Current Molecular Pharmacology - Volume 14, Issue 4, 2021

Background: Allosteric modulators of G-protein coupled receptors regulate receptor activity by binding to sites other than the active site and have emerged as a new and highly desirable class of drugs. PAOPA (3(R)-[(2(S)-pyrrolidinylcarbonyl)amino]-2-oxo-1-pyrrolidineacetamide), a peptidomimetic analog of L-prolyl-L-leucyl-glycinamide, is a potent dopamine D2 receptor allosteric modulator. PAOPA has shown therapeutic effects in pre-clinical models of schizophrenia and extrapyramidal dysfunction. Objective: In this study, we sought to examine the biomolecular underpinnings of PAOPA‘s therapeutic outcomes in pre-clinical models of schizophrenia. Methods: Following sub-chronic (daily for 7 days) administration of PAOPA, we assessed levels of dopamine D2 receptors, receptor kinases (GRK2 (G protein-coupled receptor kinase 2) and Arrestin- 3), and phosphorylated mitogen-activated protein kinase (MAPKs), namely, extracellular signal- regulated kinases (ERK1/2) in the hippocampus, medial pre-frontal cortex, nucleus accumbens, pre-frontal cortex, and dorsal striatum via protein quantification. Results: Following 7 days of daily PAOPA treatment, we observed decreased GRK2 and increased dopamine D2 receptor expression in the dorsal striatum. These findings potentially underscore the therapeutic mechanism of action of PAOPA for the positive-like symptoms of schizophrenia in pre-clinical animal models. Additionally, we observed a decline in GRK2 in the hippocampus and an increase in phosphorylated ERK1 in the pre-frontal cortex, suggesting a role of PAOPA in treating cognitive and/or affective dysfunction in pre-clinical models. Conclusion: While further studies are required to elucidate the mechanism of action of PAOPA, this study discusses prior investigations and develops an early framework to describe the therapeutic mechanism of action of PAOPA.

Background: Piperine is a key bioactive alkaloid found in plants of piperaceae family. The compound possesses various medicinal and pharmacological activities (cholesterol-lowering, anti-cancer, Alzheimer’s disease etc.). Owing to its various target receptors (TRPV1, P-gp, CYP3A4 etc.) and several mechanisms, piperine has been studied as bio-enhancer for other drugs and its role has been evidenced in the literature. When administered with other drugs, it increases the absorption of other drugs, thereby reducing the dose and dose-related toxic potential. There are various mechanisms of piperine as a bio-enhancer and the common ones are i) prevention of efflux of drug molecules out of the cells; ii) decreased metabolism of drugs, thereby prolonging the halflife of drugs resulting in reduced urinary excretion. The detailed mechanism indicating the bio-enhancing role of piperine along with various target receptors has not been comprehensively summarised to date. Methods: Literature related to the molecular, enzymatic and receptor targets of piperine were studied, and database was collected using various search engines such as j-gate, google scholar, scihub, pubmed, sciencedirect, etc. The literature related to therapeutic activities of piperine and its bio-enhancer role for other drugs has been thoroughly studied and compiled in brief. Results: A detailed summary of piperine targets, along with related mechanisms, has been stated. A brief therapeutic profile of piperine alone has been produced with supporting literature. Piperine role as a potential bio-enhancer for other drugs has been summarized. Conclusion: Piperine is a fascinating molecule of natural origin with several modes of its action, not only possesses its own therapeutic activity but also enhances the therapeutic efficacy of other synthetic and natural drug molecules. Combination dosage forms of various API incorporating piperine as a bio-enhancer can be a potential area of thrust for upcoming drug design and development.

A chronic metabolic disease, diabetes mellitus (DM), is associated with various comorbidities that considerably decrease the quality of life. Sodium glucose linked transporter 2 (SGLT2) receptors are mainly situated in the proximal tubule of nephron. About 90% of glucose concentration is reabsorbed by these receptors in the nephron. The advanced remedy for the management of DM is sodium glucose co-transporter 2 inhibitors (SGLT2-Is), which inhibits or lowers the reabsorption of glucose. Furthermore, SGLT2-Is enhance the elimination of glucose level in urine (glycosuria). Empagliglozin, canagliflozin, ertugliflozin and dapagliflozin are the standard medications which have been authorized recently, for the management of DM by The Food and Drug Administration (FDA). Besides, having optimistic efficacy to attenuate blood glucose level, these medications have exhibited impressive cardioprotective and renoprotective effects in major clinical trials. Unlike other hypoglycaemic medications, it is found that these agents help in a consistent reduction in hospitalization, due to heart failure with probably multifactorial mechanisms. The cardioprotective efficacy of SGLT2-Is is characterized by enhancement in ventricular loading condition, in metabolism of cardiac cell, adipokines alteration, cardiac fibrosis, and reduction in the necrosis of cardiac cell. Recently confirmed results depict that dapagliflozin gradually decreases the frequency of co-morbidity and mortality in heart failure patients. The present review explores the mechanistic principle and the clinical trial data of SGLT2-Is, which further support cardioprotective effects associated with these medications.

Understanding organogenesis, disorders, and repairing processes is particularly important for understanding the disease occurrence and developing treatment approaches. At present, liver- related studies are mainly conducted using in vivo models and cell lines, making it difficult to generalize the full picture of the structural characteristics and functions of human organs. Organoid is a three-dimensional (3D) culture system in vitro, which holds the promise to establish various disease models and conduct in-depth research by generating organ-like tissues in a dish. Recent advances in human liver organoids have provided a deeper understanding of this complex organ. In this review, we provide a systematic overview of the construction methods of organoids, focusing on their applications in the hepatic organogenesis and various liver disease models, as well as the limitations of current models. The development of organoid models is proving to be crucial in future liver research.

Coronavirus disease 2019 (COVID-19) is caused by Severe Acute Respiratory Syndrome Coronaviruses 2 (SARS-CoV-2). At present, it is a potentially fatal disease and is of great global public health concern. The pathophysiological understanding of the mode of transmission of COVID-9 and the possible molecular targets are exploring successively to fight against this contagious disease. In this pandemic situation, a large number of countries have been forced to do social distancing and lockdown. The two main pathways of SARS-CoV-2 transmission include (1) droplet infection via the respiratory secretions or by close person to person contact, whereas (2) faecal to oral route transmission is also possible. Thus, the route of entry of SARS-CoV-2 is through the nasal and or oral cavity. Here, we briefly reviewed the current knowledge about COVID-19, considering the potential explanation of the mode of transmission and the different possible molecular drug targets. We highlighted potential approaches to address the antiviral therapy inhibiting the replication of SARS-CoV-2 in the host targeting (a.) RNA-dependent RNA polymerase (b.) serine protease and (c.) proteolytic activation pathways or the cell membrane receptor called the angiotensin- converting enzyme-2 (ACE2). The recently exercised immuno-enhancement therapy to fight against SARS-CoV-2 and treatment strategy using drug combination are also explored here in this review.

Renal Carcinoma (RC) is the ninth most prevalent cancer in men. Advancements in high- throughput technology have begun to scratch the surface of the complex landscape of renal cancer. Development, progression, invasion and metastasis are the key mechanism modulated by the microRNAs (miRNAs). Recent pieces of evidence have delineated the role of these micro steering wheels in the regulation of vital processes of RC biology, therefore miRNAs can be implemented as a new therapeutic target for RC. MiRNAs also negatively affect the process of apoptosis in cancer cells leading to their survival and growth. The role of dysregulated mRNAs in hindering the TRAIL- mediated apoptotic pathway is also known. Therapeutic interventions targeting tumor-suppressive miRNAs to promote apoptosis through extrinsic/intrinsic pathways seem a promising approach for advanced stage and metastatic renal cancers. This article aims to discuss RC-specific microRNAs, their roles in the TRAIL pathway and highlight the distinguished microRNAs that could serve as a diagnostic biomarker and therapeutic targets for this cancer.

Protein kinase B (AKT) PI3K / AKT / mTOR signaling pathways play a crucial role in modulating cell survival, proliferation, metastasis, metabolism, angiogenesis, and apoptosis. The AKT family consists of three isoforms: AKT1, AKT2, and AKT3. Moreover, it has high sequence homology in the kinase domain and has similar substrate specificity to other members of AGC protein kinase. Recent studies have shown that AKT signals disappear in some tumors. Overexpression and activation of AKT are not sufficient to induce the phenotype of malignant tumors. However, many studies have shown the importance of AKT in carcinogenesis including, breast and prostate cancers, second and third global cancer burden, respectively, in terms of incidence and death. Inhibition of AKT signaling may be beneficial in terms of therapeutic use and understanding of the function of AKT. To date, limited numbers of AKT inhibitors have been identified, and none are strongly selective for AKT isoforms. In this regard, we discussed the current insight of AKT inhibitors in drug development, protein structure, and mechanism as well as the role of AKT in the development of drug targets for breast cancer and prostate cancer.

Ischemia/reperfusion (I/R) injury is a serious pathologic event that occurs due to restriction in blood supply to an organ, followed by hypoxia. This condition leads to enhanced levels of pro-inflammatory cytokines such as IL-6 and TNF-α, and stimulation of oxidative stress via enhancing reactive oxygen species (ROS) levels. Upon reperfusion, blood supply incz reases, but it deteriorates condition and leads to the generation of ROS, cell membrane disruption and finally, cell death. Plant derived-natural compounds are well-known due to their excellent antioxidant and anti-inflammatory activities. Quercetin is a flavonoid exclusively found in different vegetables, herbs, and fruits. This naturally occurring compound possesses different pharmacological activities making it an appropriate option in disease therapy. Quercetin can also demonstrate therapeutic effects via affecting molecular pathways such as NF-ΚB, PI3K/Akt and so on. In the present review, we demonstrate that quercetin administration is beneficial in ameliorating I/R injury via reducing ROS levels, inhibition of inflammation, and affecting molecular pathways such as TLR4/NF-ΚB, MAPK and so on. Quercetin can improve cell membrane integrity via decreasing lipid peroxidation. Apoptotic cell death is inhibited by quercetin via downregulation of Bax, and caspases, and upregulation of Bcl-2. Quercetin is able to modulate autophagy (inhibition/induction) in decreasing I/R injury. Nanoparticles have been applied for the delivery of quercetin, enhancing its bioavailability and efficacy in the alleviation of I/R injury. Noteworthy, clinical trials have also confirmed the capability of quercetin in reducing I/R injury.

Prostate cancer (PCa) is the second most prevalent cancer and the fifth leading cause of cancer-related deaths among men. Androgen deprivation therapy (ADT) is the most frequently used therapeutic strategy in PCa; however, the development of resistance to ADT, known as castration- resistant prostate cancer (CRPC), continues to be a major obstacle against the successful treatment of PCa. The abnormal activation of the androgen receptor (AR) signaling pathway has been found as one of the main contributing factors to the development of resistance in CRPC. Therefore, AR regulatory strategies are urgently required to combat resistance. Recently, microRNAs (miRNAs) have been found as major AR regulatory factors affecting ADT resistance. MiRNAs can target AR itself, AR-related genes, AR splice variants, AR-related signaling pathways as well as cancer stem cells (CSCs), and play critical roles in regulating ADT resistance. Due to their capability to affect various genes and signaling pathways, miRNAs are now being studied for their potential role as a new therapeutic target in CRPC. It has been recommended that combination therapies, including miRNAs and existing drugs, can synergistically decrease castration resistance. miRNAs also have prognostic values for ADT, and their expression profiling in CRPC patients before therapeutic scheduling may enable the physician to diagnose patients who are ADT-resistant. Overall, extant evidence obviously supports the predictive and therapeutic potential of miRNAs in CRPC patients. This review summarizes the available information about the microRNA-mediated AR controlling mechanisms involved in ADT resistance.

Background: Valproic acid (VPA) is an HDAC inhibitor (HDACI) with an anticancer activity, but is hepatotoxic. N-(2-hydroxyphenyl)-2-propylpentanamide (o-OH-VPA) is a VPA aryl derivative designed in silico as a selective inhibitor of HDAC8 with biological properties against HeLa, rhabdomyosarcoma and breast cancer cell cultures. Objective: We studied the epigenetic mechanism of o-OH-VPA as an HDACI and evaluated whether it was toxic to normal cells. Methods: HeLa cells and primary human fibroblasts were used for this study as carcinogenic and normal cells, respectively. Cell survival was evaluated by MTT assay, whereas viability and doubling time were determined by the Trypan-blue method. HDAC activity was tested using the colorimetric HDAC activity assay. The expression of p21 was analyzed by PCR and HDAC8 expression was also evaluated by real-time PCR. Cell cycle and caspase-3 activity were analyzed by flow cytometry and caspase-3 colorimetric assay, respectively. Results: o-OH-VPA (IC50 = 0.1 mM) was fifty-eight times more effective than VPA (IC50 = 5.8 mM) to reduce HeLa cell survival. Furthermore, o-OH-VPA increased the doubling time of HeLa cells by 33% with respect to the control. o-OH-VPA acted as HDACI in HeLa cells without affecting the HDAC8 expression, arresting the cell cycle of HeLa cells in the G0/G1 phase due to the increase in p21 expression with the inhibition of caspase-3 activity without exhibiting toxicity toward normal cells. Conclusion: Our results revealed that o-OH-VPA is an HDACI with a selective effect against HeLa cells but without the known toxicity exerted by most pan-HDACIs on normal cells.

Background: While our previous research has demonstrated that the NLRP3 inflammasome is involved in epilepsy progression, the effects of the specific NLRP3 inhibitor CY-09 remain poorly understood. Therefore, the aim of the present study was to investigate the efficacy of CY-09 against pentylenetetrazole (PTZ)-induced neuronal loss in mice. Methods: The expressions of the proinflammatory factors interleukin-1β and interleukin-18 were examined by western blot and enzyme-linked immunosorbent assays. Western blot analysis was applied to detect the level of astrocyte activation. Neuronal apoptosis was determined by western blot analysis combined with immunostaining specific for neuronal nuclei. Results: We found that CY-09 ameliorated the progression of the kindling process and inhibited PTZ-induced neuronal loss by attenuating the activation of astrocytes and the secretion of NLRP3- dependent neuroinflammation. Conclumsion: These findings indicate that CY-09 may represent an important treatment agent for epilepsy and other NLRP3 inflammasome-associated diseases.

Objective: The study aimed to investigate the effects of quercetin on Aquaporin 1 (AQP1) translocation in high glucose condition and made an attempt to clarify the underlying mechanisms and provide new ideas for the treatment of diabetic cataract (DC). Methods: The human lens epithelial line SRA01/04 cells were divided into groups mentioned below: normal glucose, high glucose with a specific time (0 h, 2 h, 4 h, 8 h, 12 h, 24 h), high glucose plus the phosphoinositide 3-kinase (PI3K) inhibitor LY294002, high glucose plus the mammalian target of rapamycin (mTOR) inhibitor rapamycin, and high glucose plus quercetin with different doses (2 μmol/L, 4 μmol/L and 8 μmol/L). The western blotting assay was used to detect the protein kinase B (Akt), phosphorylated protein kinase B (p-Akt), mammalian target of rapamycin (m- TOR), phosphorylated mammalian target of rapamycin (p-mTOR) and AQP1. Real-time polymerase chain reaction (RT-PCR) was used to detect the expression of AQP1. A Membrane and Cytosol Protein Extraction Kit was applied to separate membrane proteins. Immunofluorescence assay was performed to evaluate the expression and location of AQP1. The effect of quercetin on the expression of AQP1 and PI3K/Akt/mTOR signaling was detected. Results: AQP1 protein was found to be significantly increased in 24 hour when exposed to high glucose condition (P<0.01). LY294002 and rapamycin inhibited PI3K/Akt/mTOR and AQP1 expression (P<0.01), preventing the change of AQP1 location in the SRA01/04 plasma membrane (P<0.01). This effect was further proved by immunofluorescence. In different doses of quercetin groups (2 μmol/L, 4 μmol/L and 8 μmol/L), the phosphorylation of mTOR and Akt were decreased and AQP1 in the membrane was changed compared with high glucose group (P<0.01). Conclusion: Quercetin significantly decreased the AQP1 elevation and prevented the change of AQP1 location through inhibiting the activation of the PI3K/Akt/mTOR signaling in high-glucose-- cultured SRA01/04 cells, which might have the preventable and inhibitory effects on the early development of diabetic cataract. The specific pathophysiological role of quercetin still needs to be verified.

Background: Buprenorphine (BUP), a “synthetic derivative of the opioid alkaloid thebaine”, may be associated with cellular damage in the central nervous system. Aims: This study was designed to investigate the effects of low and high doses of BUP on oxidative and inflammatory indices in the hippocampus and learning and memory behavior in an animal model. Objective: The association between BUP administration and oxidative and inflammatory damage and also learning and memory impairment is not clear. Methods: For this reason, twenty-four male Wistar rats were randomly allocated into one control and two BUP-treated groups (0.3 and 1 mg/kg, SC), (n=8, for each group). After 4 weeks, learning and memory abilities were assessed by using Y-maze test. Then, oxidative stress indices including glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) were assessed in the serum and hippocampus of each animal by using spectrophotometer. Inflammatory parameters such as tumor necrotic factor-α (TNF-α), interleukin- 6 (IL-6), and interleukin-1β (IL-1β) were also measured in the serum and hippocampus of rats by using ELISA. Results: The present findings indicated that the memory and learning time was lengthened in BUP (1mg/kg)-treated rats versus control animals (p<0.05). Additionally, it was observed that BUP (1 mg/kg) significantly increased the serum and hippocampal levels of MDA and TNF-α and also decreased GSH levels versus the control group (p< 0.05). Conclusion: The results of the present study revealed that BUP may cause learning and memory dysfunction by inducing oxidative stress and inflammation in the hippocampus.

Background: Earlier diagnosis and advances in treatment strategies have increased the average survival of cancer patients over the last decades. Despite the increased number of new anti- neoplastic agents, there has been no adequate therapy for intricate malignancies, such as pancreatic cancer. Cancer metabolism is the main building block standing behind cancer promotion and progression, even in the presence of a harsh environment. Targeting metabolic pathways, such as glycolysis and pentose phosphate pathway, are regarded as a promising new strategy for cancer treatment. Objective: The current study aimed to investigate the effects of knocking-down pancreatic cancer glycolytic and pentose phosphate pathway's regulators (HIF-1α, ARNT, PFKFB4, and RBKS) on cell’s viability and resistance to Gemcitabine and Doxorubicin, using small interference RNA. Methodology: The human pancreatic ductal adenocarcinoma cell line, Panc-1, was used to study the anti-proliferative activity of targeting HIF-1α, ARNT, PFKFB4, and RBKS mRNAs by transfection with small interference RNAs, alone and in combination. The transfected cells were also treated with Doxorubicin and Gemcitabine to study the relationship between the concerned genes and the resistance of Panc-1 cells to these drugs. The effect on cell proliferation was determined using a colorimetric assay and Inhibitory Concentration ((IC50) calculation. A cross-talk study was done to investigate the silencing effect of one of the above genes on the expression of others using Real Time-Polymerase Chain Reaction. Results: In vitro transfection with small interference-RNAs, siHIF-1α, siPFKFB4, and siARNT decreased tumor cell proliferation with a maximum effect shown by siPFKFB4; but there was no anti- proliferative effect with RBKS silencing. Suppression of transcription of HIF-1α, ARNT, PFKFB4, and RBKS sensitize pancreatic cancer cells, Panc-1, to Doxorubicin and Gemcitabine. Conclusion: This study demonstrated the major tumor-promoting and progressive effects of PFKFB4, while HIF-1α and ARNT had modulator effects in pancreatic cancer cells (Panc-1). RBKS had a chemo-resistant role, justifying its enhanced expression in Panc-1 cells, but not a proliferative one. Silencing of all genes of interest decreased Doxorubicin and Gemcitabine's resistance and improved their antitumor effect Din the pancreatic cancer cell line, Panc-1.

Background: Anti-cancer effect of lapachol contained in Tabebuia avellandae has been poorly understood until now. Objective: The aim of this study was to investigate the inhibitory effect of lapachol on MMPs related to cell invasion. Its action mechanism was elucidated by analyzing the activity and the expression of MMPs and the proteins involved in the signaling pathway of cell invasion. Methods: The cytotoxicity of lapachol was evaluated by MTT assay in HT1080 cells. The effects of lapachol on the expression and the activation of MMPs were analyzed by western blot, immunofluorescence staining, and gelatin zymography assays. Their gene expression was analyzed by RT-PCR, and metastasis was evaluated by cell invasion assay. Results: Lapachol below 2 μM showed no cytotoxicity. It was observed that lapachol above 0.5 μM inhibited the activation of MMP-2 and MMP-9 stimulated by PMA. In particular, the protein and gene expression levels of MMP-2 stimulated by PMA were remarkably decreased in the presence of lapachol at 1 μM compared with the PMA treatment group. In addition, lapachol increased the expression level of TIMP-1 compared with the PMA treatment group. Moreover, lapachol decreased the expression level of p-p38 among MAPKs compared with the PMA treatment group. It was also found that the expression level of p65, a part of NF-kB, in nuclei was reduced in the presence of lapachol above 0.5 μM compared with the PMA treatment group. In addition, lapachol inhibited the invasion of human fibrosarcoma cells stimulated with VEGF. Conclusion: Above results suggest that lapachol could play an important role in the modulation of MMPs related to cell invasion via the increase in TIMP-1 expression as well as the inactivation of p38 through NF-kB transcription factor.

Background: Crocin is a known compound with the antioxidant and anti-inflammatory properties which may help to reduce the progression of neurological disorders. In this study, we aimed to investigate the protective effects of crocin on beta-amyloid peptide Aβ (1-40) and hydrogen peroxide (H2O2) induced neurotoxicity in PC12 cells. Methods: PC12 cells were pretreated with crocin and donepezil (5 and 10 μM) for 2 h and then treated with Aβ (1-40) (25 μM) for 24 h. In parallel, after pretreatment with crocin (5 and 10 μM) and donepezil (5 and 10 μM) for 24 h, cells were treated with H2O2 (800 μM) for 4 h. Finally, the cell viability and intracellular reactive oxygen species (ROS) generation were evaluated using Alamar- Blue® and 2', 7'-dichlorodihydrofluorescein diacetate (DCFH-DA), respectively. The western blot test was done to compare the protein level of phospho SAPK/JNK, SAPK/JNK, PI3 Kinase P85, Phospho-PI3 Kinase P85, caspase-3 and cytochrome c) cyt c). Results: Crocin and donepezil could significantly decrease the Aβ toxicity and ROS level. While treatment with Aβ increased Cyt c release from mitochondria to cytosol, cleaved form of caspase-3 (17 kDa) and activated form of SAPK/JNK p44/4 decreased the activated form of PI3 Kinase P85 protein, indicating that crocin could significantly block the apoptosis initiated with Aβ. Conclusion: According to the results, crocin could be a promising candidate for further evaluations against the development of Alzheimer's disease through mitogen-activated protein kinases (MAPK) and the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling (PI3 K/AKT) pathways.

Background and Aim: Cisplatin (cis-diamminedichloroplatinum [II]; CDDP) is the most widely used drug in cancer chemotherapy. The nephrotoxicity of CDDP is one of its major side effects. Vorinostat (VST) has been reported to have antioxidant and anti-inflammatory effects in bothin-vitro and in vivo models. The present study aimed to explore the potential protective effects of VST against CDDP-induced nephrotoxicity in rats. Materials and Methods: The rats were randomly divided into 4 groups; control group, CDDP group (received CDDP 7.5 mg/kg IP single dose 5 days before the end of the experiment), VST group, (received VST 15 mg/kg/day by gastric gavage for 28 days), and CDDP + VST group (received CDDP + VST as above). Blood and kidney samples were collected on the 28th day for biochemical and histopathological examinations. Results: Administration of CDDP single dose (7.5 mg/kg IP) 5 days before the end of the experiment (at day 23) produced a significant decrease in renal glutathione levels and a significant increase in serum urea nitrogen, creatinine, renal malondialdehyde, tumor necrosis factor-alpha, tumor suppressor protein (p53) and nuclear factor kappa B levels compared to the control group. Pretreatment with VST for 28 days significantly attenuated all unfavorable changes of these parameters. Histopathological analysis showed that VST significantly decreased kidney inflammatory and degenerative changes induced by CDDP. VST also significantly increased Bcl-2 and decreased Caspas- 3 immunoexpression in renal tissues. Conclusion: These results suggest that VST alleviates CDDP-induced nephrotoxicity in rats showing a novel therapeutic potential for the management of nephrotoxicity induced by CDDP.

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.

Background: Rhinitis medicamentosa, also known as ‘rebound congestion,’ is inflammation of the nasal mucosa caused by the overuse of topical nasal decongestants. Although local decongestants resolve the initial nasal obstruction, the overuse causes rebound obstruction. However, how the overuse of the decongestant causes rhinitis medicamentosa is not known. Objectives: Here, we show the intracellular effects of oxymetazoline, commonly used a local decongestant, on the cell death pathways. We also investigated the antioxidative effects of erdosteine suspension (175 mg/5mL), an antioxidative agent. Methods: Thirty Wistar-albino rats were used to form the rhinitis medicamentosa model. After rhinitis medicamentosa was clinically detected, we removed the whole lungs of animals to perform the molecular analyses of cell death pathways. Results: We found a statistically significant decrease in the expression levels of Atg5 (p=0.021), Atg7 (p=0.013) and Ulk1 (p=0.036) in the oxymetazoline group compared to the control group (p<0.05); however, Caspase 3 expression level was recorded to be significantly increased in the oxymetazoline group, and the expression level of Beclin1 recorded to be substantially increased in the erdosteine group (p=0.001). Conclusion: Based on these grounds, we suggest that vasoconstriction in capillary vessels caused by oxymetazoline could lead to a decrease in the blood supply, which triggers autophagy to ensure cellular homeostasis.

Background: Cell adhesion, as dynamic interactions between cell-cell and cell-matrix, has an essential role in cancer cell migration. Integrins as cell membrane receptors are involved in cell adhesion and signal transduction. Aberrant expression of integrins is associated with the cancer cell adhesion. Objective: Targeting the process of cell adhesion and migration could be helpful to prevent cancer cell metastasis. Amygdalin is a cyanoglycoside compound with anti-cancer properties, while its effect on cancer cell adhesion is not completely clear. Methods: The cytotoxic effect of amygdalin on breast cancer cell lines (MCF-7 and MDA-MB- 231) and human skin fibroblast cell line as a normal cell, was evaluated through MTT assay. The cell adhesion assay and wound healing assay were performed to determine amygdalin effects on adhesion and migration of cancer cells. Further analysis was carried out to evaluate integrin α and β levels through real-time PCR. Results: We demonstrated that amygdalin diminished the cell viability of both cell lines in a time and dose-dependent manner, while amygdalin did not have any toxicity on the human skin fibroblast cell line in the same dosages. Following amygdalin treatment, the adhesion of both studied cell lines to fibronectin and collagen I decrease, and this reduction is significantly greater in the case of binding to fibronectin compared to binding to collagen. The MDA-MB-231 cell migration was decreased greater than MCF-7 cells. The levels of α and β integrin were differentially regulated by amygdalin in both cancer cell lines. Conclusion: These results suggest that depending on cancer cell lines, amygdalin affects cancer cell adhesion and migration.