Iranian Journal of Basic Medical Sciences
Volume:24 Issue: 5, May 2021

Flaxseed is a plant that grows and is cultivated in more than 50 countries; the main flax producer countries are Canada, China, the United States, and India. The purpose of the present study was to overview the source, chemical compounds, and mechanisms of the therapeutic effects of this valuable plant. For writing this manuscript, we made a list of relevant keywords and phrases, and then we started searching for studies in PubMed, Scopus, and Web of Science databases. The main constituents of flaxseed include lipids, proteins, lignans, fibers, and minerals. Flaxseed is full of antioxidants such as tocopherols, betacarotene, cysteine, and methionine which result in a decrease in blood pressure, heart disease, hepatic and neurological disorders, and increased insulin sensitivity. Flaxseed is commonly used for its antidiabetic and anticancer activities and also it is beneficial for cardiovascular, gastrointestinal, hepatic, urological, and reproductive disorders, and because of these beneficial effects, it is recognized as a medical plant.

Considering the high incidence and mortality rate of gastrointestinal cancers (GIs) worldwide and partial success of the current available GI cancer treatments, there is a necessity to discover more effective approaches in cancer therapy. The failure in conventional therapies seems to be related to the resistance of cancer cells to chemotherapy, inability to target tumor cells especially in metastatic cancers, deficient drug concentrations in tumor sites, and unfavorable effects on pivotal non-malignant bodily tissues following systemic administration. In this context, we need an appropriate carrier for the delivery of therapeutic agents specifically to the GI cancer site. Mesenchymal stem cells (MSCs), a prominent cell-based strategy for cancer treatment, overcome various cancer therapy limitations and could be used as vehicles to deliver many anticancer agents such as therapeutic genes (DNA or interference RNA), oncolytic viruses, and chemotherapeutic or nanoparticle drugs. Moreover, secreted molecules of unmodified MSCs lead to deregulation of several proteins and different signaling pathways eradicating cancer cells. In the present review, at first, we overview the characteristics and utility of MSCs in cancer therapy, secondly, we discuss the application of naïve MSCs and utilization of MSCs in the delivery of therapeutic agents in GI cancer therapy and, finally, more information about harnessing of genetically modified MSCs in GI cancer treatment will be presented.

A variety of cytokines are involved in cognitive functioning. Balance restoration between protective and degenerative neuro-inflammation is of great interest in newer therapeutic approaches. In the current study, we investigated the effect of pramipexole (PMX) on memory functions, hippocampal amyloid deposition, serum cytokines, and brain-derived neurotrophic factor (BDNF)  levels in lipopolysaccharide (LPS) challenged-rats.

Male Wistar rats were divided into 5 groups (n=8): control (saline), lipoppolysacharide (LPS 250 mcg/kg bw), and experimental groups (LPS and PMX 0.5, 1, and 3 mg/kg bw). Learning and memory were assessed by the novel object recognition test (NORT), Y-maze, and step-through test. Immunological and histological assays were performed.

In memory tasks, LPS-challenged rats showed reduction in the observed parameters. In NORT, PMX 1 mg/kg increased recognition index compared with controls, whereas the other two doses increased this index only against the LPS-control. In Y-maze, all doses of PMX significantly had increased alternation when compared with LPS. In the step-through test, only the lowest dose of PMX extended the latency compared with LPS. Histological examination revealed that PMX at doses of 0.5 and 1 mg/kg reduced amyloid deposition in the hippocampus. Interleukin (IL)-10 serum levels were elevated by 1 mg/kg PMX. Tumor necrosis factor (TNF)-α and transforming growth factor (TGF)-β1 serum levels remained under the detectable minimum in all experimental groups. PMX at all doses significantly decreased BDNF serum concentration.

In rats with LPS-induced neuro-inflammation PMX improved hippocampal-dependent memory and exerted immuno-modulatory effects by increasing IL-10.

Periaqueductal gray (PAG) is a mesencephalic area divided into four columns including ventrolateral periaqueductal gray (vlPAG). vlPAG plays a role in cardiovascular regulation during normal and hemorrhagic (Hem) conditions. Due to presence of glutamate in this area, we evaluated the effect of glutamatergic receptors of this area on cardiovascular activity in normotensive and hypovolemic Hem rats.

Animals were divided into twelve groups: saline (vehicle), Glutamate, GYK52466 (non-NMDA receptor antagonist), and MK801 (NMDA receptor antagonist) with and without Glu microinjected into vlPAG in normal and Hem conditions. Following the femoral artery cannulating and microinjecting, changes (Δ) of heart rate (HR), systolic blood pressure (SBP), and mean arterial pressure (MAP) were recorded via a PowerLab unit.

In normotensive conditions, microinjection of Glu increased ΔMAP, ΔSBP, and ΔHR (p <0.001). MK-801 and GYKI-52466 nonsignificant reduced cardiovascular responses than vehicle while their changes were significant compared with glutamate (p <0.001). Co-injection of GYKI- 52466 with Glu did not significantly reduce ΔSBP and ΔMAP induced by Glu (P>0.05) but co-injection of MK-801 with Glu significantly attenuate these effects(p <0.01). In Hem, Glu increased ΔSBP, ΔMAP, and ΔHR (p <0.05). GYKI-52466 alone did not change cardiovascular responses but MK-801 decreased ΔSBP than Hem (p <0.01). Co-injection of GYKI-52466 with Glu had significant(p <0.05) but MK-801 with Glu had no significant effect compared with Hem (P>0.05).

The glutamatergic system of vlPAG increases cardiovascular values that are mostly mediated through the NMDA receptor. Since vlPAG is well known as an inhibitory region, it seems that glutamate does not have a noteworthy cardiovascular role in vlPAG during Hem and normal conditions.

This study aimed to find out the protective effects and preliminary mechanisms of the flower extract of Caragana sinica (FEC) on dextran sulfate sodium salt (DSS)-induced colitis.

The ulcerative colitis models of mice induced by 3% DSS were established and treated with FEC. Body weight changes, disease activity index (DAI), colon histopathological score, anti-oxidant ability, and the level of inflammatory cytokines were determined. The expression of Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88) were assessed in colonic tissue by immunohistochemical staining. Western blot was used to analyze the expression of TLR4/ nuclear factor kappa-B (NF-κB) and TLR4/ mitogen-activated protein kinase (MAPK) signaling pathway-related proteins.

FEC significantly prevented body weight loss and colonic shortening and reduced the disease activity index and histopathological score (p <0.05). Moreover, FEC treatment remarkably down-regulated the levels of myeloperoxidase (MPO), interleukin-1beta (IL-1β), tumor necrosis factor-alpha (TNF-α), and interleukin 6 (IL-6) and up-regulated the levels of superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and interleukin 10 (IL-10) in the colon of DSS mice (p <0.05). Furthermore, the expression of TLR4/NF-κB and TLR4/MAPK pathway-related proteins was inhibited by FEC (p <0.05).

Our findings demonstrated that FEC could serve as a potential therapeutic agent for treatment of ulcerative colitis.

Cancer is the second important reason for death worldwide. In spite of advances in cancer treatment, however, survival of patients stays weak. Therefore, there is a critical need for advancement of new anticancer drugs. Regarding the hopeful biological activity of phthalimide derivatives, in this study, synthesis, cytotoxicity, and pro‐apoptosis activity of eleven derivatives of thiazole bearing phthalimide structure were evaluated.

First, target derivatives were synthesized. All synthesized compounds were characterized by spectroscopic methods. Cytotoxicity and pro‐apoptosis activity of the synthesized compounds were evaluated in MDA-MB-468, PC-12, and MCF-7 cancer cell lines by MTT assay, caspase-3 activity, and TUNEL assay. Finally, expression of BAX, BCL-2, and FAS (as markers of apoptosis) was assessed by the RT-PCR procedure.

Among the eleven compounds, 5b (IC50 = 0.2±0.01 µM) was found to be the most potent derivative against MCF-7 cells. Also, Compound 5k and 5g showed strong cytotoxic activity against MDA-MB-468 and PC-12 cells with IC50 value of 0.6±0.04 µM and 0.43±0.06 µM, respectively.  DNA fragmentation and activity of caspase-3 data suggest that cytotoxic activity of the compounds on cancer cells might be related to apoptosis. Also, RT-PCR of apoptosis markers indicated that these compounds induce apoptosis through the intrinsic pathway.

Our findings suggest that para chloro derivative (5c) may be a promising agent for treatment of cancer cells by the targeted intrinsic pathway of apoptosis and could be used as a drug candidate for in vivo assessment in the treatment of cancer.

To evaluate the pleiotropic potential and underlying mechanism of pantoprazole (PPZ) (common Proton Pump Inhibitors, PPIs) in type 2 diabetes mellitus (T2DM) -associated ischemia/reperfusion (I-R)-induced myocardial infarction which is still uncharted. Whereas some other PPIs have demonstrated their anti-diabetic, antioxidant, and anti-inflammatory potential.

We evaluated the potential of coinciding treatment of PPZ (4 mg/kg/po/day for 8 weeks) in Wistar albino rats against STZ (50 mg/kg/IP) induced T2DM model and I-R provoked cardiac infarction model in diabetic and non-diabetic condition.

PPZ significantly inhibited the perturbed deviations in blood glucose concentration, HbA1c, C-peptide, plasma insulin, and ameliorated the lipid profile (dyslipidemia). PPZ protected myocardial tissue against lipid peroxidation by restoring the levels of serum TBARS and reduced NBT. The significant protective effects of PPZ were evident by ameliorating CKMB, LDH, cTnI, and myocardial oxidative stress in PPZ treated animals. Additionally, PPZ prominently reduced various proinflammatory cytokines release including TGF-β1, TNF-α, and IL-6. PPZ upsurges the bioavailability of nitrite/nitrate concentration which may pacify the impact of myocardial infarction in diabetic I-R injury.

The consequences indicate that PPZ possesses a potent protective effect against diabetic I-R-induced myocardial infarction via suppressing oxidative stress, inflammation, and dyslipidemia-associated tissue damage.

The increase in multidrug-resistant Escherichia coli strains with an overactivated AcrAB-TolC efflux pump has reduced the effectiveness of synthetic antibiotics, such as ciprofloxacin. The activity of this efflux pump can be reduced by using natural products. This study aimed to use a combination of ciprofloxacin, honey, and alkaloid extract of Sophora alopecuroides against an E. coli mutant with an overactivated AcrAB-TolC pump.  

First the physicochemical properties, total alkaloid content, antioxidant activity, and the minimum inhibitory concentration (MIC) of three local honey samples: Konar (lotus), Avishan (Thyme), and Gavan (Astragalus) were evaluated. Then, the MIC of different combinations of honey, ciprofloxacin, and plant alkaloid extract and expression of acrA and soxS genes were carried out using the agar dilution method and quantitative RT- PCR methods.

The net absorbance, total alkaloid content, and DPPH radical scavenging activity of Konar honey were significantly higher than those of Avishan and Gavan honeys (p <0.05). However, the MIC of lotus honey was nearly similar to other honey types, and all honey (30% w/v)-ciprofloxacin combinations decreased the viability of mutant more than ciprofloxacin alone. A synergistic interaction (FICI =0.48) was observed in triplex complex of ciprofloxacin (10 µg/ml), honey (20% w/v), and plant extract (1 mg/ml). A significant decrease (p <0.05) in the expression level of genes was seen in the presence of the triplex complex.

It is concluded that the interaction between honey and plant alkaloid extract enhanced the anti-pump activity and reduced the oxidative stress response of the E. coli mutant.

Sirt3 may regulate ROS production and might be involved in β‑cell apoptosis, which plays an important role in the progression of type 2 diabetes mellitus (T2DM). Quercetin is a potent anti-oxidative bioflavonoid, but its effects on T2DM remain to be explored. This study aimed to investigate the effects of quercetin on β‑cell apoptosis and explore its mechanisms.

The effects of quercetin were conducted on db/db mice and INS1 cells. Fasting blood glucose was determined by the colorimetric method, serum insulin was measured by enzyme‑linked immunosorbent assay (ELISA). Meanwhile, Sirt3 in INS1 cells was knocked down by plasmid transfection. The antioxidant proteins (SOD2 and CAT), apoptosis proteins (cleaved Caspase-3, Bax, and BCL-2), and Sirt3 protein in pancreases and INS1 cells were determined by western blotting.

When INS1 cells and diabetic mice were treated with quercetin, the levels of SOD2, CAT, and Sirt3 proteins were increased, the levels of cleaved Caspase-3 and the ratio of Bax to BCL-2 were decreased at different degrees, along with reduced blood glucose levels and elevated insulin levels in diabetic mice. When Sirt3 was knocked down in INS1 cells, increase of two antioxidants and decrease of cell apoptosis generated by quercetin could not occur.

Quercetin protected islet β‑cells from oxidation-induced apoptosis via Sirt3 in T2DM, which would be beneficial to develop new strategies for preventing β‑cell failure in T2DM.

In this study, cardiovascular disorders were examined with a focus on the aging pathway and autophagy involvement in cardiac samples isolated from male rats with type 2 diabetes mellitus.

In the present study, male Wistar rats became diabetic with the help of a high-fat diet. Gene and protein expression levels (to evaluate Tumor Necrosis Factor-α, TNF-α) were measured by the ELISA method. Nrf2, p38, and GSK-3β proteins in cardiac tissue samples were measured by the western blotting method. Autophagy examination was performed with immunofluorescence staining. Finally, quantitative results were calculated using statistical analysis.

The expression of beta-galactosidase genes had a significant increase in the diabetic group (P=0.0001). However, there was no significant difference in the expression of the SERCA2a gene between the diabetic and control groups. In terms of protein expression, the amount of TNF-α protein in the diabetic group was significantly different from that of the control group (P=0.0102). The expression levels of p38, Nrf2, and GSK-3β proteins increased compared with the control group. The use of the LC3 immunofluorescence staining technique revealed that autophagy increased in the diabetic group.

Type 2 diabetes mellitus in rats will increase aging in cardiac cells. Examination of the signaling pathway indicates that this effect is related to the increase of ROS and the activity of the signaling pathway. In response, the cardiac cells try to maintain their homeostasis by increasing autophagy and decreasing inflammatory cytokines.

The present study determines the chemical constituents of Persea americana using gas chromatography-mass spectrometry (GC-MS) and its different activities.

Air-dried powdered leaves of Persea americana were extracted by 95% methanol and fractionated consecutively with petroleum ether, chloroform, and ethyl acetate. The saponifiable matter, EtOAc and aqueous fractions were subjected to GC-MS. The analgesic, anti-inflammatory, antipyretic, and antihyperglycemic properties of extracts, different fractions, and crude polysaccharide were determined by hot plate, carrageenan-induced paw edema, yeast-induced pyrexia, and alloxan-induced hyperglycemia methods, respectively.

Fourteen fatty acid methyl esters were identified in GC-MS-based profiling of the saponifiable matter. Alongside, 13 compounds were determined from EtOAc fraction and 6 compounds from the aqueous fraction of P. americana leaves. The ethyl acetate fraction and total stem extract displayed high anti-inflammatory potential with percentage of paw edema reduction by 48.99 and 47.54 %, respectively, compared with that of indomethacin (42.90 %). The ethyl acetate fraction and total stem extract revealed the highest analgesic activity with 137.95 and 137.12 % percent of protection against external stimulus, respectively. Investigation of antipyretic efficiency showed the total stem extract and crude polysaccharides attained normal temperature after 3 hr, which was very close to that of acetylsalicylic acid. The total leaf and stem extracts displayed significant antihyperglycemic activity with significant reduction in the level of blood glucose by 76.67 and 59.05 %, respectively.

P. americana had analgesic, anti-inflammatory, antipyretic, and antihyperglycemic properties, which refer to its bioactive metabolites.

β-LAPachone (B-LAP) is a natural product with established anti-inflammatory properties. In this study, we investigated the protective potential of B-LAP against diabetic nephropathy in streptozotocin (STZ) induced diabetic mice.

Diabetes induction in mice was carried out by a single intraperitoneal injection of STZ. 2.5 mg/kg/day and 5 mg/kg/day doses of B-LAP were administered orally for twelve weeks and renal histoarchitecture, caspase-3, tumor necrosis factor-alpha (TNF-α), malondialdehyde (MDA), glutathione peroxidase (GPX), as well as urinary nephrin and neutrophil gelatinase-associated lipocalin (NGAL) were evaluated. Additionally, kidney levels of PI3K, phosphorylated (p)-Akt, p-mTOR, p-CREB, and SIRT1 were assessed in the present investigation.

5 mg/kg B-LAP significantly decreased urinary excretions of nephrin and NGAL. It also mitigated renal TNF-α and MDA levels and simultaneously improved GPX activities. 5 mg/kg B-LAP improved renal function in diabetic mice as indicated by elevated values of creatinine clearance. While B-LAP elevated renal levels of SIRT1, it alleviated PI3K, p-Akt, p-mTOR, and p-CREB levels in the kidneys of diabetic mice.

Collectively, these findings suggest B-LAP as a potential renoprotective agent in STZ-induced diabetic mice probably via modulating the PI3K/Akt/mTOR pathway.

Experimental studies have revealed that Alpinia officinarum Hance (Zingiberaceae) exhibits a gastrointestinal protective effect. The present study aimed to investigate the effects of diphenylheptanes (DPHs) extracted from A. officinarum rhizomes on ethanol-induced gastric ulcers in BALB/c mice.

A total of 60 female BALB/c mice were divided into six groups as follows: negative control, which received sodium carboxymethyl cellulose; positive control, which received ethanol; treatment control, which received ethanol+ranitidine; ethanol+high dose of DPHs; ethanol+medium dose of DPHs; ethanol+low dose of DPHs. Different doses of DPHs were administered orally once daily for seven consecutive days before the animals were subjected to ethanol-induced gastric ulcers.

Various doses of DPHs significantly reduced Gastric ulcers index when compared with the positive control. DPHs treatments and treatment control increased the activity of superoxide dismutase; decreased the levels of inflammatory mediators, malondialdehyde, motilin, and gastrin; decreased the activity of inducible nitric oxide synthase and cyclooxygenase-2; and inhibited the expression of Toll-like receptor 4, myeloid differentiation factor 88, and nuclear factor-κB at the protein and mRNA levels. In addition, DPHs inhibited the expression of transient receptor potential vanilloid 1, calcitonin gene-related peptide, and increased the expression of substance P at the protein and mRNA levels.

The protective effect of DPHs extracted from A. officinarum rhizomes against ethanol-induced gastric damages in mice suggests that the extract can be used as an auxiliary supplement for the prevention and treatment of gastric ulcers.

The multi-drug resistant bacteria and clinical infections are some of the biggest global concerns, so new drugs are needed. Antimicrobial peptides and lipopeptides are new bioactive agents with great potential that can become a new strategy for clinical applications.

Some Bacillus strains were isolated based on hemolytic antimicrobial production from the soil. The extracellular proteins were extracted by acidic precipitation and chloroform/methanol method and analyzed by SDS-PAGE electrophoresis and stained with Sudan black. The black fragment was purified and characterized by FTIR, GC/MS, and HPLC analysis to demonstrate the presence of lipids and proteins. The anti-microbial ability and stability of the purified lipopeptide were assayed by the Kirby-Bauer method. Also, it was examined for metal removal.

A new Bacillus halotolerans strain SCM 034 with hemolytic antimicrobial production was isolated. According to GC/MS (detecting C16, C17) and HPLC (detecting leucine, glutamic acid, valine, arginine, glycine, and aspartic acid) data, the black fragment was lipopeptide. Polyacrylamide hydrogel containing lipopeptide and gel purified lipopeptide showed anti-microbial activities against S. aureus and S. cerevisiae that were stable for a few months. Also, the lipopeptide was useful for cation removal and decreased cobalt, nickel, and calcium by 10.81 %, 24.39 %, and 34 %, respectively.

Production of antibacterial lipopeptide hemolysin from this strain is reported for the first time and according to the results, lipopeptides have unique properties with biomedical and pharmaceutical applications. Also, polyacrylamide hydrogel lipopeptide is a promising candidate for wound healing.

To explore the regulation mechanism of Sirtuin 3 (SIRT3) on the mitochondrial function and apoptosis of acute kidney injury (AKI) in septic mice. The sepsis-induced AKI model was constructed in the wild-type and SIRT3 knockout (KO) mice, and the levels of serum creatinine (Scr) and plasma kidney injury molecule 1 (pKIM-1) in mice were detected by ELISA. The mitochondrial damage of kidney tubular epithelial cells (KTEC) was observed by electron microscopy, the apoptosis of KTEC was detected by TUNEL assay, and the mRNA levels of SIRT3, Bax, Caspase-3, and Bcl-2 were detected by RT-qPCR. SIRT3 KO caused increased expression of Scr, pKIM-1, and inducible nitric oxide synthase protein in the kidneys of septic mice, and decreased the levels of superoxide dismutase, catalase, and mitochondrial complex enzymes I/II/III/IV. SIRT3 deficiency exacerbated histopathological and mitochondrial damage to the proximal tubules of the kidney. In addition, SIRT3 KO resulted in a significantly increased apoptosis of KTEC, increased the mRNA levels of Bax and Caspase-3, and decreased the mRNA levels of Bcl-2. Our study suggests that SIRT3 deficiency promotes sepsis-induced AKI via increasing oxidative stress, mitochondrial dysfunction, and inducing apoptosis.

Use of chemical anti-cancer drugs frequently creates serious side effects. However, probiotics are natural and treat different kinds of cancer without undesired effects. In this study, a nano delivery system was planned to transport the Lactobacillus rhamnosus GG (L. GG) cytoplasmic fraction (Cf) to cancerous tissue in a mouse model. Magnetic iron nanoparticles (MINPs) were synthesized and loaded with L. GG-Cf(0, 0.312, 0.625, 1.25, and 2.5 mg/ml) and were administrated for three weeks to treat experimentally induced murine breast cancer in a constant magnetic field. At the end of the trial, the treating efficacy of this complex molecule was evaluated via western blotting, immunohistochemistry, and qPCR. Results showed that MINPS can deliver and accumulate L. GG-Cf in cancer tissue, and reduce the size and volume of the tumors. Additionally, in cancer tissues of treated mice with 2.5 mg/ml of Cf-MINPs, significantly induced apoptosis was seen compared with untreated mice (control), and our data proved that this induction may be due to the caspase-3 pathway. L. GG-Cf could treat murine breast cancer, and MINPs are a suitable candidate for drug delivery because of their safety, uniformity, and magnetic properties.

Carbapenem-resistant Acinetobacter baumannii (CRAB) is considered highly virulent due to csgA gene-mediated biofilm formation. The present study aimed to target the same gene, employing the antibiofilm effect of Ocimum sanctum (O. sanctum) essential oil compounds among CRAB strains.

A semi-quantitative adherent bioassay was performed to detect the biofilm formation in 73 CRAB strains. This was followed by molecular characterization, Polymerase Chain Reaction (PCR) amplification, and csgA gene sequencing. An antibiofilm assay under in vitro conditions, with essential oils of O. sanctum was performed. This was followed with further docking analysis of csgA protein with the selected compounds from the O. sanctum essential oils. A Molinspiration assessment was also done to elicit the drug likeliness of the biocompounds.

The biofilm assay showed 58.9% as high-grade and 31.5% as low-grade biofilm formers, while 9.58% were non-biofilm formers. Molecular characterization of the csgA gene showed 20.54% (15/73) positivity. The strains that were imipenem resistant also showed the csgA gene to be present (100%; 15/15), with 60% (9/15) and 20% (3/15) for meropenem and doripenem resistance respectively. A crystal violet assay for determining cell viability was done in vitro, which gave Minimum biofilm inhibition concentrations of 50% (MBEC50) at 25 µl and 90% (MBEC90) at 50 µl. The docking analysis done in silico showed benzofuran to possess the lowest binding energy and highest hydrogen bond interactions.

The results indicate benzofuran, from the O. sanctum essential oils, to be effective in targeting the csgA gene among CRAB strains. Additionally, validation of these findings through in vivo studies is required.