Noncoding RNA therapeutics for substance use disorder.

Although noncoding RNAs (ncRNAs) have been shown to regulate maladaptive neuroadaptations that drive compulsive drug use, ncRNA-targeting therapeutics for substance use disorder (SUD) have yet to be clinically tested. Recent advances in RNA-based drugs have improved many therapeutic issues related to immune response, specificity, and delivery, leading to multiple successful clinical trials for other diseases. As the need for safe and effective treatments for SUD continues to grow, novel nucleic acid-based therapeutics represent an appealing approach to target ncRNA mechanisms in SUD. Here, we review ncRNA processes implicated in SUD, discuss recent therapeutic approaches for targeting ncRNAs, and highlight potential opportunities and challenges of ncRNA-targeting therapeutics for SUD.

Evaluating human epidermal growth factor receptor 2 roles in the efficacy of Tamoxifen treatment in breast cancer, a systematic review.

PURPOSE: Hormone therapy with Tamoxifen is an effective treatment that can decrease recurrence rate and mortality. Numerous molecular mechanisms can modify the response to Tamoxifen. The objective of this study was to determine Tamoxifen efficacy on patients' recurrence and mortality rates, according to the human epidermal growth factor receptor 2 (HER2) status. METHODS: In this meta-analysis of published studies, relapse and death rates were measured in both HER2 negative and positive patients treated with Tamoxifen. Besides, the relative risk of treatment with Tamoxifen compared to no Tamoxifen treatment was evaluated in both HER2 positive and negative patients. RESULTS: There was an increased risk of recurrence in HER2 positive patients who received Tamoxifen compared with HER2 negative ones (RR = 1.63, p value < 0.001). Tamoxifen treatment is associated with decreased relapse rate (RR = 0.70, p value < 0.001); however, it did not effect on HER2 positive ones (RR = 1, p value = 0.99). CONCLUSION: According to the analysis result, the relapse rate in breast cancer patients who were treated with Tamoxifen depends on the HER2 situation. Despite the limited sample size, it is revealed that Tamoxifen can decrease the relapse rate only in HER2 negative patients.

Association Between CYP3A5 Genetic Polymorphisms with Tacrolimus Dose Requirement and Allograft Outcomes in Iranian Kidney Transplant Recipients.

INTRODUCTION: Tacrolimus is the cornerstone of immunosuppressive therapy in organ transplantation with variable inter-individual pharmacokinetics. This study assessed the relationship between CYP3A5/3A4 polymorphisms and tacrolimus dose requirement as well as 6-month transplant outcomes in Iranian kidney transplant recipients. METHODS: In this prospective study, 110 adult kidney transplant recipients treated with tacrolimus were genotyped for the presence of common SNPs: rs776746: A > G (CYP3A5*3). Patients who carried at least one CYP3A5*1 allele were known as CYP3A5 expressers while those who were CYP3A5*3/*3 homozygotes were classified as CYP3A5 non-expressers. RESULTS: The daily tacrolimus dose was significantly higher and tacrolimus dose adjusted trough levels (C/D ratio) was significantly lower in CYP3A5 expressers compared with non-expressers (P < .05). Although the incidence of clinically suggested acute allograft rejection was significantly higher (OR = 0.365 [95% CI: 0.14 - 0.93]; P < .05) and median time to first acute rejection was sooner among CYP3A5 expressers compared with non-expressers (12.17 vs. 26.83 days, P < .05); however, estimated glomerular filtration rate, incidence of biopsy proven acute rejection and delayed graft function and 6-month patients' and grafts' survival did not differ between the two groups. CONCLUSION: CYP3A5 genetic polymorphism is significantly associated with required tacrolimus dose. After achieving desired tacrolimus blood level, although some transplant outcomes such as the incidence of clinically suggested acute rejection and time to first rejection were different between CYP3A5 expressers and non-expressers, however, other clinical outcomes did not differ between groups. Therefore, it is not the time to routinely assess kidney transplant recipients for CYP3A5 genetic polymorphism before transplantation.

Ellagic acid reduces methotrexate-induced apoptosis and mitochondrial dysfunction via up-regulating Nrf2 expression and inhibiting the IĸBα/NFĸB in rats.

BACKGROUND: The clinical application of methotrexate (MTX), an efficacious cytotoxic drug, is restricted due to its associated liver toxicity. Ellagic acid (EA), a natural polyphenol, possesses hepatoprotective, antioxidant and anti-inflammatory properties. OBJECTIVES: The present study seeks to address the hepatoprotective effects of Ellagic acid (EA) against MTX-mediated oxidative stress (OS) and widen our current knowledge of the underlying molecular mechanisms of MTX toxicity. METHODS: Wistar rats were orally given EA (5 mg/kg and 10 mg/kg) for 10 successive days and at the end of the third day they were administered a single dose of MTX (20 mg/kg i.p). RESULTS: After performing biochemical analysis, liver enzymes and malondialdehyde were significantly higher in the MTX group, indicating hepatic oxidative damage. MTX-induced OS was further confirmed with observation of events such as reactive oxygen species (ROS) overproduction, mitochondrial outer membrane potential decrease, mitochondrial swelling, cytochrome c release and caspase-3/9 increase, resulting in apoptosis. Furthermore, overexpression of pro-inflammatory factors such as nuclear factor kappa B (NF-ĸB) and interleukin 6 (IL-6) indicated the MTX-induced inflammation in MTX-treated group. Interestingly, EA was able to significantly prevent OS, mitochondrial dysfunction, apoptosis and inflammation induced by MTX. Also, EA-treated rats demonstrated significant upregulation of both nuclear factor erythroid 2-related factor 2 (Nrf2) and hemoxygenase-1 (HO-1), which were considerably downregulated in MTX-treated rats. CONCLUSIONS: EA protects rats against MTX-induced apoptosis and mitochondrial dysfunction via up-Regulating Nrf2 and HO-1 expression and inhibiting the NF-κB signaling pathway. Therefore, EA may protect patients against MTX-induced hepatotoxicity and encourage its clinical application. Graphical abstract Beneficial effect of Ellagic acid (EA) on Methotrexate (MTX)-induced liver injury: molecular mechanism.

How can we develop better antispasmodics for irritable bowel syndrome?

INTRODUCTION: Irritable bowel syndrome (IBS) is a prevalent gastrointestinal (GI) disease. Antispasmodics are a heterogeneous group of drugs that tackle IBS-associated altered bowel habit and abdominal pain. However, some studies have shown their failure to exhibit benefit over placebo. Considering the place of antispasmodics in managing key symptoms of IBS, there is a growing need for developing more efficacious and safe antispasmodics. Areas covered: The authors discuss the role of rational drug design (RDD) in developing new antispasmodics with desired features. Furthermore, they review the potential pharmacological targets and herbal medicines with spasmolytic activity. In addition, the authors present the recent findings concerning novel mechanisms involved in GI motility modulation as well as the potential antispasmodic role of drugs used in other conditions. Expert opinion: To develop better antispasmodics, it will be essential to gain a deeper insight into the underlying mechanisms involved in IBS-induced dysmotility and to uncover GI-specific receptors that regulating motility. New antispasmodics with GI-restricted and the multi-targeting features can be developed via implementation of RDD. Furthermore, the modification of current antispasmodics by formulation technologies might expedite the development of better antispasmodics. To conclude, the complex nature of IBS means that future successful drug discovery will require a multi-disciplinary approach.

Emerging Roles of Probiotics in Prevention and Treatment of Breast Cancer: A Comprehensive Review of Their Therapeutic Potential.

Breast cancer is the most common cancer among women. Need for novel preventive and curative approaches with more safety than the present one seems inevitable. This review is devoted to potentially favorable role of probiotics in prevention and treatment of breast cancer as well as their alleviating role regarding chemotherapy-induced side effects. Literature was searched for human, animal, and in vitro studies about the role of probiotics in breast cancer. In vitro studies showed that probiotic intervention induces cancer cells apoptosis and inhibits their proliferation. In animal models, treatment with probiotics inhibited tumor growth and reduced tumor size; also, the immunomodulatory, antiangiogenesis and antimetastatic activities of probiotics were illustrated. Human studies showed that intake of Lactobacillus casei shirota reduced the breast cancer incidence and consumption of fermented milk products and yogurt was inversely associated with breast cancer incidence; however, no study regarding the curative role of probiotics in breast cancer is available. Studies on the effect of probiotics on chemotherapy-induced side effects in breast cancer were contradictory but showed potential for more investigation. Probiotics seem to have a potential role in both prevention and treatment of breast cancer. However, more clinical studies are needed to elucidate their efficacy and safety.

A cAMP analog attenuates beta-amyloid (1-42)-induced mitochondrial dysfunction and spatial learning and memory deficits.

Alzheimer's disease (AD), a neurodegenerative disorder in elderly, is indicated with deposition of Amyloid ß (Aß) in the brain and accompanied with cognitive impairment. Bucladesine, a phosphodiesterase inhibitor, may ameliorate AD's cognitive dysfunctions through mimicking the action of cAMP and raising its intracellular level. Here, we investigated the effects of bucladesine on Aß-induced memory and learning impairment in a Morris water maze (MWM) model. Rats were injected with bucladesine (1 µl/side from a 100 µM stock solution) and Aß (1 µl/side from a 100 µM stock solution) intra-hippocampally and after 19 days were trained for 4 successive days. The oxidative stress was evaluated through measurement of thiobarbituric acid (TBARS), thiol groups, and ferric reducing antioxidant power (FRAP). Effect of Aß and its combination with bucladesine on the mitochondrial function was assessed according to changes in the ROS generation, mitochondrial membrane potential (MMP), mitochondrial swelling, ATP/ADP ratio, mitochondrial outer membrane damage and cytochrome C release. Our results showed a significant elevation in TBARS level after administration of Aß causing mitochondrial ROS generation, swelling, outer membrane damage, cytochrome C release and also lower thiol, FRAP, and MMP levels. Aß-induced spatial memory impairment was prevented by pre-treatment with bucladesine and the changed mitochondrial and biochemical indices upon treatment dose were improved. Taken together, we have obtained satisfactory results suggesting protecting effects of bucladesine against the Aß-mediated memory deficit and implying its plausible beneficial capacity as a therapeutic agent in oxidative stress-associated neurodegenerative diseases.

Acetyl-l-carnitine attenuates arsenic-induced liver injury by abrogation of mitochondrial dysfunction, inflammation, and apoptosis in rats.

Industrial and agricultural developments in recent years have resulted in the excessive discharge of arsenic into the environment, making arsenic toxicity a major worldwide concern. Oxidative stress is considered the primary mechanism for arsenic toxicity. The main objective of this study was to evaluate acetyl-l-carnitine's (ALC) protective ability against the arsenic-induced hepatotoxicity. For this purpose, male Wistar rats were distributed randomly into 5 groups of 8 rats each: control, arsenic (5 mg/kg) and arsenic plus ALC (5 mg/kg; 100, 200, 300 mg/kg). The animals were gavaged for 21 consecutive days. Liver tissue samples were extracted 24 h after the last treatment and were later analyzed for biochemical and histological alterations. The arsenic-induced oxidative damage was confirmed by elevation of malondialdehyde (MDA), a lipid peroxidation byproduct, as well as depletion in physiological antioxidant content such as superoxide dismutase (SOD) and catalase (CAT). Furthermore, alterations in mitochondrial functions including a significant decrease of mitochondrial outer membrane potential and reactive oxygen species (ROS) generation increase, mitochondrial swelling, release of cytochrome c and consequent activation of caspase-3 and caspase-9 and initiation of apoptosis, was observed following arsenic administration. Moreover, the inflammation was confirmed by the overexpression of inflammatory mediators such as NF-ĸB and IL-1 and IL-6. The present study demonstrated that ALC ameliorates arsenic-induced oxidative damage, mitochondrial dysfunction, apoptosis, inflammation and histological damage. ALC's protective features against arsenic hepatotoxicity may be due to this agent's antioxidant and anti-inflammatory properties as well as its stabilizing effects on mitochondrial function.