 4.29 ± 1.90 vs MDAafter silymarin = 1.66 ± 0.84, p < 0.001) while MMSE increased notably (MMSEbefore silymarin = 10.39 ± 6.42 vs MMSEafter silymarin = 13.37 ± 6.81, p < 0.001). CONCLUSION: Silymarin can be effective as an adjunct drug and a powerful antioxidant in reducing oxidative stress and improving the course of AD.

Defining the mechanisms behind the hepatoprotective properties of curcumin.

As a critical cause of human dysfunctionality, hepatic failure leads to approximately two million deaths per year and is on the rise. Considering multiple inflammatory, oxidative, and apoptotic mechanisms behind hepatotoxicity, it urges the need for finding novel multi-targeting agents. Curcumin is a phenolic compound with anti-inflammatory, antioxidant, and anti-apoptotic roles. Curcumin possesses auspicious health benefits and protects against several diseases with exceptional safety and tolerability. This review focused on the hepatoprotective mechanisms of curcumin. The need to develop novel delivery systems of curcumin (e.g., nanoparticles, self-micro emulsifying, lipid-based colloids, solid lipid nanoparticles, cyclodextrin inclusion, phospholipid complexes, and nanoemulsions) is also considered.

Synergistic Effect of Gefitinib and Temozolomide on U87MG Glioblastoma Angiogenesis.

One of the most common and deadly brain tumors is Glioblastoma multiforme (GBM). Due to recent advances in angiogenesis and its related key factors, this process as a hallmark in glioblastoma has attracted more consideration from the research community. Temozolomide (TMZ) as the first-line treatment used to treat GBM but, resistance to TMZ limits its effectiveness and the need for better treatments is still felt. Therefore, we aimed to examine the Synergistic effects of Gefitinib (GFI) in combination with Temozolomide on VEGF and MMPs in glioma cell line (U87MG). Our results displayed that GFI could induce cytotoxic effects in U87MG with IC50 values of 11 µM. U87MG cells produced large amounts of VEGF without any stimuli, and the results showed that GFI in combination with TMZ caused a significant decrease in VEGF production in these cells. In this study, we demonstrated that after treating with TMZ and GFI, there was more decrease in the levels of MMP 2 and 9 secretions in cells than treatment with GFI and TMZ doses alone. This study indicates synergistic effects of GFI plus TMZ against glioma are mediated by the potentiated anti-angiogenesis. Therefore, it can be considered as a promising plan for future studies.

The role of caveolin-1 and endothelial nitric oxide synthase polymorphisms in susceptibility to prostate cancer.

Caveolin-1(cav-1) is overexpressed in prostate cancer (PC) and is associated with progression of the disease. We investigated the effects of CAV1-T29107A and endothelial nitric oxide synthase (eNOS) G894T polymorphisms on the serum levels of testosterone, NO and prostate-specific antigen (PSA) in patients with PC. We genotyped cav-1 and eNOS genes in 112 PC patients and 150 healthy controls by PCR-RFLP. Serum levels of NO2- and NO3- were measured using spectrophotometry, and serum levels of testosterone and PSA were measured by ELISA. The frequencies of CAV1 genotypes A/T vs. A/A according to the dominant model AT + TT vs. AA genotype and T allele were significantly higher in PC patients in comparison with the control group and considerably increased the risk of disease by 2.19-, 1.44- and 1.6-fold, respectively. AT + TT genotypes were associated significantly with the increased risk of PC in those with smoking or diabetes by 3.08-fold (P = .004). Individuals carrying concurrently the T allele of CAV1 A29107T and the T allele of eNOS G894T genes had a significantly increased risk of PC by 2.52-fold (P = .009). We did not find any significant relationship between eNOS G894T genotypes and alleles with susceptibility to PC. Our results highlighted the significance of CAV1-T29107A SNP but not (eNOS) G894T in the susceptibility to PC in our the population that we have studied.

Increased risk of subclinical atherosclerosis and metabolic syndrome in patients with vitiligo: a real association or a coincidence?

Inflammatory and autoimmune skin diseases such as vitiligo may be associated with systemic disorders, including endocrine and cardiovascular diseases, due to some similarities in the pathogenesis. It was aimed to evaluate metabolic syndrome and subclinical atherosclerosis in patients with vitiligo. Seventy patients with nonsegmental vitiligo and 70 age-matched and gender-matched healthy controls participated in the study. These participants were investigated for metabolic syndrome criteria. The mean intima-media thickness of the common carotid artery (MIMT-CCA) of the subjects was measured for assessment of subclinical atherosclerosis. Metabolic syndrome and subclinical atherosclerosis were significantly more frequent in vitiligo patients compared with the controls (P = .006 and P = .002, respectively). In addition, metabolic syndrome and subclinical atherosclerosis had positive, significant correlations with the severity and duration of vitiligo (P = .031 and r = .482; P < .01, respectively). Our study suggested that patients with vitiligo, especially those with more chronic and severe disease or concomitant metabolic syndrome, are at a higher risk of developing cardiovascular diseases. Therefore, early diagnosis and treatment of metabolic syndrome in patients with vitiligo to prevent cardiovascular complications were recommended.

Association of AHSG gene polymorphisms with serum Fetuin-A levels in individuals with cardiovascular calcification in west of Iran.

Fetuin-A (AHSG) is a multifunctional secretory protein and acts as an ectopic valve and artery calcification inhibitor. We assessed the correlation between serum levels of Fetuin-A and both exon 6 (248 C/T) and exon 7 (256 C/G) mutations in patients with coronary artery calcification (CAC), mitral annular calcification (MAC), and aortic valve calcification (AVC). 184 patients and 184 healthy individuals as control group were included. The genetic variants of rs4917 and rs4918 for the AHSG gene were determined by PCR-RFLP and T-ARMS PCR techniques. Fetuin-A levels, fasting blood sugar (FBS), urea, creatinine, calcium phosphorus, and lipid profile were measured. Fetuin-A levels were remarkedly lower in individuals with AVC, MAC, and CAC comparing to the control group (p < 0.001). The CT + TT genotypes and the T allele (AHSG Thr248Met) were associated with the risk of calcification of heart valves and coronary artery by 1.31 and 1.27 times in the patient group, respectively. The frequency of CT genotype and T allele was considerably higher in the patient group comparing to the control group. Patients with T allele (CT + TT) had higher levels of FBS, urea, low-density lipoproteins (LDL)-C, phosphorus, systolic blood pressure (SBP), diastolic blood pressure (DBP) while decreased levels of triglyceride, high-density lipoproteins (HDL)-C, calcium and fetuin-A in comparison to control group. Additionally, there was a positive correlation between serum FBS, urea, creatinine, HDL-C, calcium with fetuin-A, and a negative correlation between phosphorous level, SBP, and DBP with fetuin-A. T allele in rs4917 Single nucleotide polymorphism (SNP) is the risk allele of calcification of heart valves and coronary arteries and fetuin-A levels correlates negatively with the occurrence of the disease.

Effects of silymarin as adjuvant drug on serum levels of CTRP3, anti-cyclic citrullinated peptide (CCP), and high-sensitivity C-reactive protein (hs-CRP) in rheumatoid arthritis patients.

Silymarin is known for its anti-inflammatory and antioxidant properties. We investigated these effects on serum levels of CTRP3, Anti-CCP, and hs-CRP in individuals with Rheumatoid arthritis (RA). In this study, 42 individuals with RA were recruited and their serum specimens were collected, serum levels of hs-CRP, AntiCCP antibodies, and CTRP3 were measured using ELISA. DNA was extracted and investigated for the existence of possible new mutations in the gene encoding CTRP3 using the PCR technique; the desired fragments were then amplified and sequenced. Another blood sample was collected from the case group after taking livergol for three months (3 doses of 140 mg/day) and the tests were repeated. Anti-CCP Abs levels in the postintervention responding group decreased compared to preintervention (p<0.001) while in the non-responding group, the levels increased after the intervention compared to the levels before the intervention (p=0.019). Additionally, CTRP3 levels in the responding group increased postintervention (p=0.003), however, in the non-responding group the levels decreased postintervention when compared to preintervention (p=0.02). The responding group had significantly lower levels of hs-CRP when compared to that of preintervention (p=0.005) whereas the non-responding group had significantly higher levels of postintervention (p<0.001). Moreover, the results of sequencings of exon 6 on CTRP3 gene showed the presence of mutations in exon 6 (position 215:C>T, 338:G>A, 359:A>C, and 153:T>C). Silymarin could be used as an adjuvant in the treatment of rheumatoid arthritis.

Investigating salivary matrix metalloproteinase-2 and matrix metalloproteinase-9 activity in fixed orthodontic-induced gingival enlargement.

Background: Gingival enlargement (GE) is a common clinical observation among orthodontic patients, yet its underlying causes remain unclear. This study aims to investigate the potential involvement of salivary matrix metalloproteinase (MMP)-2 and MMP-9 activity in orthodontic-induced GE. Materials and Methods: In this case-control study, we enrolled 50 subjects, including 25 individuals with GE and 25 without. The participants, aged 10-35 years, were in the 4th or 5th month of their orthodontic treatment. Comprehensive clinical assessments, encompassing plaque index, gingival index, and GE score were performed, and saliva samples were subjected to gelatin zymography to assess enzyme activity. Statistical analysis, including the Chi-square test for age distribution, independent samples t-test for age comparison between study groups, Mann-Whitney U test for MMP activity comparison, and Wilcoxon signed-rank test for comparison of data from the 4th to 5th months of treatment, was performed using SPSS version 23.0, with a significance level set at 0.05. Results: MMP-2 activity was undetectable in the zymograms. In the 4th month of treatment, MMP-9 activity was more prominent in the case group, though this disparity did not reach statistical significance in the 5th month. Furthermore, MMP-9 activity did not exhibit a correlation with the GE score. Conclusion: The activity of MMP-9 in the saliva of orthodontic patients with GE increases during the 4th month of treatment, but no correlation exists with the degree of GE.

Mitigating effects of agmatine on myocardial infarction in rats subjected to isoproterenol.

Isoproterenol (ISO) usage is limited by its potential for cardiotoxicity. We sought to investigate the potential of agmatine in mitigating ISO-induced cardiotoxicity. Agmatine (100 mg/kg/day) was intraperitoneally administered to Wistar rats for 7 days in the presence or absence of cardiotoxicity induced by subcutaneous injection of ISO (85 mg/kg) on the sixth and seventh days. ECG parameters, lactate dehydrogenase (LDH), malondialdehyde (MDA), and creatinine phosphokinase (CPK) were investigated. Changes in cardiac tissue were also investigated using H&E staining. The heart weight/body weight ratio increased in ISO-treated rats. In the agmatine + ISO group, the increased heart rate observed in ISO-treated rats was reversed (317.2 ± 10.5 vs 452.2 ± 10.61, P < 0.001). Agmatine ameliorated the change in PR, RR, and ST intervals and the QRS complex, which was reduced by ISO. Treatment with saline, ISO, and agmatine had no significant effect on papillary muscle stimulation (P > 0.05). The administration of agmatine to ISO-receiving group could mitigate several parameters when compared to ISO-receiving group including increasing papillary muscle contraction (0.83 vs 0.71 N/M2 respectively, P < 0.01), decreasing LDH levels (660 ng/ml vs 1080 ng/ml, respectively, P < 0.05), decreasing CPK levels (377 U/l vs 642 U/l, respectively, P < 0.05) and decreasing MDA levels (20.32 µM/l vs 46.83 µM/l, P < 0.001). Coadministration of agmatine and ISO is capable of ameliorating ISO cardiotoxicity by antioxidant effects and controlling the hemostasis of calcium in myocytes.

Association of Matrix Metalloproteinase-2 (MMP-2) and MMP-9 Promoter Variants, Their Serum Levels, and Activities with Aortic Valve Calcification (AVC) in a Population from Western Iran.

Background: Matrix metalloproteinase (MMP) enzyme gene polymorphisms MMP-2-1575G/A and MMP-9-1562C/T promoter polymorphism, their serum levels, and activity are associated with aortic valve calcification (AVC). Materials and Methods: The synergistic link between the risk of AVC and the alleles T and A of MMP-9 and MMP-2 was investigated, respectively. Ninety-two cases with AVC and 92 healthy individuals from the west of Iran were included, and MMP- 2-1575G/A and MMP-9-1562C/T promoter polymorphisms were detected using PCR-RFLP. The serum levels and activity of MMP-2 and -9 were assessed using ELISA and gelatin zymography methods, respectively. In addition, serum biochemical markers, including FBS, urea and creatinine, cholesterol, triglyceride, HDL, LDL, calcium, phosphorus, and blood pressure: systolic blood pressure and diastolic blood pressure were measured. Results: Heart valve calcification disease was associated with a comparatively higher frequency of the A allele of the MMP2-1575 variation (p = 0.002). In addition, the frequency of T allele of the MMP9-1562 variant was higher than the control group (p = 0.007). Conclusion: MMP-2 and MMP-9 serum levels and activities were observed to be considerably higher in the experimental group than in the control group (p < 0.001). Patients are more susceptible to cardiovascular disease than the control group due to elevated serum levels and activity of MMP-2 and MMP-9.

Rutin-loaded chitosan nanoparticles alleviated Freund's adjuvant induced rheumatoid arthritis via modulating oxidative stress and inflammatory parameters in Wistar rats.

Rheumatoid arthritis (RA) is the most common chronic inflammatory disease, primarily affecting the joints and with stromal tissue dysregulation causing chronic inflammation and joint destruction. Rutin is a natural flavonoid with potential therapeutic properties in chronic destructive conditions including rheumatoid diseases. In this study, the protective effects of rutin nanoformulation in an animal model of rheumatoid arthritis caused by Freund's complete adjuvant (FCA) were investigated. Sixty male rats were randomly divided into ten groups including normal, negative control, prednisolone 10 mg/kg (positive control), 3 doses of rutin (15, 30, 45mg/kg), rutin nanoparticles (15, 30, 45 mg/kg), and nanoparticle without rutin, for 28 days. Different behavioral parameters including the open field test, acetone drop test, hot plate test, Von Frey test, and inclined plane test were evaluated. Serum levels of glutathione (GSH), catalase, and nitric oxide as well as histopathological analyses were measured in different groups. Also, matrix metalloproteinase (MMP)-2 and MMP-9 activity were appraised by gelatin zymography. The injection of FCA prolonged the rats' immobility duration in comparison to the control group. Rheumatoid arthritis induction also increased nitric oxide and decreased GSH and catalase levels, while these effects were reversed in the groups that received nanoparticles containing rutin and prednisolone. Rutin nanoparticles suppressed MMP-9 and activated MMP-2. Also, this rutin drug delivery system plays a significant role in the improvement of histopathological symptoms. Considering the improvement of behavioral and tissue symptoms and the modulation of the level of inflammatory cytokines, nanoparticles containing rutin can be proposed as a suitable approach in the management of patients with rheumatoid arthritis.

Polydatin attenuated neuropathic pain and motor dysfunction following spinal cord injury in rats by employing its anti-inflammatory and antioxidant effects.

Background: Considering the complex pathological mechanisms behind spinal cord injury (SCI) and the adverse effects of present non-approved drugs against SCI, new studies are needed to introduce novel multi-target active ingredients with higher efficacy and lower side effects. Polydatin (PLD) is a naturally occurring stilbenoid glucoside recognized for its antioxidative and anti-inflammatory properties. This study aimed to assess the effects of PLD on sensory-motor function following SCI in rats. Methods: Following laminectomy and clip compression injury at the thoracic 8 (T8)-T9 level of the spinal cord, rats were randomly assigned to five groups: Sham, SCI, and three groups receiving different doses of PLD treatment (1, 2, and 3 mg/kg). Over 4 weeks, behavioral tests were done such as von Frey, acetone drop, hot plate, Basso-Beattie-Bresnahan, and inclined plane test. At the end of the study, changes in catalase and glutathione activity, nitrite level, activity of matrix metalloproteinase 2 (MMP2) and MMP9 as well as spinal tissue remyelination/neurogenesis, were evaluated. Results: The results revealed that PLD treatment significantly improved the behavioral performance of the animals starting from the first week after SCI. Additionally, PLD increased catalase, and glutathione levels, and MMP2 activity while reduced serum nitrite levels and MMP9. These positive effects were accompanied by a reduction in the size of the lesion and preservation of neuronal count. Conclusion: In conclusion, PLD showed neuroprotective effects in SCI rats by employing anti-inflammatory and antioxidant effects, through which improve sensory and motor function.

Probiotic properties and antimicrobial evaluation of silymarin-enriched Lactobacillus bacteria isolated from traditional curd.

Nowadays, the increasing use of medicinal plants in the treatment and prevention of diseases has attracted the attention of researchers. The aim of this work was to investigate the probiotic properties and antibacterial and antifungal activity of silymarin-enriched Lactobacillus bacteria against several important pathogenic bacteria and also Aspergillus flavus as one of the harmful molds in the food and health industries. For this purpose, 52 g-positive and catalase-negative bacteria were isolated from 60 traditional curd samples from Ilam province. Five of the 52 bacterial strains had more than 90% viability in high bile salt and acidic conditions and were selected for further investigation. The five strains with positive results showed good hydrophobicity (≥ 50.30%), auto-aggregation (≥ 53.70%), coaggregation (≥ 28.20%), and high cholesterol removal ability (from 09.20 to 67.20%) and therefore can be considered potential probiotics. The tested strains displayed acceptable antibacterial and antifungal activity against all 12 pathogenic bacteria and A. flavus. Also, the results of the simultaneous antifungal activity of probiotic strains and silymarin showed that the combination of silymarin and probiotics has a significantly better (P < 0.05) antifungal effect than the control group or the probiotic groups alone. Interestingly, in addition to the Limosilactobacillus fermentum C3 strain, the Limosilactobacillus fermentum C18 and Lactiplantibacillus pentosus C20 strains also had significant inhibitory effects against A. flavus when used with silymarin extract in methanol. Meanwhile, silymarin extract in DMSO and PEG increased the antagonistic activity of all five potential probiotic strains.

Anti-nociceptive and anti-inflammatory activities of the essential oil isolated from Cupressus arizonica Greene fruits.

BACKGROUND: Cupressus arizonica Greene is a coniferous tree with great importance in fragrance and pharmaceutical industries. Essential oils from C. arizonica (EC) have shown potential antioxidant, and anti-microbial activities. This study aimed at investigating the anti-nociceptive and anti-inflammatory effects/mechanisms of EC. METHODS: The EC was evaluated for anti-nociceptive and anti-inflammatory activities on male Wistar rats using a formalin test and carrageenan-induced paw edema, respectively. Also, we pre-treated some of the animals with naloxone and flumazenil in the formalin test to find out the possible contributions of opioid and benzodiazepine receptors to EC anti-nociceptive effects. Finally, gas chromatography/mass spectrometry (GC/MS) analysis was used to identify the EC's constituents. RESULTS: EC in intraperitoneal doses of 0.5 and 1 g/kg significantly decrease the nociceptive responses in both early and late phases of the formalin test. From a mechanistic point of view, flumazenil administration 20 minutes before the most effective dose of EC (1 g/kg) showed a meaningful reduction in the associated antinociceptive responses during the early and late phases of the formalin test. Naloxone also reduced the anti-nociceptive role of EC in the late phase. Furthermore, EC at the doses of 1, 0.5, and 0.25 g/kg significantly reduced paw edema from 0.5 hours after carrageenan injection to 4 hours. GC/MS analysis showed that isolated EC is a monoterpene-rich oil with the major presence of α-pinene (71.92%), myrcene (6.37%), δ-3-carene (4.68%), ß-pinene (3.71%), and limonene (3.34%). CONCLUSIONS: EC showed potent anti-nociceptive and anti-inflammatory activities with the relative involvement of opioid and benzodiazepine receptors.

The Effect of Oral Administration of Silymarin on Serum Levels of Tumor Necrosis Factor-α and Interleukin-1ß in Patients with Rheumatoid Arthritis.

BACKGROUND: Rheumatoid Arthritis (RA) is a systemic chronic autoimmune disease. Several inflammatory agents play key roles in RA pathogenesis, among which tumor necrosis factor-alpha (TNF-α) and interleukin 1 beta (IL-1ß) are of great importance. Silymarin is a potent anti-oxidant extracted from Silybummarianum L. seeds. OBJECTIVE: To study the effect of silymarin on serum levels of TNF-α and IL-1ß in patients with RA. METHODS: Patients with stable RA received 140 mg of silymarin, 3 times a day, for 3 months. Serum samples were collected before and after the treatment. Both TNF-α and IL-1ß serum levels were measured by ELISA. RESULTS: 42 patients (14.3% male, and 85.7% female, with a mean age of 47.59±12.8 years old) completed the treatment course. There was no significant difference in the overall mean concentration of either TNF-α (p=0.14) or IL-1ß (p=0.27) in all 42 patients after the treatment with silymarin. CONCLUSION: The addition of silymarin to the treatment regimen of patients with stable RA has no significant effect on the serum levels of TNF-α and IL-1ß, however, this study needs further evaluation with a larger sample size.

Naringenin Improves Ovalbumin-Induced Allergic Asthma in Rats through Antioxidant and Anti-Inflammatory Effects.

Asthma is a chronic disease with eosinophilic inflammation and oxidative damages leading to airway obstruction. Naringenin is a phytochemical possessing strong antioxidant and anti-inflammatory activities against chronic destructive conditions. The current study is devoted to evaluating naringenin's effects on the attenuation of inflammation and oxidative stress in lung tissue in a rat model of ovalbumin-induced asthma. Male Wistar rats were allocated to five groups of six: normal control (NC, receiving 1 ml/day of normal saline, orally), asthmatic (AS, receiving ovalbumin (1 mg/mL), and alum (1 mg/mL in saline) on days 0 and 14. Then, on days 21, 22, and 23, they were sensitized with the inhalation of ovalbumin), AS treated with dexamethasone (AS, 1 mg/kg/day, orally) [AS + D1], AS treated with naringenin (20 mg/kg/day, orally) [AS + N20], and AS treated with naringenin (40 mg/kg/day, orally) [AS + N40]. All the groups received associated drugs/agents for 28 days. Finally, bronchoalveolar lavage fluid (BALF) and lung tissue samples were taken off from the animals. The eosinophil count in BALF and malondialdehyde (MDA), glutathione (GSH), interleukin-13 and -4 (IL-13 and IL-4) levels were measured. Besides, the expression of urocortin (UCN) and surfactant protein-D (SP-D) were evaluated in the lung tissue using immunohistochemistry (IHC) and western blotting methods, respectively. Hematoxylin and eosin (H&E) staining were utilized to conduct histopathological analysis. Naringenin treatment significantly reduced MDA, remarkably increased GSH, and meaningfully reduced IL-4 and IL-13 levels in lung tissue. The count of eosinophils in the BALF of AS + N20 and AS + N40 was significantly reduced in comparison with the AS group. The UCN and SP-D protein levels were significantly decreased in the AS + N20 and AS + N40 groups compared to the AS group, using the IHC and western blot methods, respectively. Histopathological analysis data also confirm the results. Naringenin improves the symptoms of allergic asthma through antioxidant and anti-inflammatory effects.

Association Between Vitamin D Binding Protein Gene Polymorphism (rs7041), Vitamin D Receptor, and 25-Hydroxyvitamin D Serum Levels With Prostate Cancer in Kurdish Population in West of Iran.

Prostate cancer (PCa) pathology has been linked to vitamin D, vitamin D receptors (VDRs), and vitamin D binding proteins (VDBPs). We sought to investigate the association between VDR rs2228570 and rs1544410 as well as VDBP rs7041 polymorphisms and serum 25-hydroxyvitamin D (25(OH)-vitamin D) levels in PCa patients. Blood samples were collected from 111 PCa patients and 150 age-matched healthy volunteers. The VDR rs2228570 T/C, rs1544410 G/A, and VDBP rs7041 T/G genotypes were determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). 25(OH)-vitamin D and PSA (Total and Free) serum levels were measured. The frequencies of VDBP genotypes T/G vs. T/T (56.5% vs. 44.5%, p = 0.01) according to the dominant model T/G + G/G vs. T/T (84.3% vs. 71.5%, p = 0.01) were significantly higher in PCa patients when compared to control group and considerably increased the risk of disease by 2.29, 1.44, and 2.13 folds respectively. Interestingly, the results demonstrated that PCa patients with the dominant model (T/G + G/G vs. T/T) of VDBP had significantly lower serum levels of vitamin D and higher serum levels of total and free PSA in comparison to the controls. Furthermore, when compared to controls, PCa patients with the dominant model T allele (T/G + G/G vs. TT) of VDBP had significantly higher vitamin D, total PSA, and free PSA concentrations. Serum levels of 25(OH)-vitamin D and rs7041 T/G polymorphism of the VDBP gene could be potential risk factors for PCa.

Intrathecal administration of naringenin improves motor dysfunction and neuropathic pain following compression spinal cord injury in rats: relevance to its antioxidant and anti-inflammatory activities.

Background: Spinal cord injury (SCI) is one of the most debilitating disorders throughout the world, causing persistent sensory-motor dysfunction, with no effective treatment. Oxidative stress and inflammatory responses play key roles in the secondary phase of SCI. Naringenin (NAR) is a natural flavonoid with known anti-inflammatory and antioxidative properties. This study aims at evaluating the effects of intrathecal NAR administration on sensory-motor disability after SCI. Methods: Animals underwent a severe compression injury using an aneurysm clip. About 30 minutes after surgery, NAR was injected intrathecally at the doses of 5, 10, and 15 mM in 20 µL volumes. For the assessment of neuropathic pain and locomotor function, acetone drop, hot plate, inclined plane, and Basso, Beattie, Bresnahan tests were carried out weekly till day 28 post-SCI. Effects of NAR on matrix metalloproteinase (MMP)-2 and MMP-9 activity was appraised by gelatin zymography. Also, histopathological analyses and serum levels of glutathione (GSH), catalase and nitrite were measured in different groups. Results: NAR reduced neuropathic pain, improved locomotor function, and also attenuated SCI-induced weight loss weekly till day 28 post-SCI. Zymography analysis showed that NAR suppressed MMP-9 activity, whereas it increased that of MMP-2, indicating its anti-neuroinflammatory effects. Also, intrathecal NAR modified oxidative stress related markers GSH, catalase, and nitrite levels. Besides, the neuroprotective effect of NAR was corroborated through increased survival of sensory and motor neurons after SCI. Conclusions: These results suggest intrathecal NAR as a promising candidate for medical therapeutics for SCI-induced sensory and motor dysfunction.

Association of Matrix Metalloproteinase-2 (MMP-2) and MMP-9 Promoter Polymorphisms, Their Serum Levels, and Activities with Coronary Artery Calcification (CAC) in an Iranian Population.

The serum levels and activity of matrix metalloproteinases (MMPs) are associated with the risk of coronary artery calcification (CAC). We sought to investigate the association between MMP-2 -1575G>A (rs243866) and MMP-9 -1562 C>T (rs3918242) SNPs with MMP-2 and MMP-9 serum levels and activity in individuals with CAC. One hundred and fifty-five cases with CAC and 155 healthy individuals as control group from West of Iran were included and frequency of genotypes and alleles of rs243866 and rs3918242 in MMP-2 and MMP-9 genes were determined using PCR-RFLP. We also investigated the serum levels of MMP-2 and MMP-9 and their activity using ELISA and gelatin zymography, respectively. Additionally, serum biochemical parameters including FBS (fasting blood sugar), urea, creatinine, cholesterol, triglyceride, HDL (high-density lipoprotein), LDL (low-density lipoprotein), calcium, and phosphorus as well as blood pressure (systolic blood pressure (SBP) and diastolic blood pressure (DBP)) were measured. Our results showed that both serum levels of MMP-2 and MMP-9 (P < 0.001) and their activity (P < 0.001) were higher in individuals with CAC when compared to the control group. Carrying A and T alleles in MMP-2 -1575G>A (rs243866) and MMP-9 -1562 C>T (rs3918242) SNPs, respectively, may predispose the individuals to CAC by acting as the risk factors. Serum levels and activity of MMP-2 and MMP-9 were found to be higher in CAC cases when compared to the healthy controls. Carriers of A allele in rs243866 SNP and T allele in rs3918242 SNP were shown to have higher MMP-2 and MMP-9 serum levels and activity that may result in increased ECM degradation and support the initiation and development of calcification.

Intrathecal Administration of Melatonin Ameliorates the Neuroinflammation- Mediated Sensory and Motor Dysfunction in A Rat Model of Compression Spinal Cord Injury.

BACKGROUND: Spinal cord injury (SCI), often characterized by sensory-motor dysfunction, is a major debilitating disorder of the central nervous system. As no useful treatment for post- SCI complications has been approved thus far, finding novel treatments is of great importance. OBJECTIVE: Considering the promising effects of melatonin (MEL) against destructive mechanisms in other models of brain damage, in the current study, we evaluated its ameliorative effects on sensory- motor outcomes, inflammatory mediators, histological changes and other post-SCI complications. METHODS: Rats in SCI and MEL groups underwent laminectomy followed by a severe compression injury by an aneurysm clip. Then, intrathecal treatment with vehicle (5% dimethyl sulfoxide) or MEL was carried out post-injury. Acetone drop, von Frey, inclined plane, and BBB tests as well as weight changes and auricle temperature, were used to evaluate the neuropathic pain, motor function, and other post-SCI complications. The effects of MEL on the activity of MMP-2 and MMP-9 were assessed using the gelatin zymography method every week till day 28 post-SCI. Histopathological assessments were performed on days 14, 21, and 28. RESULTS: MEL treatment resulted in decreased motor dysfunction, mechanical and cold allodynia, auricle temperature, and also ameliorated weight loss. Moreover, MEL suppressed MMP-9 activity while increasing that of MMP-2 post-SCI, indicating its anti-neuroinflammatory effects. Also, MEL significantly preserved white matter myelinated areas and the number of sensory neurons post-SCI. CONCLUSION: The results suggest MEL as a promising candidate for medical therapies with advantageous effects on improving functional recovery through suppressing inflammatory mediators, and attenuating spinal tissue damages.