Nanoliposomal VEGF-R2 peptide vaccine acts as an effective therapeutic vaccine in a murine B16F10 model of melanoma.

Background: The vascular endothelial growth factor receptor-2 (VEGFR-2) plays an important role in melanoma development and progression. Peptide vaccines have shown great potential in cancer immunotherapy by targeting VEGFR-2 as a tumor-associated antigen and boosting the immune response against both tumor cells and tumor endothelial cells. Despite this, the low efficiency of peptide vaccines has resulted in moderate therapeutic results in the majority of studies. Enhancing the delivery of peptide vaccines using nanoliposomes is an important strategy for improving the efficacy of peptide vaccines. In this regard, we designed VEGFR-2-derived peptides restricted to both mouse MHC I and human HLA-A*02:01 using immunoinformatic tools and selected three peptides representing the highest binding affinities. The peptides were encapsulated in nanoliposomal formulations using the film method plus bath sonication and characterized for their colloidal properties. Results: The mean diameter of peptide-encapsulated liposomes was around 135 nm, zeta potential of - 17 mV, and encapsulation efficiency of approximately 70%. Then, vaccine formulations were injected subcutaneously in mice bearing B16F10-established melanoma tumors and their efficiency in triggering immunological, and anti-tumor responses was evaluated. Our results represented that one of our designed VEGFR-2 peptide nanoliposomal formulations (Lip-V1) substantially activated CD4+ (p < 0.0001) and CD8+ (P < 0.001) T cell responses and significantly boosted the production of IFN-γ (P < 0.0001) and IL-4 (P < 0.0001). Furthermore, this formulation led to a significant decrease in tumor volume (P < 0.0001) and enhanced survival (P < 0.05) in mice. Conclusion: Our findings suggest that the nanoliposomal formulation containing VEGFR-2 peptides could be a promising therapeutic vaccination approach capable of eliciting strong antigen-specific immunologic and anti-tumor responses. Supplementary Information: The online version contains supplementary material available at 10.1186/s12645-023-00213-7.

The effects of melatonin on the concentrations of inflammatory cytokines and proteins, serotonin, cortisol and melatonin in ovariohysterectomised female dogs.

BACKGROUND: Ovariohysterectomy (OHE) induces inflammation and stress in female dogs. The anti-inflammatory effects of melatonin have been reported in several studies. OBJECTIVES: The goal of this study was to assess the effects of melatonin on the concentrations of melatonin, cortisol, serotonin, α-1-acid glycoprotein (AGP), serum amyloid A (SAA), c-reactive protein (CRP), interleukin-10 (IL-10), interleukin-8 (IL-8), interleukin-1ß (IL-1ß) and tumour necrosis factor-α (TNF-α) before and after OHE. METHODS: The total number of animals was 25 and aligned in 5 groups. Fifteen dogs were divided into three groups (n = 5): melatonin, melatonin+anaesthesia and melatonin+OHE and received melatonin (0.3 mg/kg, p.o.) on days -1, 0, 1, 2 and 3. Ten dogs were assigned to the control and OHE groups (n = 5) without melatonin treatment. OHE and anaesthesia were performed on day 0. Blood samples were obtained via jugular vein on days -1, 1, 3 and 5. RESULTS: Melatonin and serotonin concentrations significantly increased in the melatonin, melatonin+OHE and melatonin+anaesthesia groups compared with the control group, while cortisol concentration decreased in the melatonin+OHE group compared with the OHE group. The concentrations of acute-phase proteins (APPs) and inflammatory cytokines significantly increased after OHE. The CRP, SAA and IL-10 concentrations decreased significantly in the melatonin+OHE group compared with the OHE group. The concentrations of cortisol, APPs and proinflammatory cytokines increased significantly in the melatonin+anaesthesia group compared with the melatonin group. CONCLUSIONS: The oral administration of melatonin before and after OHE help controlling the high levels of inflammatory APPs, cytokines and cortisol induced by OHE in female dogs.

Evidence for the Benefits of Melatonin in Cardiovascular Disease.

The pineal gland is a neuroendocrine gland which produces melatonin, a neuroendocrine hormone with critical physiological roles in the circadian rhythm and sleep-wake cycle. Melatonin has been shown to possess anti-oxidant activity and neuroprotective properties. Numerous studies have shown that melatonin has significant functions in cardiovascular disease, and may have anti-aging properties. The ability of melatonin to decrease primary hypertension needs to be more extensively evaluated. Melatonin has shown significant benefits in reducing cardiac pathology, and preventing the death of cardiac muscle in response to ischemia-reperfusion in rodent species. Moreover, melatonin may also prevent the hypertrophy of the heart muscle under some circumstances, which in turn would lessen the development of heart failure. Several currently used conventional drugs show cardiotoxicity as an adverse effect. Recent rodent studies have shown that melatonin acts as an anti-oxidant and is effective in suppressing heart damage mediated by pharmacologic drugs. Therefore, melatonin has been shown to have cardioprotective activity in multiple animal and human studies. Herein, we summarize the most established benefits of melatonin in the cardiovascular system with a focus on the molecular mechanisms of action.

Therapeutic effect of curcumin in gastrointestinal cancers: A comprehensive review.

Gastrointestinal (GI) cancers with a high global prevalence are a leading cause of morbidity and mortality. Accordingly, there is a great need to develop efficient therapeutic approaches. Curcumin, a naturally occurring agent, is a promising compound with documented safety and anticancer activities. Recent studies have demonstrated the activity of curcumin in the prevention and treatment of different cancers. According to systematic studies on curcumin use in various diseases, it can be particularly effective in GI cancers because of its high bioavailability in the gastrointestinal tract. Nevertheless, the clinical applications of curcumin are largely limited because of its low solubility and low chemical stability in water. These limitations may be addressed by the use of relevant analogues or novel delivery systems. Herein, we summarize the pharmacological effects of curcumin against GI cancers. Moreover, we highlight the application of curcumin's analogues and novel delivery systems in the treatment of GI cancers.

Non-coding RNAs role in intracranial aneurysm: General principles with focus on inflammation.

Intracranial aneurysm (IA) is one of the most challenging vascular lesions in the brain for clinicians. It was reported that 1%-6% of the world's population is affected by IAs. Owing to serious complications arising from these lesions, much attention has been paid to better understand their pathophysiology. Non-coding RNAs including short non-coding RNAs and long non-coding RNAs, have critical roles in modulating physiologic and pathological processes. These RNAs are emerging as new fundamental regulators of gene expression, are related with the progression of IA. Non-coding RNAs act via multiple mechanisms and be involved in vascular development, growth and remodeling. Furthermore, these molecules are involved in the regulation of inflammation, a key process in the formation and rupture of IA. Studying non-coding RNAs can yield a hypothetical mechanism for better understanding IA. The present study aims to focus on the role of these non-coding RNAs in the pathogenesis of IA.

Plant-based vaccines and cancer therapy: Where are we now and where are we going?

Therapeutic vaccines are an effective approach in cancer therapy for treating the disease at later stages. The Food and Drug Administration (FDA) recently approved the first therapeutic cancer vaccine, and further studies are ongoing in clinical trials. These are expected to result in the future development of vaccines with relatively improved efficacy. Several vaccination approaches are being studied in pre-clinical and clinical trials, including the generation of anti-cancer vaccines by plant expression systems.This approach has advantages, such as high safety and low costs, especially for the synthesis of recombinant proteins. Nevertheless, the development of anti-cancer vaccines in plants is faced with some technical obstacles.Herein, we summarize some vaccines that have been used in cancer therapy, with an emphasis on plant-based vaccines.

The effects of melatonin treatment on oxidative stress induced by ovariohysterectomy in dogs.

BACKGROUND: As one of the most common surgeries performed in veterinary medicine, ovariohysterectomy (OHE) can induce oxidative stress in dogs. The antioxidant properties of melatonin have been confirmed in various studies. This study aimed to investigate the effects of melatonin administration on oxidative stress in dogs before and after OHE. In this study, 25 mature female intact dogs were selected and randomly divided into five equal groups: Melatonin (melatonin, no surgery), OHE (no melatonin, surgery), OHE + melatonin (melatonin, surgery), anesthesia+melatonin (melatonin, sham surgery), and control (no melatonin, no surgery) groups. Melatonin (0.3 mg/Kg/day, p.o.) was administrated to the dogs in the melatonin, OHE + melatonin, and anesthesia+melatonin groups on days - 1, 0, 1, 2, and 3 (day 0 = OHE). Blood sampling was performed on days - 1, 1, 3, and 5 of the study. Blood samples were immediately transferred to the laboratory and sera were separated and stored at - 20 °C. Superoxide dismutase (SOD), glutathione peroxidase (GPX), catalase (CAT) and malondialdehyde (MDA) concentrations were measured with commercial kits. RESULTS: The levels of SOD, GPX and CAT were significantly higher in the melatonin and anesthesia+melatonin groups compared to those of the control group at days 3 and 5. The level of antioxidant enzymes significantly decreased in the OHE group compared to that of other groups at days 3 and 5. The administration of melatonin increased the level of antioxidant enzymes in ovariohysterectomized dogs. Ovariohysterectomy significantly increased the concentration of MDA in comparison to that of other groups at day 3. Melatonin administration significantly decreased the level of MDA in melatonin, anesthetized, and ovariohysterectomized dogs at day 3. CONCLUSIONS: Administration of melatonin on day - 1, 0, 1, 2 and 3 modulate the oxidative stress induced by OHE in dogs by increasing antioxidant enzymes concentration and decreasing MDA levels.

siRNA Therapeutics: Future Promise for Neurodegenerative Diseases.

Neurodegenerative diseases (ND), as a group of central nervous system (CNS) disorders, are among the most prominent medical problems of the 21st century. They are often associated with considerable disability, motor dysfunction and dementia and are more common in the aged population. ND imposes a psychologic, economic and social burden on the patients and their families. Currently, there is no effective treatment for ND. Since many ND result from the gain of function of a mutant allele, small interference RNA (siRNA) can be a potential therapeutic agent for ND management. Based on the RNA interference (RNAi) approach, siRNA is a powerful tool for modulating gene expression through gene silencing. However, there are some obstacles in the clinical application of siRNA, including unfavorable immune response, off-target effects, instability of naked siRNA, nuclease susceptibility and a need to develop a suitable delivery system. Since there are some issues related to siRNA delivery routes, in this review, we focus on the application of siRNA in the management of ND treatment from 2000 to 2020.

Role of Resveratrol in Modulating microRNAs in Human Diseases: From Cancer to Inflammatory Disorder.

Cancer and inflammatory disorders are two important public health issues worldwide with significant socio.economic impacts. Despite several efforts, the current therapeutic platforms are associated with severe limitations. Therefore, developing new therapeutic strategies for the treatment of these diseases is a top priority. Besides current therapies, the utilization of natural compounds has emerged as a new horizon for the treatment of cancer and inflammatory disorders as well. Such natural compounds could be used either alone or in combination with the standard cancer therapeutic modalities such as chemotherapy, radiotherapy, and immunotherapy. Resveratrol is a polyphenolic compound that is found in grapes as well as other foods. It has been found that this medicinal agent displays a wide pharmacological spectrum, including anti-cancer, anti-inflammatory, anti-microbial, and antioxidant activities. Recently, clinical and pre-clinical studies have highlighted the anti-cancer and anti-inflammatory effects of resveratrol. Increasing evidence revealed that resveratrol exerts its therapeutic effects by targeting various cellular and molecular mechanisms. Among cellular and molecular targets that are modulated by resveratrol, microRNAs (miRNAs) have appeared as key targets. MiRNAs are short non-coding RNAs that act as epigenetic regulators. These molecules are involved in many processes that are involved in the initiation and progression of cancer and inflammatory disorders. Herein, we summarized various miRNAs that are directly/indirectly influenced by resveratrol in cancer and inflammatory disorders.

Glyco-nanoparticles: New drug delivery systems in cancer therapy.

Cancer is known as one of the most common diseases that are associated with high mobility and mortality in the world. Despite several efforts, current cancer treatment modalities often are highly toxic and lack efficacy and specificity. However, the application of nanotechnology has led to the development of effective nanosized drug delivery systems which are highly selective for tumors and allow a slow release of active anticancer agents. Different Nanoparticles (NPs) such as the silicon-based nano-materials, polymers, liposomes and metal NPs have been designed to deliver anti-cancer drugs to tumor sites. Among different drug delivery systems, carbohydrate-functionalized nanomaterials, specially based on their multi-valent binding capacities and desirable bio-compatibility, have attracted considerable attention as an excellent candidate for controlled release of therapeutic agents. In addition, these carbohydrate functionalized nano-carriers are more compatible with construction of the intracellular delivery platforms like the carbohydrate-modified metal NPs, quantum dots, and magnetic nano-materials. In this review, we discuss recent research in the field of multifunctional glycol-nanoparticles (GNPs) intended for cancer drug delivery applications.

Exosomes and Lung Cancer: Roles in Pathophysiology, Diagnosis and Therapeutic Applications.

Lung cancer is a malignancy with a high morbidity and mortality rate, and affected patients have low survival and poor prognosis. The therapeutic approaches for the treatment of this cancer, including radiotherapy and chemotherapy, are not particularly effective partly due to late diagnosis. Therefore, the search for new diagnostic and prognostic tools is a critical issue. Novel biomarkers, such as exosomes, could be considered as potential diagnostic tools for malignancies, particularly lung cancer. Exosomes are nanovesicles, which are associated with different physiological and pathological conditions. It has been shown that these particles are released from many cells, such as cancer cells, immune cells and to some degree normal cells. Exosomes could alter the behavior of target cells through intercellular transfer of their cargo (e.g. DNA, mRNA, long non-coding RNAs, microRNAs and proteins). Thus, these vehicles may play pivotal roles in various physiological and pathological conditions. The current insights into lung cancer pathogenesis suggest that exosomes are key players in the pathogenesis of this cancer. Hence, these nanovesicles and their cargos could be used as new diagnostic, prognostic and therapeutic biomarkers in the treatment of lung cancer. Besides the diagnostic roles of exosomes, their use as drug delivery systems and as cancer vaccines is under investigation. The present review summarizes the current information on the diagnostic and pathogenic functions of exosomes in lung cancer.

The Association between Inflammatory Cytokines and miRNAs with Slow Coronary Flow Phenomenon.

Slow coronary flow (SCF) is a coronary artery disorder. Several inflammatory mediators have been reported to be associated with vascular homeostasis and endothelial dysfunction. The aim of this study was to investigate the association between cytokines and miRNAs in patients with SCF compared to the controls. In this regard, blood samples were acquired from 45 SCF patients and 45 age- and sex-matched healthy control subjects. Serum and peripheral blood mononuclear cells (PBMCs) were separated. Expression levels of miRNAs and cytokines in PBMCs were measured by real-time PCR. As a final point, serum levels of cytokines were quantified by ELISA. Expression levels of miR-1, miR-133, miR-208a, miR-206, miR-17, miR-29, miR-223, miR-326, and miR-155 as considerable indicators of inflammatory function significantly increased in SCF patients while the expression levels of miR-15a, miR-21, miR-25, miR-126, miR-17, miR-16 and miR-18a as considerable indicators of anti-inflammatory function significantly decreased in patients with SCF compared to the control group. Additionally, serum IL-1ß, IL-8, and TNF-α concentrations were significantly higher in the SCF group than controls. However, no significant differences were observed in IL-10 production in SCF patients compared to the controls. This study provided the potential role of miRNAs as biomarkers for SCF diagnosis as well as suitable markers for monitoring coronary artery disease (CAD) development in these patients. More investigations are still necessary to unravel the detailed essential mechanisms of circulating miRNA levels in patients with heart failure and SCF.

Lower serum 25-hydroxyvitamin D3 concentration is associated with higher pain and disability in subjects with low back pain: a case-control study.

OBJECTIVES: Low back pain (LBP) is a common medical problem worldwide. The aim of this study is to evaluate the association between serum concentration of 25-hydroxivitamin D3 and functional disability in patients suffering from LBP in a sample of Azeri middle-aged subjects, North West of Iran. RESULTS: In this case-control study, 63 eligible patients with LBP and 55 healthy subjects enrolled in the study. Peripheral venous blood was taken for evaluating the serum concentration of 25-hydroxivitamin D3. We recognized factors related with LBP by multiple regression analyses. The average serum 25-hydroxivitamin D3 concentration in case group was significantly lower than that of the matched controlled group (26.25 ± 15.95 vs. 34.20 ± 14.92, p-value < 0.01 respectively). Subjects with vitamin D deficiency or insufficiency were more likely to exhibit LBP than subjects with normal serum 25-hydroxivitamin D3 concentration [(OR = 2.388, 95% CI (1.114 to 5.119)]. According to the partial correlation analysis, there was a reverse correlation between serum 25-hydroxivitamin D3 concentration with functional disability measured by Modified Oswestry Questionnaire (r = - 0.307, p = 0.017) and also with pain intensity according to Visual Analogue Scale (VAS) score (r = - 0.268, p = 0.040) whilst adjusting for age, sex and body mass index (BMI).

MicroRNAs as Diagnostic, Prognostic, and Therapeutic Biomarkers in Prostate Cancer.

Prostate cancer is the most prevalent nonskin cancer and a major cause of cancer-related deaths worldwide. Prostate-specific antigen (PSA) testing is routinely used for screening and early detection of prostate cancer; however, it does not reduce death from prostate cancer. Moreover, PSA is not specific for prostate cancer and results in high false-positive rates, and it is poorly correlated with cancer stage. Therefore, the need for another diagnostic and prognostic factor in prostate cancer is apparent. MicroRNAs (miRNAs) are small, single-stranded, noncoding RNAs which are involved in modulation of gene expression posttranscriptionally. Multiple lines of evidence indicate that miRNAs play key roles in various physiological events. Deregulation of miRNAs is related to initiation and development of various diseases such as prostate cancer. It has been shown that various miRNAs (miR-34, miR-21, miR-155, miR-221, miR-222, and let-7) exert their effects by targeting a variety of cellular and molecular pathways (c-Myc, EZH2, c-RSC, BCL2L2, E2F6, ZEB, HMGA251, and CCND2) involved in prostate cancer pathogenesis. Hence, it seems that miRNA expression profiles can be seen as potential candidates for prognosis, diagnosis, and treatment of prostate cancer. Here, we summarize various miRNAs as prognostic, diagnostic, and therapeutic biomarkers for prostate cancer therapy.

Comparative studies of cytotoxic and apoptotic properties of different extracts and the essential oil of Lavandula angustifolia on malignant and normal cells.

Lavender (Lavandula angustifolia Mill.) is a bush-like shrub from Lamiaceae. The herb has been used in alternative medicine for several centuries. In this study, the cytotoxicity and the mechanisms of cell death induced by 3 different extracts of aerial parts and the essential oil of L. angustifolia were compared in normal and cancerous human cells. Malignant (HeLa and MCF-7 cell lines) and nonmalignant (human fibroblasts) cells were incubated with different concentrations of the plant extracts. Cell viability was quantified by MTS assay. Apoptotic cells were determined using propidium iodide staining of DNA fragmentation by flow cytometry (sub-G1 peak). The molecules as apoptotic signal translation, including Bax and cleaved PARP, were identified by Western blot. Ethanol and n-hexane extracts and essential oil exhibited significant cytotoxicity to malignant cells but marginal cytotoxicity to human fibroblasts in vitro and induced a sub-G1 peak in flow cytometry histogram of treated cells compared to the control. Western blot analysis demonstrated that EtOH and n-hexane extracts upregulated Bax expression, also it induced cleavage of PARP in HeLa cells compared to the control. In conclusion, L. angustifolia has cytotoxic and apoptotic effects in HeLa and MCF-7 cell lines, and apoptosis is proposed as the possible mechanism of action.