Efficacy and safety of N-acetyl-L-leucine in patients with ataxia telangiectasia: A randomized, double-blind, placebo-controlled, crossover clinical trial.

BACKGROUND: Ataxia telangiectasia (AT) is an autosomal recessive multisystem disorder. Most patients have progressive cerebellar ataxia, oculocutaneous telangiectasia, frequent pulmonary infection, and an increased risk of malignancies. Although N-acetyl-dl-leucine (ADLL) has shown some efficacy in patients with AT, its more pharmacologically active enantiomer, N-acetyl-l-leucine (NALL), has just recently been investigated in ataxic individuals. The current study assessed the efficacy of NALL in patients with AT. METHODS: This 2 × 2 crossover, double-blind, randomized clinical trial was conducted on 20 patients with AT. After excluding four patients, 16 subjects (eight females, eight males; mean age 9.8 ± 3.5 years) with a definitive genetic diagnosis of AT were randomly assigned to one of two study groups, with one group receiving 1-4 g/day NALL or a placebo for six weeks. Subjects then had a 4-week washout before crossing over to the other treatment for an additional six weeks. The Spinocerebellar Ataxia Functional Index (SCAFI) and the Scale for Assessment and Rating of Ataxia (SARA) score assessed patients' motor function. Quality of life (QOL) was evaluated by a specialist using the PedsQL questionnaire. Fasting blood samples were taken from all subjects before and after each intervention to determine potential side effects. RESULTS: Although patients' nausea and constipation were improved, the results failed to reveal any significant benefits of NALL treatment on ataxia symptoms. NALL treatment had no significant effects on SARA, SCAFI-9HPT (9-hole peg test) nondominant, SCAFI-9HPT dominant, or SCAFI-8WMT (8 m walking time) (p > 0.05). Our patient's Physical Health score in Child self-report and Parent proxy-report did not significantly change in the treatment group compared to the placebo (p > 0.05). Furthermore, there were no significant changes in energy and macronutrient intake after NALL treatment. None of the volunteers reported serious or moderate side effects. CONCLUSIONS: To the best of our knowledge, this was the first placebo-controlled, randomized clinical trial exploring NALL's potential effects for treating AT. Despite improvements in some symptomss, NALL intervention failed to improve motor function significantly. However, patients' nausea and constipation were improved by NALL, which can be a relevant benefit clinically.

Recent update on the protective potentials of resveratrol against cisplatin-induced ototoxicity: a systematic review.

INTRODUCTION: Although cancer treatment with cisplatin is effective, dose-dependent adverse effects such as ototoxicity occurs often, which limits its clinical use. The use of resveratrol may alleviate the cisplatin-induced ototoxic effects. This study is aimed to review the potential otoprotective effects of resveratrol against cisplatin-induced ototoxicity. METHOD: According to the PRISMA guideline, a systematic search was accomplished to identify all relevant scientific papers on "the role of resveratrol against cisplatin-induced ototoxicity" in different electronic databases up to May 2021. Fifty-five articles were screened based on a pre-defined set of inclusion and exclusion criteria. Eight eligible studies were finally included in the current systematic review. The in-vitro findings revealed that cisplatin administration significantly decreased the HEI-OC1 cell viability compared to the untreated cells; however, resveratrol co-treatment (in a dose-dependent manner) could protect HEI-OC1 cells against cisplatin-induced decrease in cell viability. RESULTS: Furthermore, the in-vivo finding showed a decreased value of DPOAE, and increased values of ABR threshold, ABR-I, ABR-IV, and ABR I-IV interval in cisplatin-treated animals; in contrast, resveratrol co-administration demonstrated an opposite pattern on these parameters. CONCLUSION: Thus, it can be mentioned that resveratrol co-treatment alleviates cisplatin-induced ototoxicity. Mechanically, resveratrol exerts its otoprotective effects through various mechanisms such as anti-oxidant, anti-apoptosis, and anti-inflammatory.

Radiotherapy-associated sensorineural hearing loss in pediatric oncology patients.

During the radiotherapeutic treatment of pediatric oncology patients, they would be at a latent risk of developing ionizing radiation-induced ototoxicity when the cochlea or auditory nerve is located within the radiation field. Sensorineural hearing loss (SNHL) is an irreversible late complication of radiotherapy, and its incidence depends on various factors such as the patient's hearing sensitivity, total radiation dose to the cochlea, radiotherapy fractionation regimen, age and chemoradiation. Importantly, this complication exhibits serious challenges to adult survivors of childhood cancer, as it has been linked to impairments in academic achievement, psychosocial development, independent living skills, and employment in the survivor population. Therefore, early detection and proper management can alleviate academic, speech, language, social, and psychological morbidity arising from hearing deficits. In the present review, we have addressed issues such as underlying mechanisms of radiation-induced SNHL, audiometric findings of pediatric cancer patients treated with radiotherapy, and management and protection measures against radiation-induced ototoxicity.

The Effects of N-Acetyl-L-Leucine on the Improvement of Symptoms in a Patient with Multiple Sulfatase Deficiency.

Multiple Sulfatase Deficiency (MSD) is a rare autosomal recessive disease with specific clinical findings such as psychomotor retardation and neurological deterioration. No therapy is available for this genetic disorder. Previous studies have shown that N-acetyl-L-leucine (NALL) can improve the neurological inflammation in the cerebellum.In the current study, the effects of NALL on ataxia symptoms and quality of life were explored in a patient with MSD.This study was a crossover case study. The subject, a girl aged 12 years old, received NALL at a dose of 3 g/day (1 g in the morning, 1 g in the afternoon, and 1 g in the evening). A fasting blood sample was taken from the subject to evaluate side effects before the intervention and 4 weeks after taking supplement/placebo in every study stage. The ataxia moving symptoms were evaluated using the Scale for the Assessment and Rating of Ataxia (SARA) score in every study stage. Dietary intake was measured using 24-h dietary recall before and after the intervention. The diet compositions were assessed by Nutritionist IV software. Serum IL-6 level was measured using an ELISA kit.There was no significant change in complete blood count (CBC) and serum biochemical factors in the patient with MSD after receiving NALL (3 g/day) over 4 weeks. The SARA score was reduced by 25%. The gait whose maximum score accounts for approximately one-fifth of the maximum total SARA score (8/40) was decreased. The heel-to-shin slide, the only SARA item performed without visual control, was also improved after therapy. Furthermore, there was a downward trend in the 8MWT (8.71 to 7.93 s). Regarding quality of life assessments, the parent and child reported improved quality of life index, physical health, and emotional function after taking NALL. Moreover, total energy intake was increased with NALL treatment through the study period.Supplementation with NALL at a dose of 3 g/day over 4 weeks was well tolerated and improved ataxia symptoms, quality of life measure, and serum IL-6 levels in the patient with MSD. Further proof-of-concept trials are warranted to confirm the present findings.

The Effect of N-Acetyl-DL-Leucine on Neurological Symptoms in a Patient with Ataxia-Telangiectasia: a Case Study.

Ataxia-telangiectasia (AT) is a rare autosomal recessive disorder with no available curative treatment. Although the positive effects of N-acetyl-DL-leucine on cerebellar ataxia have been reported previously, there is little evidence of N-acetyl-DL-leucine's effects in patients with AT. This study assessed the effect of 16 weeks N-acetyl-DL-leucine supplementation on ataxia symptoms in a 9-year-old female with AT. The subject consumed 4 g/day N-acetyl-DL-leucine (2 g in the morning and 2 g in the evening) for 16 weeks. Safety was assessed via clinical blood chemistry prior to the intervention and after 6 and 16 weeks. Additionally, The Scale for the Assessment and Rating of Ataxia (SARA) score was used to assess the drug's effects on ataxia symptoms at baseline, 6, 12, and 16 weeks. Quality of life has also been evaluated by a specialist using the PedsQL questionnaire.Despite some initial (first week only) nausea and constipation, supplementation with N-acetyl-DL-leucine was well tolerated and safe according to blood chemistry measures. The SARA score progressively improved, and by week 16 had improved by 11.0 points (48.88%). Parent and self-reported quality of life assessments indicated physical, emotional, social, and school functions all improved by 16 weeks. Supplementation with N-acetyl-DL-leucine at a dose of 4 g/day for 16 weeks was well tolerated and significantly improved ataxia symptoms and quality of life measures in a young child with AT.

Association of ANGPTL3 polymorphisms with high-density lipoprotein cholesterol uptake capacity in patients with cardiovascular disease.

INTRODUCTION: Previous studies have shown the importance of angiopoietin-like 3 (ANGPTL3) as a modulator of lipid profiles. Cholesterol uptake capacity (CUC) is one means for assessing high-density lipoprotein (HDL) functionality. This study for the first time has investigated the relationship between genetic ANGPTL3 polymorphism and CUC in patients with cardiovascular disease. METHODS: Five hundred three subjects comprising 350 healthy subjects and 153 individuals who developed a cardiovascular disease (CVD) event during follow-up were recruited as part of the Mashhad Stroke and Heart Atherosclerotic Disorder (MASHAD) cohort study. A modified CUC method was used to determine the CUC of serum samples. Applied amplification refractory mutation system PCR was performed for ANGPTL3 variants genotyping including: rs10789117, rs1748195, and rs11207997. Sanger sequencing was applied to confirm the genotypes. RESULTS: The results showed that there was a significant relationship between the rs1748195 genotypes and HDL concentration in the CVD group (p = 0.02). Moreover, individuals with a GG genotype of the rs1748195 were associated with a lower risk of CVD (OR = 0.49, 95% CI = 0.24-0.98, p = 0.04) compared with CC genotype in the CUC ≤ 1.7 a.u subgroup. Moreover, the CT genotype of rs11207997 was associated with a lower risk of CVD (OR = 0.74, 95% CI = 0.41-1.3, p = 0.01) compared with CC genotype in CUC > 1.7 a.u subgroup. CONCLUSION: The results showed that the CT genotype of the rs11207997 variant was associated with a lower risk of incident CVD in patients with higher HDL functionality. As well, the rs1748195 gene variant may contribute to a reduced risk of CVD.

Research in the Middle East into the Health Benefits of Curcumin.

The Middle East is known as the cradle of civilization. It was the crossroads of ancient empires and the birthplace of major world religions. Today, it is the center of many world issues due to economic, religious, and political reasons. Although it has lagged behind many other regions of the world in medicinal research, this has increased dramatically in recent years with increasing numbers of relevant publications. Much of this research has focused on increasing our understanding of the aging process and attempting to identify biomarkers and natural products to improve the human health span. This review provides a brief overview of the research conducted in the Middle East on the health benefits of curcumin, a phytochemical derived from the famous spice turmeric. These efforts have been mainly spearheaded by Iran.

Curcumin: A Review of Its Effects on Epilepsy.

Central nervous system (CNS) diseases pose an enormous healthcare burden, at both an individual and a societal level. Epilepsy has now become one of the most prevalent CNS disorders. Pharmaceutical drugs prescribed for epilepsy often have serious side effects and, for this reason, attention has turned to the use of medicinal plants. Curcumin (diferuloylmethane) is a major component of Curcuma longa and exhibits various pharmacological effects, including anti-inflammatory, antioxidant, and immunoregulatory properties. Here, we have reviewed the literature relating specifically to the antiepileptic effects of curcumin. The evidence suggests a protective effect of curcumin in the control of epileptic seizures, together with a protective effect on the relief of memory impairment, which may stem from its influence on monoamine levels in the brain.

Does curcumin have an effect on sleep duration in metabolic syndrome patients?

OBJECTIVE: Sleep-duration is related to obesity. Curcumin can affect behavioral changes that arise from sleep deprivation in animal models. In this study, we assessed the effects of curcumin on sleep-duration in metabolic-syndrome (MetS) patients. MATERIALS AND METHODS: This study was a double-blind clinical trial in 120 adults with MetS. All participants received crude curcuminoids in a simple formulation (n=40), phospholipidated curcuminoids (n=40) or placebo (n=40) 1 g/day during 6 weeks. Demographic data, anthropometric indices and serum biochemical factors were documented for all volunteers at baseline and after the intervention. A standard questionnaire was used for evaluating physical-activity-level (PAL) and patients' sleep-duration, including night time sleep and daily napping. Based on the time of sleep, sleeping hours were classified into: night time sleep; daily naps and total sleeping hours in 24 hours. RESULTS: A total of 120 participants aged 38.72±10.05 years old were enrolled into the study. We did not find significant differences in biochemical factors, sleep-duration or PAL at baseline among the 3 groups (p>0·05). Moreover, curcumin did not exert any significant effect on sleep-duration before, or after, adjustment for confounding factors in the overweight and obese individuals, or in total population (p>0.05). CONCLUSION: The results showed that curcumin does not have an effect on sleep-duration in subject with MetS.

Effects of Curcuminoids on Systemic Inflammation and Quality of Life in Patients with Colorectal Cancer Undergoing Chemotherapy: A Randomized Controlled Trial.

BACKGROUND: Colorectal cancer (CRC) is the third and the fourth most common cancer in Iranian men and women, respectively. Curcuminoids are known to exertprotective effects against several kinds of cancers. We aim to assess the effects of curcuminoids on serum pro- and anti-inflammatory cytokines and quality of life in patients with colorectal cancer undergoing chemotherapy. MATERIAL AND METHODS: This study was a double-blind placebo-controlled trial in patients with CRC (stage 3) aged ≥20 years, who had chemotherapy after the surgery and were referred to Baqiyatallah Oncology Clinic. Patients were randomly assigned to the treatment group receiving curcuminoids capsules (500 mg/day) (n = 36), or the control group taking placebo capsules (n = 36) for 8 weeks. Erythrocyte sedimentation rate (ESR) and serum levels of C-reactive protein (CRP) and 12 pro- and anti-inflammatory cytokines including tumor necrosis factor (TNF-α), interleukin-1α (IL-1α), IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, monocyte chemoattractant protein (MCP-1), interferon γ (IFN-γ), epidermal growth factor (EGF), and vascular endothelial growth factor (VEGF)] were measured at baseline and at the end of the intervention. The EORTC-QLQ-C30 instrument was used to assess the quality of life before and after the intervention. Statistical analyses were performed using SPSS software. RESULTS: A total of 67 subjects completed the study as three and two subjects were lost to follow-up in the curcuminoid and placebo groups, respectively. A significant change in CRP (p = 0.002) and ESR (p = 0.0001) was observed in patients supplemented with curcuminoids at the end of 8 weeks compared to placebo. Moreover, IL-1α showed a decreasing trend after curcuminoid supplementation compared to placebo (p = 0.077). A significant improvement in functional (p = 0.002) and global quality of life (p = 0.020) scales was observed in the curcuminoid group. CONCLUSIONS: The results showed that curcuminoids supplementation for a period of 8 weeks (500 mg/day) can improve ESR and serum levels of CRP in stage-3 CRC subjects and improve the global quality of life and functional scales compared to placebo.

Efficacy of phytosomal curcumin among patients with non-alcoholic fatty liver disease.

Scientists proposed that curcumin could be used for treatment of non-alcoholic fatty liver disease (NAFLD). In this article, we aimed to identify the effect of curcumin on NAFLD improvement. Fifty patients with NAFLD, were divided into two groups in this randomized, double-blind, and controlled clinical trial. Patients in the curcumin group received 250 mg/day of phytosomal curcumin, while those in the control group received 250 mg/day of placebo for duration of eight weeks. Anthropometric measurements and fasting blood samples were taken once at the baseline and once at the end of the study. Analysis was performed on 45 patients (curcumin group n = 22, placebo group n = 22). According to between groups analysis, curcumin significantly reduced the carboxymethyl lisine (CML) (148 ± 108 ng/mL vs 197 ± 101 ng/mL, P = 0.04), 8-hydroxy-2' -deoxyguanosine (8-OHdG) (46.9 ± 31.1 ng/mL vs 52.1 ± 43.1 ng/mL P = 0.03), liver enzymes (P < 0.001), weight (P < 0.001), waist circumference (P < 0.001), body fat percent (P < 0.01), and body mass index (BMI) (P < 0.01) in comparison with placebo. However, curcumin supplementation compared to placebo did not reduce soluble receptors for advanced glycation end products (sRAGE), hip circumference, waist/hip, and fat free mass by the end of the study. Our study indicated that phytosamal curcumin might be able to reduce the NAFLD progress by reducing the anthropometric measures, AGEs, and DNA damage. However, we need more studies with longer intervention duration, and larger sample size.

A pilot study of the effect of curcumin on epigenetic changes and DNA damage among patients with non-alcoholic fatty liver disease: A randomized, double-blind, placebo-controlled, clinical trial.

BACKGROUND: The enhancement of oxidative stress in non-alcoholic fatty liver disease (NAFLD) patients may cause mutation in DNA by deamination of cytosine to 5-hydroxyuracil or uracil. This study aimed to discover the effects of curcumin on NAFLD progress, DNA damage caused by oxidative stress, and promoter methylation of mismatch repair enzymes. MATERIAL AND METHODS: in this study, 54 NAFLD patients were randomly devided into two groups, according to a double blind parallel design either phytosomal curcumin (250 mg/day) or placebo for 8 weeks. Fasting blood samples and anthropometric measures were taken twice, once at the baseline and once at the end of the study. Promoter methylation and 8-hydroxy-2' -deoxyguanosine (8-OHdG) concentration as DNA damage mediator were measured by restriction enzymes and enzyme-linked immunosorbent assay, respectively. RESULT: Analysis was performed on 44 patients. According to our between groups analysis, curcumin significantly reduced the methylation in MutL homolog 1 (MLH1) and MutS homolog 2 (MSH2) promoter regions. The within-group comparison revealed that anthropometric variables significantly decreased. However, the result of the between groups comparison indicated no significant changes in the anthropometric variables except for BMI. Liver enzymes and 8-OHdG did not significantly change at the end of the study, neither in curcumin group nor in placebo group. CONCLUSION: Curcumin might be able to reduce the risk of mismatch base pair in DNA among the NAFLD patients. However, it did not change the DNA damage mediator and liver enzymes. For confirming these results, more studies with longer duration, more numbers of examined genes, higher dose of curcumin, and larger sample size are required.

Neuroprotective effects of minocycline on focal cerebral ischemia injury: a systematic review.

To review the neuroprotective effects of minocycline in focal cerebral ischemia in animal models. By searching in the databases of PubMed, ScienceDirect, and Scopus, and considering the inclusion and exclusion criteria of the study. Studies were included if focal cerebral ischemia model was performed in mammals and including a control group that has been compared with a minocycline group. Written in languages other than English; duplicate data; in vitro studies and combination of minocycline with other neuroprotective agents were excluded. Neurological function of patients was assessed by National Institute of Health Stroke Scale, modified Rankin Scale, and modified Barthel Index. Neuroprotective effects were assessed by detecting the expression of inflammatory cytokines. We examined 35 papers concerning the protective effects of minocycline in focal cerebral ischemia in animal models and 6 clinical trials which had evaluated the neuroprotective effects of minocycline in ischemic stroke. These studies revealed that minocycline increases the viability of neurons and decreases the infarct volume following cerebral ischemia. The mechanisms that were reported in these studies included anti-inflammatory, antioxidant, as well as anti-apoptotic effects. Minocycline also increases the neuronal regeneration following cerebral ischemia. Minocycline has considerable neuroprotective effects against cerebral ischemia-induced neuronal damages. However, larger clinical trials may be required before using minocycline as a neuroprotective drug in ischemic stroke.

Shedding light on the EpCAM: An overview.

The epithelial cell adhesion molecule (EpCAM) is a Type I transmembrane superficial glycoprotein antigen that is expressed on the surface of basolateral membrane of multiple epithelial cells with some exceptions such as epidermal keratinocytes, hepatocytes, thymic cortical epithelial cells, squamous stratified epithelial cells, and myoepithelial cells that do not express the molecule. The molecule plays a pivotal role in the structural integrity, adhesion of the epithelial tissues and their interaction with the underlying layers. EpCAM prevents claudin-7 and claudin-1 molecules from degradation, thereby, decreasing the number of tight junctions and cellular interconnections, and promoting the cells toward carcinogenic transformation. Moreover, the mutations in the EpCAM gene lead to congenital tufting enteropathy, severe intestinal epithelium homeostasis disorders, and Lynch and Lynch syndrome. Overexpression of EpCAM on stem cells of some cancers and the presence of this molecule on circulating tumor cells (CTCs) makes it a promising candidate for cancer diagnosis as well as tracing and isolation of CTCs.

The Effects of Curcumin on Serum Heat Shock Protein 27 Antibody Titers in Patients with Metabolic Syndrome.

Metabolic syndrome (MetS) is associated with an increased risk of cardiovascular disease and diabetes mellitus. Inflammation and oxidant stress are features of MetS that can enhance the expression and release of heat shock proteins (Hsps), including the small heat shock protein, Hsp 27, and that may subsequently lead to the production of Hsp27 antibodies (anti-Hsp 27). Curcumin is an anti-inflammatory and antioxidant phytochemical that may ameliorate these features of MetS. We investigated the effects of unformulated curcumin and phospholipidated curcumin on antibody titers to heat shock protein 27 (anti-Hsp 27) in patients with MetS. A randomized double-blind, placebo-controlled clinical trial design was used in 120 patients with MetS (diagnosed according to the International Diabetes Federation [IDF] criteria). Participants were randomly allocated to 3 groups, with 40 individuals per group, that received either 1 g/d curcumin, phospholipidated curcumin, or a placebo for 6 weeks. The changes in serum concentrations of anti-Hsp 27 did not differ significantly between study groups (p = .283). There was no significant difference between baseline and end-of-trial concentrations of anti-Hsp 27 in groups supplemented with curcumin (p = .177), phospholipidated curcumin (p = .798), or placebo (p = .663). Curcumin supplementation (1 g/d) has no significant effects on anti-Hsp 27 titers in patients with MetS.

The role of microRNAs in embryonic stem cell and induced pluripotent stem cell differentiation in male germ cells.

New perspectives have been opened by advances in stem cell research for reproductive and regenerative medicine. Several different cell types can be differentiated from stem cells (SCs) under suitable in vitro and in vivo conditions. The differentiation of SCs into male germ cells has been reported by many groups. Due to their unlimited pluripotency and self-renewal, embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) can be used as valuable tools for drug delivery, disease modeling, developmental studies, and cell-based therapies in regenerative medicine. The unique features of SCs are controlled by a dynamic interplay between extrinsic signaling pathways, and regulations at epigenetic, transcriptional and posttranscriptional levels. In recent years, significant progress has been made toward better understanding of the functions and expression of specific microRNAs (miRNAs) in the maintenance of SC pluripotency. miRNAs are short noncoding molecules, which play a functional role in the regulation of gene expression. In addition, the important regulatory role of miRNAs in differentiation and dedifferentiation has been recently demonstrated. A balance between differentiation and pluripotency is maintained by miRNAs in the embryo and stem cells. This review summarizes the recent findings about the role of miRNAs in the regulation of self-renewal and pluripotency of iPSCs and ESCs, as well as their impact on cellular reprogramming and stem cell differentiation into male germ cells.

The effects of curcumin and a modified curcumin formulation on serum Cholesteryl Ester Transfer Protein concentrations in patients with metabolic syndrome: A randomized, placebo-controlled clinical trial.

OBJECTIVE: Cholesteryl Ester Transfer Protein (CETP) mediates the transfer of cholesteryl ester from HDL-C to LDL-C and VLDL-C. The aim of the present trial was to evaluate the effect of curcumin and its modified formulation on serum CETP concentrations in patients with metabolic syndrome. MATERIALS AND METHODS: Participants were randomly allocated to one of three groups of 40 subjects receiving either unmodified curcumin or its phospholipid complex or placebo. Lipid profile and plasma CETP were measured at the start and six weeks after initiation of the treatment. The normality of data distribution was assessed by Kolmogorov-Smirnov test. Wilcoxon test was used for comparing the data before and after the intervention. The percent changes of CETP and biochemical factors among the three groups were compared using Kruskal-Wallis test. RESULTS: Serum CETP levels were not significantly altered among patients receiving curcumin. CONCLUSION: Curcumin and its complex had no significant effect on serum CETP concentrations.

Demethoxycurcumin: A naturally occurring curcumin analogue with antitumor properties.

The eradication of cancer in a patient remains an elusive challenge despite advances in early detection and diagnosis, chemo- and immunotherapy, pinpoint radiation treatments, and expert surgical intervention. Although significant gains have been made in our understanding of cancer cell biology, a definite cure for most cancers does not exist at present. Thus, it is not surprising that the research and medical communities continue to explore the importance and therapeutic potential of natural products in their multimodality cancer treatment approach. Curcuminoids found in turmeric are one such class of natural products that have been extensively investigated for their potential to halt the progression of cancer cell proliferation and, more important, to stop metastasis from occurring. In this review, we examine one curcuminoid (demethoxycurcumin [DMC]) largely because of its increased stability and better aqueous solubility at physiological pH, unlike the more well-known curcuminoid (curcumin), which is largely unabsorbed after oral ingestion. The present review will focus on the signaling pathways that DMC utilizes to modulate the growth, invasion, and metastasis of cancer cells in an effort to provide enhanced mechanistic insight into DMC's action as it pertains to brain, ovarian, breast, lung, skin, and prostate cancer. Additionally, this review will attempt to provide an overview of DMC's mechanism of action by modulating apoptosis, cell cycle, angiogenesis, metastasis, and chemosensitivity. Lastly, it is hoped that increased understanding will be gained concerning DMC's interactive role with microRNA-551a, 5' adenosine monophosphate-activated protein kinase, nuclear factor-κB, Wnt inhibitory factor-1, and heat shock protein 70 to affect the progression of cancer.

Phytosomal curcumin inhibits tumor growth in colitis-associated colorectal cancer.

Colorectal-cancer (CRC) is the third leading cause of death due to cancer, supporting the need for identification of novel anticancer drug to improve the efficacy of current-therapy. There is growing bodies of data showing the antitumor-activity of curcumin, although it is associated with low absorption. The aim of current study was explored the therapeutic-potential of novel phytosomal curcumin as well as its application in combination with 5-Flurouracil (5-FU) in a mouse-model of colitis-associated colon-cancer. The anti-proliferative-activity of phytosomal curcumin was assessed in 2- and 3-dimensional cell-culture-models as well as in a mouse-model of colitis-associated colon-cancer. The expression-levels of CyclinD1, beclin, E-cadherin, and p-GSK3a/b were investigated by qRT-PCR and/or Western-blotting. We evaluated the anti-inflammatory of this agent by pathological-evaluation and disease-activity-index (DAI). Moreover, oxidant/antioxidant activity was examined by malondialdehyde (MDA), total-thiols (T-SH), superoxide-dismutase (SOD), and catalase (CAT) activity parameters. Our data showed that phytosomal curcumin and its combination with 5-FU inhibited cell growth and invasive behavior of CRC cells through modulation of Wnt-pathway and E-cadherin. Combination of curcumin with 5-FU dramatically reduced the tumor-number and tumor-size in both distal and middle parts of colon in colitis-associated colon cancer followed by reduction in DAI. Also, curcumin suppressed the colonic inflammation and notably recovered the increased levels of MDA, decreased thiol level and reduced activity of CAT. We demonstrated the antitumor-activity of novel form of curcumin in CRC, supporting further investigations on the therapeutic-potential of this approach in colorectal-cancer.

IL-35, a hallmark of immune-regulation in cancer progression, chronic infections and inflammatory diseases.

Cytokine members of the IL-12 family have attracted enormous attention in the last few years, with IL-35 being the one of the most attractive-suppressive cytokine. IL-35 is an important mediator of regulatory T cell function. Regulatory T cells play key roles in restoring immune homeostasis after facing challenges such as infection by specific pathogens. Moreover, a crucial role for regulatory T cell populations has been demonstrated in several physiological processes, including establishment of fetal-maternal tolerance, maintenance of self-tolerance and prevention of autoimmune diseases. However, a deleterious involvement of immune regulatory T cells has been documented in specific inhibition of immune responses against tumor cells, promotion of chronic infections and establishment of chronic inflammatory disorders. In this review, we attempt to shed light on the concept of immune-homoeostasis on the aforementioned issues, taking IL-35 as the hallmark of regulatory responses. The dilemma between immune-mediated cancer treatment and inflammation is discussed. Histopathological indications of chronic vs. acute infections are elaborated. Moreover, the evidence that IL-35 requires additional immune-regulatory cytokines, such as IL-10 and TGF-ß, to induce effective and maximal anti-inflammatory effects suggest that immune-regulation requires multi-factorial analysis of many immune playmakers rather than a specific immune target.