The Efficacy and Safety of Intrathecal Autologous Bone Marrow-Derived Mesenchymal Stromal Cells in Amyotrophic Lateral Sclerosis: A Pilot Study.

Purpose: Amyotrophic lateral sclerosis (ALS) is an uncommon and aggressive neurodegenerative disorder that influences the lower and upper motor neurons. There are low eligible drugs for ALS treatment; in this regard, supplemental and replacement treatments are essential. There are relative studies in the field of mesenchymal stromal cells (MSCs) therapy in ALS, but the different methods, differently used medium, and difference in follow-up periods affect the outcome treatment. Methods: The current survey is a single-center, phase I clinical trial to evaluating the efficacy and safety of autologous bone marrow (BM)-derived MSCs through intrathecal administration in ALS patients. MNCs were isolated from BM specimens and cultured. The clinical outcome was evaluated based Revised Amyotrophic Lateral Sclerosis Functional Rating (ALSFRS-R) Scale. Results: Each patient received 15±3×106 cells through subarachnoid space. No adverse events (AEs) were detected. Just one patient experienced a mild headache after injection. Following injection, no new intradural cerebrospinal pathology transplant-related was observed. None of the patients' pathologic disruptions following transplantation were detected by magnetic resonance imaging (MRI). The additional analyses have shown the average rate of ALSFRS-R score and forced vital capacity (FVC) reduction have decreased during 10 months following MSCs transplantation versus the pretreatment period, from -5.4±2.3 to -2±3.08 ALSFRS-R points/period (P=0.014) and -12.6±5.22% to -4.8±14.72%/period (P<0.001), respectively. Conclusion: These results have shown that autologous MSCs transplantation reduces the disease's progression and has favorable safety. Trial Registration: This study performed as a phase I clinical trial (code IRCT20200828048551N1).

Taurine ameliorates cytotoxic effects of Di(2-ethylhexyl) phthalate on Leydig cells.

It has been revealed that di(2-ethylhexyl)phthalate (DEHP) has toxic impacts on the male reproductive system. Taurine (TAU) is an amino acid with antioxidant property and beneficial impacts on the male reproductive system. In this study, protective impacts of Taurine (TAU) on DEHP-induced Leydig TM3 cell toxicity were investigated. The cells exposed to DEHP (0.8 µmol) or TAU (100 mg/ml) for 24 hr. Cell viability (MTT assay), apoptosis, oxidative stress and testosterone level were examined. DEHP could significantly decrease the cell viability percentage, reduce testosterone level, increase apoptosis, elevate Bax/ Bcl-2 ratio and enhance caspase-3 and -9 activity in the TM3 cells. Additionally, DEHP significantly elevated malondialdehyde contents and reactive oxygen species levels. It also augmented superoxide dismutase and catalase activity in the Leydig cells. Co-treatment of DEHP with TAU increased viability and testosterone level, while oxidative stress and apoptosis significantly reduced. TAU could decrease Bax/Bcl-2 ratio and caspase-3 and -9 activity in the DEHP-intoxicated cells. Our results have clearly shown that TAU protects TM3 cells against oxidative stress and apoptosis induced by DEHP.

p-Coumaric acid alleviates adriamycin-induced hepatotoxicity in rats

Objective: To evaluate the effect of p-coumaric acid against adriamycin-induced hepatotoxicity in rats. Methods: The rats were divided into 4 groups. The control group received solvent; the p-coumaric acid group was treated with 100 mg/kg of p-coumaric acid orally for five consecutive days; the adriamycin group was administered with a single dose of adriamycin (15 mg/kg, i.p.), and the p-coumaric acid + adriamycin group was given p-coumaric acid five days before adriamycin administration. Twenty-four hours after the last administration, blood samples were collected for biochemical analysis, and liver tissues were removed for histopathological and immunohistochemistrical studies. Moreover, the levels of tissue lipid peroxidation and enzyme activities of glutathione peroxidase, superoxide dismutase, and catalase in liver tissue were measured. Results: Treatment with p-coumaric acid protected the liver from the toxicity of adriamycin by attenuating the increase in alkaline phosphatase, alanine transaminase, aspartate transaminase, total bilirubin, total cholesterol, triglyceride, and low-density lipoprotein cholesterol and lessening the decrease in high-density lipoprotein cholesterol and albumin. p-Coumaric acid also raised the levels of glutathione peroxidase, superoxide dismutase, and catalase, as well as decreased lipid peroxidation in liver tissue and hepatic IL-1β expression. Additionally, histopathological study confirmed the protective effect of p-coumaric acid against liver damage. Conclusions: p-Coumaric acid can alleviate adriamycin-induced hepatotoxicity.

The Efficacy and Safety of Modified Docetaxel, Cisplatin, and 5-Fluorouracil Vs. Epirubicin, Oxaliplatin, and Capecitabine Regimen in the Advanced Gastric Cancer: A Randomized Controlled Clinical Trial.

INTRODUCTION: One of the major challenges of advanced gastric cancer treatment is the lack of a standard regimen for patients. However, several clinical trials have shown that modified docetaxel, cisplatin, and 5-fluorouracil (m-DCF) and epirubicin, oxaliplatin, and capecitabine (EOX) regimens are superior to other regimens. METHODS: This randomized, single-center clinical trial was performed on 40 patients with advanced gastric cancer. The first group received the m-DCF regimen as follows: docetaxel (40 mg/m2) on the first day; cisplatin (40 mg/m2) on the first and second days; and 5-fluorouracil (400 mg/m2) from the first to fourth day. The second group received the EOX regimen, including epirubicin (50 mg/m2) and oxaliplatin (130 mg/m2) i.v on the first day and capecitabine at a twice-daily dose of 625 mg/m2 p.o for 21 days. Treatment was applied every three weeks for a total of eight cycles in both groups. In each group, the overall and progression-free survival rates and toxicity were assessed. RESULTS: A total of 40 patients were enrolled in this study (21 samples in the m-DCF group and 19 samples in the EOX group), 62.5% of whom were male. The median survival rate was 14.00 (95% CI: 11.82-16.18) months in the m-DCF group and 15.00 (95% CI: 9.56-20.43) months in the EOX group; however, differences between the groups were not significant. The progression-free survival rate was higher in the EOX group, although there was no significant difference between the two groups. Also, there was no significant difference regarding the side effects (e.g., toxicity) or need for supportive care between the groups. CONCLUSION: It seems that both m-DCF and EOX regimens are similar in terms of survival and toxicity and are recommended as first-line treatment for advanced gastric cancer with respect to the patient's status.

Taurine induces autophagy and inhibits oxidative stress in mice Leydig cells.

OBJECTIVES: This study evaluated taurine (TAU) effects on autophagy, apoptosis and oxidative stress in mice Leydig TM3 cells. METHODS: We treated TM3 cells with TAU (100 µg/mL) or 3-Methyladenine (3-MA, an autophagy inhibitor) for 24 h, and assessed cell viability, testosterone level, oxidative stress, apoptosis, and autophagy. RESULTS: The results showed that TAU markedly increased cell viability, testosterone levels, expression of autophagy-related genes and percentage of LC3-II-positive cells. TAU significantly reduced malondialdehyde (MDA) contents and reactive oxygen species (ROS) levels and increased the activities of SOD (superoxide dismutase) and CAT (Catalase) enzymes in the TM3 cells. TAU in the presence of autophagy inhibitor (3-MA) increased oxidative stress and decreased testosterone levels. CONCLUSION: The results showed that autophagy might be involved in TAU-increased testosterone levels in mice Leydig TM3 cells.

Anticancer activity and molecular mechanisms of α-conidendrin, a polyphenolic compound present in Taxus yunnanensis, on human breast cancer cell lines.

α-Conidendrin is a polyphenolic compound found mainly in Taxus yunnanensis, as the source of chemotherapy drug paclitaxel, which has been used in traditional medicine for treatment of cancer. This study aimed to investigate the anticancer activity and molecular mechanisms of α-conidendrin on breast cancer cell lines. The results of the present study show that α-conidendrin possesses potent antiproliferative effects on breast cancer cell lines MCF-7 and MDA-MB-231. α-Conidendrin significantly induced apoptosis in breast cancer cells via reactive oxygen species generation, upregulation of p53 and Bax, downregulation of Bcl-2, depolarization of mitochondrial membrane potential (MMP), release of cytochrome c from mitochondria, and activation of caspases-3 and -9. α-Conidendrin remarkably inhibited the proliferation of breast cancer cells through induction of cell cycle arrest by upregulating p53 and p21 and downregulating cyclin D1 and CDK4. Unlike breast cancer cells, the antiproliferative effect of α-conidendrin on human foreskin fibroblast cells (normal cells) was very small. In normal cells, reactive oxygen species levels, loss of MMP, release of cytochrome c, mRNA expression of p53, p21, cyclin D1, CDK4, Bax, and Bcl-2 as well as mRNA expression and activity of caspases-3 and -9 were significantly less affected by α-conidendrin compared with cancer cells. These results suggest that α-conidendrin can be a promising agent for treatment of breast cancer with little or no toxicity against normal cells.

3-Bromopyruvate potentiates TRAIL-induced apoptosis in human colon cancer cells through a reactive oxygen species- and caspase-dependent mitochondrial pathway.

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a promising anticancer cytokine with minimal toxicity towards normal cells. Nevertheless, most primary cancers are often intrinsically TRAIL-resistant or can acquire resistance after TRAIL therapy. This study aimed to investigate the inhibitory effect of co-treatment of 3-bromopyruvate (3-BP) as a potent anticancer agent with TRAIL on colon cancer cells (HT-29). The results of present study indicated that combined treatment with 3-BP and TRAIL inhibited the proliferation of HT-29 cells to a greater extent (88.4%) compared with 3-BP (54%) or TRAIL (11%) treatment alone. In contrast, the combination of 3-BP and TRAIL had no significant inhibitory effect on the proliferation of normal cells (HEK-293) (8.4%). At a cellular mechanistic level, the present study showed that 3-BP sensitized human colon cancer cells to TRAIL-induced apoptosis via reactive oxygen species generation, upregulation of Bax, downregulation of Bcl-2 and survivin, release of cytochrome c into the cytosol, and activation of caspase-3. In normal cells, 3-BP, TRAIL, or combination of both had no significant effect on the reactive oxygen species levels, release of cytochrome c, and caspase-3 activity. Therefore, the combination of 3-BP and TRAIL can be a promising therapeutic strategy for treatment of colon cancer.

Sodium hydrogen sulfide (NaHS) ameliorates alterations caused by cisplatin in filtration slit diaphragm and podocyte cytoskeletal in rat kidney.

BACKGROUND: Hydrogen sulfide (H2S) has been shown to have a protective role in various kidney disorders. OBJECTIVES: This study investigated the molecular mechanism of NaHS (a H2S donor) in treating on the renal damage induced by cisplatin (CP). MATERIALS AND METHODS: Thirty-two male rats were randomly divided into 4 groups: Normal control group (group A)' NaHS group (group B) which received 200 µg/kg/d (intraperitoneal injection; i.p.) for 15 days' CP group (group C) which rats were injected with CP (5 mg/kg, single dose, i.p.), and CP + NaHS group (group D) (5 mg/kg and 200 µg/kg, respectively, i.p.). Samples of urine and serum, tissue of kidney were collected for analysis after treatments for 15 days. Morphological changes were elevated under light microscope' protein expression of desmin and nephrin were determined by immunohistochemistry and western blotting and also malondialdehyde (MDA) level was determined by spectrophotometer. RESULTS: Compared to the CP group, NaHS treatment mitigated histological damages, decreased 24-hour urine protein excretion, serum urea and creatinine as well as MDA level. NaHS treatment increased protein levels of nephrin. Moreover, NaHS treatment decreased protein levels of desmin. CONCLUSIONS: NaHS can ameliorate CP -induced renal damage in rats which is associated with the increase in nephrin protein expression, and the decrease in MDA level and desmin protein expression.

Role of Tumor Necrosis Factor-Producing Mesenchymal Stem Cells on Apoptosis of Chronic B-lymphocytic Tumor Cells Resistant to Fludarabine-based Chemotherapy.

BACKGROUND: B-cell chronic lymphocytic leukemia B (B-CLL), the most common type of leukemia, may be caused by apoptosis deficiency in the body. Adipose tissue-derived mesenchymal stem cells (AD-MSCs) as providers of pro-apoptotic molecules such as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), can be considered as an effective anti-cancer therapy candidate. Therefore, in this study we assessed the role of tumor necrosis factor-producing mesenchymal stem cells oin apoptosis of B-CLL cells resistant to fludarabine- based chemotherapy. MATERIALS AND METHODS: In this study, after isolation and culture of AD-MSCs, a lentiviral LeGO-iG2-TRAIL-GFP vector containing a gene producing the ligand pro-apoptotic with plasmid PsPAX2 and PMDG2 virus were transfected into cell-lines to generate T293HEK. Then, T293HEK cell supernatant containing the virus produced after 48 and 72 hours was collected, and these viruses were transduced to reprogram AD-MSCs. Apoptosis rates were separately studied in four groups: group 1, AD-MSCs-TRAIL; group 2, AD-MSCs-GFP; group 3, AD-MSCs; and group 4, CLL. RESULTS: Observed apoptosis rates were: group 1, 42 ± 1.04%; group 2, 21 ± 0.57%; group 3, 19± 2.6%; and group 4, % 0.01 ± 0.01. The highest rate of apoptosis thus occurred ingroup 1 (transduced TRAIL encoding vector). In this group, the average medium-soluble TRAIL was 72.7pg/m and flow cytometry analysis showed a pro-apoptosis rate of 63 ± 1.6%, which was again higher than in other groups. CONCLUSIONS: In this study we have shown that tumor necrosis factor (TNF) secreted by AD-MSCs may play an effective role in inducing B-CLL cell apoptosis.

Effects of TNF secreting HEK cells on B lymphocytes' apoptosis in human chronic lymphocytic leukemias.

BACKGROUND: Tumor necrosis factor (TNF) related apoptosis-inducing ligand (TRAIL) is an antitumor candidate in cancer therapy. This study focused on effects of TRAIL, as a proapototic ligand that causes apoptosis, in B-CELL chronic lymphocytic leukemia cells (B-CLL) . MATERIALS AND METHODS: A population of HEK 293 cells was transducted by lentivirus that these achieved ability for producing the TRAIL protein and then HEK 293 cells transducted were placed in the vicinity of CLL cells. After 24 hours of co-culture, apoptosis of CLL cells was assessed by annexin V staining. RESULTS: The amount of Apoptosis was examined separately in four groups: 293 HEK TRAIL (16.17±1.04%); 293 HEK GFP (2.7±0.57%); WT 293 HEK (2±2.6%); and CLL cells (0.01±0.01%). Among the groups studied, the maximum amount of apoptosis was in the group that the vector encoding TRAIL was transducted. In this group, the mean level of soluble TRAIL in the culture medium was 253 pg/ml; also flow cytometry analyzes showed that proapotosis in this group was 32.8±1.6%, which was higher than the other groups. CONCLUSIONS: In this study, we have demonstrated that TNF secreted from HEK 293 cells are effective in death of CLL cells.

Evaluating the Survival Rate and the Secondary Malignancies after Treating Hodgkin's Lymphoma Patients with Chemotherapy Regimens.

In this study we surveyed the average survival time of the treated Hodgkin's lymphoma patients and also the side effects and malignancies occurring secondary to the treatment. This is a retrospective study of patients referring to Ahwaz's Shafa hospital in a period of 10 years diagnosed with Hodgkin's lymphoma without any age restriction. After gathering all their data, we calculated their survival rate and the chance for a relapse and the secondary malignancies. 389 patients were included in the study with an average age of 27.5 years old and they had received only chemotherapy regimens. 87.9% of them had been treated by ABVD and 12.1 % by Stanford V regimen. 23.1% of them experienced a relapse and 13.1% of all patients, passed away during the study. Secondary malignancies were observed in 11 cases. An overall mean survival time of 295.31 months was resulted. The secondary malignancies after treating Hodgkin's lymphoma patients are different between chemotherapy regimens and chemotherapy - radiotherapy.

Infection Pattern of Neutropenic Patients in Post-chemotherapy Phase of Acute Leukemia Treatment.

Neutropenia following chemotherapy regimens in leukemia patients is of major concern since it makes these patients vulnerable to infections. If we can identify which germs are causing these infections, they can be annihilated or, at least, the most appropriate antibiotic therapy can be started immediately, even before we have the results of the culture. This retrospective multi-center study took place in 2012 and included patients with acute leukemia who had already undergone chemotherapy and who had been febrile for at least 16 hours. In order to assess the type of infection, different environments were chosen and the results were compared by t-test and χ(2) tests. This study took place in four hospitals in Tehran and Ahwaz, Iran. The study population was made up of 89 patients: 37 with acute lymphoblastic leukemia and 52 with acute myeloid leukemia. The results revealed that blood was the most common site of infection. From all our positive cultures, it was seen that 85.4% of them had gram-negative bacteria with a dominance of E. coli of 25.8% over the other colonies. Also, antibiograms revealed the sensitivity of almost all the gram-negatives to amino glycosides. In contrast with most of the literature, in our patients, gram-negatives are the most common cause of infection and, therefore, administering amino glycosides would be the safest antibiotic therapy to prescribe before culture results are available.

Clinical, high resolution computed tomography and pulmonary function in sulphur mustard victims.

We aimed to evaluate clinical, high resolution computed tomography (HRCT) and pulmonary function test (PFT) findings after 18-23 years of exposure in veterans of sulphur mustard (SM) exposure. We performed a cross-sectional study of 106 patients. Inclusion criteria were 1: documented exposure to SM as confirmed by toxicological analysis of their urine and vesicular fluid after exposure 2: single exposure to SM that cause skin blisters and subsequent transient or permanent sequel. Cigarette smoking and pre-exposure lung diseases were of exclusion criteria. After taking history and thorough respiratory examination, patients underwent high resolution computed tomography and spirometry. Clinical diagnoses were made considering the findings. More than 85% of the patients were complaining of dyspnea and cough. Obstructive pattern (56.6%) was main finding in spirometry followed by restrictive and normal patterns. HRCT revealed air trapping (65.09%) and mosaic parenchymal attenuation patterns (58.49%) as most common results. Established diagnoses mainly were chronic obstructive pulmonary disease (COPD) (54.71%), bronchiolitis obliterans (27.35%) and asthmatic bronchitis (8.49%). There were not any significant association between the clinical findings and results of PFT and HRCT imaging and also between PFT and HRCT findings (P-values were more than 0.05). Considering debilitating and progressive nature of the respiratory complications of SM exposure, attempts are needed for appropriate diagnosis and treatment.

Combination of cyclophosphamide, etoposide, carboplatin and dexamethasone as a salvage regimen for refractory multiple myeloma patients: a comparison with a historical control group.

The aim of this study was to design a regimen for refractory multiple myeloma with minimum complications to achieve a reasonable response. Fifteen patients with active multiple myeloma after at least two lines of conventional treatment underwent therapy with our regimen for two cycles. Disease activity was evaluated after the last cycle. Another 15 patients with refractory multiple myelomas that had previously received only supportive therapy and pain management formed a historical control group. The follow-up period was 12 months for each study group. Of the patients receiving therapy, 6.7% achieved a complete response and 26.7% a partial response; overall response rate was 33.3%. Stable disease was achieved in 46.7% and 20% of the patients had progressive disease. There was no treatment related mortality. The hazard rate of death was 0.73 lower in the intervention group than in the historical control group. In the historical control group, 60% had progressive disease and 40% had stable disease; approximately 40% of patients died during the 12-month follow up. Also, the severity of pain was significantly reduced in the intervention group (P=0.033). Our chemotherapy regimen showed a reasonable response in end stage patients with multiple myeloma in terms of disease control, reducing bone pain and improving survival, in addition to reducing toxicity.

Six-year follow up of imatinib therapy for newly diagnosed chronic myeloid leukemia in Iranian patients.

BACKGROUND: The present study reported a six-year follow up of patients with chronic myeloid leukemia who were on imatinib therapy. METHODS: We performed a retrospective study on a total of 417 patients diagnosed with chronic-phase, Philadelphia-positive (Ph+) chronic myeloid leukemia within six months before study entry. Patients were eligible for the study if they were between 18 and 70 years of age. Enrolled patients were treated at an initial dose of 400 mg of imatinib. RESULTS: The mean age of 417 patients was 40.9±14.5 years; 220 (52%) were men and 197 (47.2%) were women. Complete hematologic response at three months occurred in 99% of patients, 221 (53%) before four weeks and 196 (47%) after four weeks. Adverse events occurred in 17 (4.1%) of patients, relapse in 46 (11%) and death in 31 (7.4%) of our studied population. At 72 months, the estimated rate of overall survival rate was 89%. DISCUSSION: Our findings showed the efficacy and safety of imatinib mesylate among Iranian patients with chronic myeloid leukemia by hematological and molecular response.

Ameliorative effects of curcumin on the structural parameters of seminiferous tubules and Leydig cells in metronidazole-treated mice: a stereological approach.

Metronidazole (MTZ), an anti-parasitic drug, induces negative effects on the testis. Curcumin exhibits antioxidant properties and anti-tumor properties. The aim was to evaluate negative effects of seminiferous tubules and Leydig cells by MTZ and ameliorative effects of curcumin. Balb/c mice were divided into six groups. The control, second, third, fourth and fifth, and sixth groups were administrated distilled water, high doses of MTZ (500 mg/kg/day), MTZ (500 mg/kg/day) +100 mg/kg/day curcumin, therapeutic doses of MTZ (165 mg/kg/day), MTZ (165 mg/kg/day) +100 mg/kg/day curcumin, and 100 mg/kg/day curcumin, respectively. The data revealed significant reduction in tubule volume, length and diameter and germinal epithelium height, and increase the number of Leydig cells in MTZ-treated (high or therapeutic doses) animals. Combined treatment of curcumin with high or therapeutic doses of MTZ ameliorated the increase in number of Leydig cell. Ameliorative effects of curcumin on the other above-mentioned parameters were observed in mice receiving therapeutic doses of MTZ. Leydig cell or nucleus volume and interstitial tissue volume did not show any significant difference in the MTZ-treated mice. It can be concluded that metronidazole can changes structural parameters of the tubules and number of Leydig cells and curcumin can ameliorate these effects.

Ameliorative effects of curcumin on the seminiferous epithelium in metronidazole-treated mice: a stereological study.

Metronidazole (MTZ) has negative effects on sperm analysis and testis structure. Curcumin is the principal curcuminoid found in turmeric and exhibits antitumor, anti-inflammatory, and anti-infectious activities with low toxicity. To evaluate stereological changes of seminiferous germinal epithelium by MTZ and ameliorative effects of curcumin, Balb-c mice were divided into 6 groups. The control, second, third, fourth, fifth, and sixth groups were administrated distilled water, high doses of MTZ (500 mg/kg/day), MTZ (500 mg/kg/day) + 100 mg/kg/d curcumin, therapeutic doses of MTZ (165 mg/kg/day), MTZ (165 mg/kg/day) + 100 mg/kg/day curcumin, and 100 mg/kg/day curcumin, respectively. Testis weight, testis volume, total epithelial volume, spermatocytes, and spermatid number showed a significant reduction in MTZ-treated (high or therapeutic doses) animals in comparison with the controls. Curcumin can protect spermatocytes after high or therapeutic doses of MTZ treatment. But curcumin is able to protect the other parameters only in the mice receiving therapeutic doses of MTZ. The total number of sertoli cells and spermatogonia did not show any significant difference in the mice that received MTZ. MTZ can reduce germinal epithelium volume and the number of spermatocytes and spermatids. Ameliorative effects of curcumin can mainly be observed in the mice receiving therapeutic doses of MTZ.