Hesperidin neuroprotective effects against carbon monoxide-induced toxicity in male rats.

Carbon monoxide (CO) is produced via incomplete combustion of fossil fuels and it may cause long-term neurological sequel upon exposure. Hesperidin (HES), a flavanone glycoside found in citrus plants, exerts diverse beneficial health effects. The present study mechanistically examined the neuroprotective effects of HES in CO-poisoned rats. Thirty male Wistar rats (five groups of six animals) were exposed to 3000 ppm CO for 1 h. Immediately after the exposure and on the next 4 consecutive days (totally five doses), rats intraperitoneally received either normal saline (the control group) or different doses of HES (25, 50, and 100 mg/kg). A sham group that was not exposed to CO was also considered. After evaluation of spatial learning and memory using a Morris water maze (MWM), animals were sacrificed and oxidative stress status in blood samples, and Akt, Bax, Bcl2, and brain-derived neurotrophic factor (BDNF) expression in brain samples were assessed. Western blot analysis indicated increased Akt but decreased Bax/Bcl2 levels in the HES 100 mg/kg, and induced BDNF levels in all HES-treated groups. MWM results showed that HES significantly decreased memory loss. The current findings indicate that HES could alleviate neurological impairments induced by CO in rats.

Hormetic effects of curcumin on oxidative stress injury induced by trivalent arsenic in isolated rat hepatocytes.

Objective: Arsenic (As) poisoning is a worldwide public health problem. Arsenic can cause cancer, diabetes, hepatic problems, etc. Hence, we investigated possible hepatoprotective properties of curcumin against As3+-induced liver damages in freshly isolated rat hepatocytes. Materials and Methods: Isolation of hepatocytes was done by the two-step liver perfusion method using collagenase. The EC50 concentration of As3+ was used in toxicity assessments and curcumin (2, 5, and 10 µM) was added 15 min before As3+ addition to isolated hepatocytes. Curcumin impact was assessed in terms of cytotoxicity, lipid peroxidation induction, reactive oxygen species (ROS) levels, and mitochondrial membrane potential. Results: As3+ significantly increased cytotoxicity, malondialdehyde and ROS levels and induced mitochondrial membrane damage and hepatocyte membrane lysis after 3 hr incubation. Curcumin 2 µM significantly prevented lipid peroxidation induction, ROS formation, and mitochondrial membrane damage; while curcumin 5 µM had no apparent effect on these parameters, curcumin 10 µM potentiated them. Conclusion: Curcumin only at low doses could ameliorate oxidative stress injury induced by As3+ in isolated rat hepatocytes.

Solid lipid nanoparticles (SLNs), the potential novel vehicle for enhanced in vivo efficacy of hesperidin as an anti-inflammatory agent.

Hesperidin (C28H34O15), a flavanone glycoside abundantly present in citrus fruits, has proven therapeutic effects including anti-inflammatory activities. Herein, we report a novel formulation of HESP loaded solid lipid nanoparticles (SLNs) using hot homogenization and ultrasound to improve the poor solubility and bioavailability. In the present study, the formulation was developed and optimized by response surface method and then characterized by scanning electron microscopy (SEM), Fourier transform infrared (FTIR) spectroscopy (FT-IR), and dynamic light scattering (DLS). Encapsulation efficiency was determined and the anti-inflammatory effect was assessed through in vivo ear edema inflammation model. According to the electron microscopy results, the product has a spherical shape. The optimized parameters produced small size (179.8 ± 3.6 nm) HESP-SLNs with high encapsulation efficiency (93.0 ± 3.8 %). The outcomes exhibited that encapsulation in SLNs carriers improves the anti-inflammatory potential of HESP.

Effects of gallic acid on intraperitoneal adhesion bands in rats.

Objective: Gallic acid (GA) is an organic acid that possesses anti-inflammatory effects as it inhibits the production of metalloproteinases, tissue plasminogen activator, growth factors and adhesion molecules. Since formation of abdominal surgery-induced adhesion bands is accompanied by inflammation, angiogenesis and cell proliferation, in the current study, we assessed potential beneficial properties of GA against adhesion bands formation in rats. Materials and Methods: Thirty-six adult male rats were assigned into six groups of six animals. After induction of anesthesia, peritoneal injury was induced using a standard method and animals received either GA (10, 25, 50 and 100 mg/kg), or normal saline, while a group of rats remained intact. Seven days after the surgery, animals were decapitated and samples were collected for pathology evaluations. Also, lipid peroxidation (TBARS) and tumor necrosis factor alpha (TNF-α) levels were determined in serum samples. Results: Our results showed that GA significantly reduced lipid peroxidation in serum samples but had no effect on TNF-α levels. Furthermore, microscopic and macroscopic injuries reduced significantly in GA-treated animals. Conclusion: Since GA reduced adhesion bands formation at microscopic and macroscopic levels, it could be considered a treatment against adhesion bands formation.

Intrahippocampal co-administration of nicotine and O-acetyl-L-carnitine prevents the H-89-induced spatial learning deficits in Morris water maze.

OBJECTIVES: H-89 (a protein kinase AII [PKA II] inhibitor) impairs the spatial memory in the Morris water maze task in rats. In the present study, we aimed to study the protective effects of nicotine and O-acetyl-L-carnitine against H-89-induced spatial memory deficits. METHODS: Spatial memory impairment was induced by the bilateral intrahippocampal administration of 10 µM H-89 (dissolved in dimethyl sulfoxide, DMSO) to rats. The rats then received bilateral administrations of either nicotine (1 µg/µL, dissolved in saline) or O-acetyl-L-carnitine (100 µM/side, dissolved in deionized water) alone and in combination. Control groups received either saline, deionized water, or DMSO. RESULTS: The H-89-treated animals showed significant increases in the time and distance travelled to find hidden platforms, and there was also a significant decrease in the time spent in the target quadrant compared to DMSO-treated animals. Nicotine and O-acetyl-L-carnitine had no significant effects on H-89-induced spatial learning impairments alone, but the bilateral intrahippocampal co-administration of nicotine and O-acetyl-L-carnitine prevented H-89-induced spatial learning deficits and increased the time spent in the target quadrant in comparison with H-89-treated animals. CONCLUSIONS: Our results indicated the potential synergistic effects of nicotine and O-acetyl-L-carnitine in preventing protein kinase AII inhibitor (H-89)-induced spatial learning impairments.

Nanoscale Metal-Organic Frameworks: Recent developments in synthesis, modifications and bioimaging applications.

Porous Metal-Organic Frameworks (MOFs) have emerged as eye-catching materials in recent years. They are widely used in numerous fields of chemistry thanks to their desirable properties. MOFs have a key role in the development of bioimaging platforms that are hopefully expected to effectually pave the way for accurate and selective detection and diagnosis of abnormalities. Recently, many types of MOFs have been employed for detection of RNA, DNA, enzyme activity and small-biomolecules, as well as for magnetic resonance imaging (MRI) and computed tomography (CT), which are valuable methods for clinical analysis. The optimal performance of the MOF in the bio-imaging field depends on the core structure, synthesis method and modifications processes. In this review, we have attempted to present crucial parameters for designing and achieving an efficient MOF as bioimaging platforms, and provide a roadmap for researchers in this field. Moreover, the influence of modifications/fractionalizations on MOFs performance has been thoroughly discussed and challenging problems have been extensively addressed. Consideration is mainly focused on the principal concepts and applications that have been achieved to modify and synthesize advanced MOFs for future applications.

Effects of Quercetin and Resveratrol on Zinc Chloride- and Sodium Metavanadate-Induced Passive Avoidance Memory Retention Deficits in Male Mice.

Quercetin and resveratrol are found in a variety of fruits and vegetables and have several biological and pharmacological properties. In this study, the effects of quercetin [50 mg/kg, intraperitoneal (i.p.)] and resveratrol (50 mg/kg, i.p.) on zinc chloride (ZnCl2; 75 mg/kg/d, 2 weeks oral gavage) and sodium metavanadate (SMV; 22.5 mg/kg/d, 2 weeks oral gavage) induced passive avoidance memory retention were investigated in step-through passive avoidance tasks. ZnCl2 was dissolved in saline and SMV was dissolved in drinking water. Mice received ZnCl2 or SMV orally for two weeks and were administered quercetin or resveratrol by i.p. injection on day 14, days 12 and 14, or days 10, 12, and 14. At the end of treatment, animals were trained for one day in a step-through passive avoidance task, then alterations in avoidance memory retention were evaluated after 24, 48, 96, and 168 h. Oral consumption of ZnCl2 and SMV decreased latency time compared with control groups. Both quercetin and resveratrol (50 mg/kg, i.p.) prevented ZnCl2- and SMV-induced avoidance memory retention impairments and did not significantly alter muscle strength, as demonstrated in rotarod tasks. No significant differences were observed between mice who received single, double, or triple doses of quercetin or resveratrol. The results suggest that quercetin and resveratrol may have preventive effects on ZnCl2- and SMV-induced memory impairment in male mice.

Knowledge, attitude, and practice of pharmacy and medical students regarding self-medication, a study in Zabol University of Medical Sciences; Sistan and Baluchestan province in south-east of Iran.

BACKGROUND: Self-medication is defined as using medicinal products to treat the disorders or symptoms diagnosed by oneself. Although informed self-medication is one of the ways to reduce health care costs, inappropriate self-treatment can pose various risks including drug side effects, recurrence of symptoms, drug resistance, etc. The purpose of this study was to investigate the knowledge, attitude, and practice of pharmacy and medical students toward self-medication. METHODS: This study was conducted in Zabol University of Medical Sciences in 2018. Overall, 170 pharmacy and medical students were included. A three-part researcher-made questionnaire was designed to address the students' knowledge, attitude, and practice. Statistical analysis was performed in SPSS 25 software. RESULTS: According to the results, 97 (57.1%) students had carried out self-medication within the past 6 months. Overall, the students self-medicated on average 4.2 ± 2.9 times per year. Self-medication was more common in male students (65.4%, P = 0.043). Cold was the most common ailment treated with self-medication (93.2%), and antibiotics (74.4%) were the most commonly used drugs. The primary information sources used by the students were their previous prescriptions (47.4%). Pharmacy students had a higher level of drug information (P < 0.001). There was a statistically significant association between the level of drug information and the tendency for self-medication (P = 0.005). Disease recurrence was the most common negative complication of self-medication. CONCLUSION: There is a need to educate pharmacy and medical students regarding self-medication and its side effects. The high prevalence of self-medication and the overuse of antibiotics can pose a significant risk of drug resistance.

A review on pain-relieving activity of berberine.

As isoquinoline alkaloid naturally occurs in Coptis and Berberis species, berberine (BER) has shown anti-oxidant, anti-tumour, anti-bacterial and hepatoprotective activities and beneficial effects against digestive, cardiovascular and neurological conditions. Also, BER antiinflammatory, pain-relieving and anti-cholinesterase activities were widely studied. The present overview discusses the analgesic effects of BER. Based on the literature, BER exerted pain-relieving activity against diabetic and chemotherapy-induced neuropathy, and sciatic nerve injury-induced pain via down-regulation of transient receptor potential vanilloid 1, suppression of NF-κB and modulation of µ and δ opioid receptors. Besides, BER could repress inflammatory markers tumour necrosis factor-α, interleukin-6 and IL-1ß, as well as prostaglandin E2, inducible nitric oxide synthase and cyclooxygenase-2. The modulatory effects of BER on dopamine and N-methyl d-aspartate systems were also noted. Moreover, BER could induce Nrf2 expression but inhibits p38-MAPK and STAT3 phosphorylation. Noteworthy, anti-cholinesterase activity, which may potentially contribute to BER analgesic properties, warrants particular attention.

Cardioprotective effects of hesperidin on carbon monoxide poisoned in rats.

Carbon monoxide (CO) poisoning causes cardiotoxicity and so far, no definite antidote has been proposed to overcome CO-induced adverse outcomes. Hesperidin, a citrus flavonoid, has shown cardio-protective effects in cardiac ischemia/reperfusion models. This study investigated the protective effects of hesperidin against CO-induced cardiac injury. To induce CO poisoning, rats were exposed to CO at 3000 ppm for 60 min. On the exposure day and the four following days, hesperidin (at three different doses of 25, 50, and 100 mg/kg/day) was administered intraperitoneally. A group of animals received normal saline and served as the control group. The electrocardiogram (ECG) was recorded and evaluated with special focus on S-T segment changes (depression or elevation), T-wave alterations, AV block and ventricular and supraventricular arrhythmias. On day 6 (i.e., the day after the last injection day), the animals were sacrificed and the hearts were harvested and evaluated for necrosis using hematoxylin and eosin staining. In addition, Akt protein expression levels and BAX/BCL2 ratio were determined by western blotting. Our results showed that hesperidin decreased cardiac necrosis. In animals treated with hesperidin 100 mg/kg, Akt protein expression was increased, while the BAX/BCL2 ratio was significantly decreased. ECG changes were reversed in all groups 2 h following CO exposure, regardless of hesperidin administration. Overall, hesperidin decreased the deleterious cardiac effects of CO poisoning in rats.

Carbon based nanomaterials for the detection of narrow therapeutic index pharmaceuticals.

Precise detection of important pharmaceuticals with narrow therapeutic index (NTI) is very critical as there is a small window between their effective dose and the doses at which the adverse reactions are very likely to appear. Regarding the fact that various pharmacokinetics will be plausible while considering pharmacogenetic factors and also differences between generic and brand name drugs, accurate detection of NTI will be more important. Current routine analytical techniques suffer from many drawbacks while using novel biosensors can bring up many advantages including fast detection, accuracy, low cost with simple and repeatable measurements. Recently the well-known carbon Nano-allotropes including carbon nanotubes and graphenes have been widely used for development of different Nano-biosensors for a diverse list of analytes because of their great physiochemical features such as high tensile strength, ultra-light weight, unique electronic construction, high thermo-chemical stability, and an appropriate capacity for electron transfer. Because of these exceptional properties, scientists have developed an immense interest in these nanomaterials. In this case, there are important reports to show the effective Nano-carbon based biosensors in the detection of NTI drugs and the present review will critically summarize the available data in this field.

Crosstalk between long non-coding RNA DLX6-AS1, microRNAs and signaling pathways: A pivotal molecular mechanism in human cancers.

Long non-coding RNAs (lncRNAs) are a type of non-protein coding RNA, which have been found to play multiple roles in various molecular and cellular processes by epigenetic regulation of gene expression at post transcriptional levels. LncRNAs may act either as an oncogene or as a tumor suppressor gene in different cancers. Aberrant expression and dysregulation of lncRNAs has been correlated with cancer development and tumor growth via several different signaling pathways. Therefore, lncRNAs could serve as diagnostic biomarkers and as therapeutic targetes in many human cancers. Previous studies have reported that dysregulated expression of the lncRNA called DLX6-AS1 in various cancer types, such as lung, colorectal, bladder, ovarian, hepatocellular, pancreatic and gastric. DLX6-AS1 plays an important role in tumorigenesis by affecting cell proliferation, migration, invasion, EMT, and apoptosis. DLX6-AS1 exerts these regulatory effects by interfering with various microRNA axes and signaling pathways including, Wnt/ßcatenin, Notch, P13/AKT/mTOR, and STAT3. This review focuses on the possible mechanisms by which DLX6-AS1 regulates tumor initiation and progression. Accordingly, DLX6-AS1 may act as a novel potential biomarker for cancer diagnosis or therapy in future.

Bispecific monoclonal antibodies for targeted immunotherapy of solid tumors: Recent advances and clinical trials.

Bispecific antibodie (BsAbs) combine two or more epitope-recognizing sequences into a single protein molecule. The first therapeutic applications of BsAbs were focused on cancer therapy. However, these antibodies have grown to cover a wider disease spectrum, including imaging, diagnosis, prophylaxis, and therapy of inflammatory and autoimmune diseases. BsAbs can be categorized into IgG-like formats and non-IgG-like formats. Different technologies have been used for the construction of BsAbs including "CrossMAb", "Quadroma", "knobs-into-holes" and molecular cloning. The mechanism of action for BsAbs includes the induction of CDC, ADCC, ADCP, apoptosis, and recruitment of cell surface receptors, as well as activation or inhibition of signaling pathways. The first clinical trials included mainly leukemia and lymphoma, but solid tumors are now being investigated. The BsAbs bind to a tumor-specific antigen using one epitope, while the second epitope binds to immune cell receptors such as CD3, CD16, CD64, and CD89, with the goal of stimulating the immune response against cancer cells. Currently, over 20 different commercial methods have been developed for the construction of BsAbs. Three BsAbs are currently clinically approved and marketed, and more than 85 clinical trials are in progress. In the present review, we discuss recent trends in the design, engineering, clinical applications, and clinical trials of BsAbs in solid tumors.

Resveratrol, curcumin and gallic acid attenuate glyoxal-induced damage to rat renal cells.

Glyoxal (GO), a by-product of glucose auto-oxidation, is involved in the glycation of proteins/ lipids and formation of advanced glycation (AGE) and lipoxidation (ALE) end products. AGE/ALE were shown to contribute to diabetic complications development/progression such as nephropathy. Diabetic nephropathy progression has an oxidative nature. Given the antioxidant effects of polyphenols, potential protective effects of resveratrol, curcumin and gallic acid, in rat renal cells treated with GO, were evaluated in the present work. According to our results, incubation of GO with the cells reduced their viability and led to membrane lysis, reactive oxygen species (ROS) formation, lipid peroxidation, mitochondrial membrane potential collapse, and lysosomal membrane leakage. These findings were prevented by pre-treatment with resveratrol, curcumin and gallic acid. Mitochondrial and lysosomal toxic interactions appear to worsen oxidative stress/cytotoxicity produced by GO. Resveratrol, curcumin and gallic acid inhibited ROS formation and attenuated GO-induced renal cell death.

Umbelliprenin relieves paclitaxel-induced neuropathy.

OBJECTIVES: Umbelliprenin (UMB) is a prenylated coumarin that acts as an in vitro antioxidant and inhibits lipoxygenase managing the inflammation pathways, while in vivo it exerts anti-inflammatory activities. METHODS: In this study, neuropathic pain was induced by four intraperitoneal doses of 2 mg/kg per day of paclitaxel (PTX) on days 1, 3, 5 and 7. Here, 49 male mice were randomly divided in the following groups: sham (not treated animals), negative control (PTX-treated receiving normal saline), single-dose UMB 6.25, 12.5 and 25 mg/kg groups (PTX-treated receiving UMB 6.25, 12.5 and 25 mg/kg, respectively), prevention (PTX-treated receiving PTX along with UMB 12.5 mg/kg on days 1, 3, 5 and 7) and positive control group (PTX-treated receiving imipramine 10 mg/kg as acute treatment). Hot-plate test was done to assess response to heat. Finally, interleukin (IL)-6 levels in the sciatic nerve and lipid peroxidation in sera were assessed. KEY FINDINGS: Umbelliprenin was found equally effective for acute treatment with imipramine, when comparing the prevention group and the positive control group. Single, 25 mg/kg UMB effectively attenuated hyperalgesia, lipid peroxidation and IL-6 levels. CONCLUSIONS: Umbelliprenin alleviated neuropathic pain, and decreased serum IL-6 levels and oxidative stress. UMB deserves further investigations, especially in clinical settings.

Recent progress in the design of DNA vaccines against tuberculosis.

Current tuberculosis (TB) vaccines have some disadvantages and many efforts have been undertaken to produce effective TB vaccines. As a result of their advantages, DNA vaccines are promising future vaccine candidates. This review focuses on the design and delivery of novel DNA-based vaccines against TB.

Thrombolytic Agents: Nanocarriers in Controlled Release.

Thrombosis is a life-threatening pathological condition in which blood clots form in blood vessels, obstructing or interfering with blood flow. Thrombolytic agents (TAs) are enzymes that can catalyze the conversion of plasminogen to plasmin to dissolve blood clots. The plasmin formed by TAs breaks down fibrin clots into soluble fibrin that finally dissolves thrombi. Several TAs have been developed to treat various thromboembolic diseases, such as pulmonary embolisms, acute myocardial infarction, deep vein thrombosis, and extensive coronary emboli. However, systemic TA administration can trigger non-specific activation that can increase the incidence of bleeding. Moreover, protein-based TAs are rapidly inactivated upon injection resulting in the need for large doses. To overcome these limitations, various types of nanocarriers have been introduced that enhance the pharmacokinetic effects by protecting the TA from the biological environment and targeting the release into coagulation. The nanocarriers show increasing half-life, reducing side effects, and improving overall TA efficacy. In this work, the recent advances in various types of TAs and nanocarriers are thoroughly reviewed. Various types of nanocarriers, including lipid-based, polymer-based, and metal-based nanoparticles are described, for the targeted delivery of TAs. This work also provides insights into issues related to the future of TA development and successful clinical translation.

Biosensing of microcystins in water samples; recent advances.

Safety and quality of water are significant matters for agriculture, animals and human health. Microcystins, as secondary metabolite of cyanobacteria (blue-green algae) and cyclic heptapeptide cyanotoxin, are one of the main marine toxins in continental aquatic ecosystems. More than 100 microcystins have been identified, of which MC-LR is the most important type due to its high toxicity and common detection in the environment. Climate change is an impressive factor with effects on cyanobacterial blooms as source of microcystins. The presence of this cyanotoxin in freshwater, drinking water, water reservoir supplies and food (vegetable, fish and shellfish) has created a common phenomenon in eutrophic freshwater ecosystems worldwide. International public health organizations have categorized microcystins as a kind of neurotoxin and carcinogen. There are several conventional methods for detection of microcystins. The limitations of traditional methods have encouraged the development of innovative methods for detection of microcystins. In recent years, the developed sensor techniques, with advantages, such as accuracy, reproducibility, portability and low cost, have attracted considerable attention. This review compares the well-known of biosensor types for detection of microcystins with a summary of their analytical performance.

Crocin: A fighter against inflammation and pain.

Crocin, a water-soluble carotenoid, is known as a pharmacologically active compound, particularly for its potent anti-oxidant activity. The present work provides a comprehensive review of the available literature concerning the anti-inflammatory properties of crocin in various organs/systems as well as its anti-nociceptive effects. PubMed, Scopus, and Web of Science electronic databases were systematically searched up to 28 March 2020 to detect all relevant preclinical and human studies in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. In total, 104 studies were included for qualitative synthesis. This systematic search and review indicated that crocin not only combats reactive oxygen species production and suppresses pro-inflammatory cytokines secretion but also alleviates inflammation in various organs (e.g. the lung, heart, brain, and kidney), in a series of animal models and in vitro experiments, via regulating mainly NF-κB pathway and NF-κBp65 translocation to the cell nucleus. In this context, modulation of PI3K/Akt appears to be a favorable crocin target contributing to NF-κB pathway inhibition. Even though data is limited in humans with only one clinically relevant study retrieved, the results of preclinical studies regarding anti-inflammatory/anti-nociceptive effects of crocin are promising and warrant further testing in clinical settings.

Anti-hypertensive effect of crocin and hesperidin combination in high-fat diet treated rats.

Cardiovascular diseases are the leading cause of death worldwide. Hypertension is the most important cause of such conditions. The use of medicinal herbs is of particular importance due to their lower cost and side effects. The aim of the present study was to compare the effect of hesperidin (HES) and crocin (CRO) alone and in combination, on blood pressure in a rat model of high-fat diet (HFD)-induced hypertension, using invasive carotid artery measurements. Animals were randomly assigned to the following groups: control group (received standard chow diet), HFD control group (received HFD containing 32% kcal of fat and 0.1% cholesterol), and three groups of HFD-treated animals that were treated with a single dose of CRO (20 mg/kg), HES (20 mg/kg), or CRO + HES (20 + 20 mg/kg). Except for the control group, rats received HFD for 7 weeks. On day 50, CRO, HES and normal saline were administered intraperitoneally and carotid arteries of the rats were cannulated. Three hours after the carotid artery cannulation, mean arterial blood pressure (MAP), systolic and diastolic blood pressure (SBP and DBP), and heart rate (HR) were measured using an intra-arterial catheter with the use of a Power Lab system. Data was analyzed using SPSS software. Rats that received HFD for 49 days presented a significant increase in SBP, HR and MAP compared to the control group (P<0.001). Whereas, HFD-treated rats of the CRO + HES group showed lower levels of SBP, HR and MAP; however, DBP remained unaffected. HES administration in HFD treated rats resulted in a significant decrease in SBP compared to the HFD control group with no significant differences in MAP. The hypotensive effects of the simultaneous administration of CRO and HES in HFD-hypertensive rats suggest the need for further study of these two natural products as a potential preventive measure against hypertension development, especially in patients with high normal blood pressure.