Iranian Journal of Basic Medical Sciences
Volume:27 Issue: 4, Apr 2024

Propolis is produced by bees using a mixture of bees wax and saliva. It contains several bioactive compounds that mainly induce anti-oxidant and anti-inflammatory effects. In this review, we aimed to investigate the effects of propolis on kidney diseases. We used “Kidney”, “Disease”, “Propolis”, “Renal”, “Constituent”, “Mechanism”, “Infection”, and other related keywords as the main keywords to search for works published before July 2023 in Google scholar, Scopus, and Pubmed databases. The search terms were selected according to Medical Subject Headings (MeSH). This review showed that propolis affects renal disorders with inflammatory and oxidative etiology due to its bioactive compounds, mainly flavonoids and polyphenols. There have been few studies on the effects of propolis on kidney diseases; nevertheless, the available studies are integrated in this review. Overall, propolis appears to be effective against several renal diseases through influencing mechanisms such as apoptosis, oxidative balance, and inflammation.

Crocus sativus L. was used for the treatment of a wide range of disorders in traditional medicine. Due to the extensive protective and treatment properties of C. sativus and its constituents in various diseases, the purpose of this review is to collect a summary of its effects, on experimental studies, both in vitro and in vivo. Databases such as PubMed, Science Direct, and Scopus were explored until January 2023 by employing suitable keywords. Several investigations have indicated that the therapeutic properties of C. sativus may be due to its anti-oxidant and anti-inflammatory effects on the nervous, cardiovascular, immune, and respiratory systems. Further research has shown that its petals also have anticonvulsant properties. Pharmacological studies have shown that crocetin and safranal have anti-oxidant properties and through inhibiting the release of free radicals lead to the prevention of disorders such as tumor cell proliferation, atherosclerosis, hepatotoxicity, bladder toxicity, and ethanol induced hippocampal disorders. Numerous studies have been performed on the effect of C. sativus and its constituents in laboratory animal models under in vitro and in vivo conditions on various disorders. This is necessary but not enough and more clinical trials are needed to investigate unknown aspects of the therapeutic properties of C. sativus and its main constituents in different disorders.

Polycystic ovary syndrome (PCOS) causes a developmental arrest of antral follicles and disrupts oocyte maturation. Retinoic acid (RA) and Fibroblast Growth Factor-2 (FGF2) are effective in follicle growth, thus their effects on histopathology and in vitro fertility of oocytes were investigated in PCOS-induced mice. Eighty female NMRI mice were randomly divided into 8 groups including 1-Normal mice, 2-PCOS mice without any treatment, 3-Normal mice treated with RA, 4-Normal mice treated with FGF2, 5-PCOS mice treated with RA, 6- PCOS mice treated with FGF2, 7- PCOS mice treated with RA and FGF2, and 8- Normal mice treated with RA and FGF2. Following PCOS induction, the mice were treated with intraperitoneal RA and FGF2 as a treatment. Then ovarian stimulation, for preparing the oocyte and embryo microscopic examinations was performed. After oocyte morphometry, through in vitro fertilization, the embryo formation was assessed. Data was analyzed by one-way ANOVA and Tukey tests. The results showed simultaneous injection of RA and FGF2 into PCOS-induced mice increases antral follicles and corpus luteum, but decreases cystic follicles. Simultaneous injection of these two substances into healthy mice increases the pre-antral follicles and corpus luteum. Simultaneous injection of RA and FGF2 increases the number of embryos in both control and intervention groups.  It can be concluded that RA and FGF2 increase the maturity of ovarian follicles, the number of two-celled embryos, and the number of grade-A embryos in mice with PCOS, which is more effective when these two substances are injected simultaneously.

Utilization of doxorubicin (DOX) as a chemotherapy medication is limited due to its cardiotoxic effects. Carnosic acid exerts antioxidant, anti-inflammatory, besides cytoprotective effects. The objective of this study was to investigate the ability of carnosic acid to protect rat hearts and the MCF7 cell line against cardiotoxicity induced by DOX. The study involved the classification of male Wistar rats into seven groups: 1) Control 2) DOX (2 mg/kg, every 48h, IP, 12d), 3-5) Carnosic acid (10, 20, 40 mg/kg/day, IP, 16d)+ DOX, 6) Vitamin E (200 mg/kg, every 48h, IP, 16d)+ DOX 7) Carnosic acid (40 mg/kg/day, IP, 16d). Finally, cardiac histopathological alterations, ECG factors, carotid blood pressure, left ventricular function, heart-to-body weight ratio, oxidative (MDA, GSH), inflammatory (IL-1β, TNF-α), plus apoptosis (caspase 3, 8, 9, Bcl-2, Bax) markers were evaluated. DOX toxicity and carnosic acid ameliorative effect were evaluated on MCF7 cells using the MTT assay. DOX augmented the QRS duration, QA, RRI, STI, and heart-to-body weight ratio, and reduced HR, LVDP, Min dP/dt, Max dP/dt, blood pressure, boosted MDA, TNF-α, IL1-β, caspase 3,8,9, Bax/Bcl-2 ratio, decreased GSH content, caused fibrosis, necrosis, and cytoplasmic vacuolization in cardiac tissue but carnosic acid administration reduced the toxic effects of DOX. The cytotoxic effects of DOX were not affected by carnosic acid at concentrations of 5 and 10 μM. Carnosic acid as an anti-inflammatory and antioxidant substance is effective in reducing DOX-induced damage by enhancing antioxidant defense and modifying inflammatory signal pathway activity and can be used as an adjunct in treating DOX cardiotoxicity.

Diabetic nephropathy (DN) is the main cause of end-stage renal disease, but the current treatment is not satisfactory. Crocin is a major bioactive compound of saffron with antioxidant and anti-endoplasmic reticulum stress (ERS) abilities used to treat diabetes. This study specifically investigated whether crocin has a regulatory role in renal injury in DN. The experiment was divided into control, (db/m mice), model (db/db mice), and experimental groups (db/db mice were intraperitoneally injected with 40 mg/kg crocin). Renal function-related indicators (Scr, BUN, FBG, UP, TG, TC, ALT, and AST) and oxidative stress-related indicators (ROS, MDA, GSH, SOD, and CAT) were assessed. The pathological changes of renal tissues were confirmed by HE, Masson, PAS, and TUNEL staining. The levels of ERS-related proteins (GRP78 and CHOP), apoptosis-related proteins, and PI3K/AKT and Nrf2 pathways-related proteins in renal tissue were detected.  In db/db mice, renal function-related indicators, apoptotic cells of renal tissues, the contents of ROS and MDA as well as the expressions of CHOP, GRP78, and Bax were increased, the degree of renal tissue damage was aggravated, while the contents of GSH, SOD, and CAT, as well as the protein levels of Nrf2, PARP, anti-apoptotic proteins (Mcl-1, Bcl-2, Bcl-xl) were decreased compared to the db/m mice. However, crocin treatment reversed the above-mentioned situation. The expressions of the PI3K/AKT and Nrf2 pathways-related proteins were also activated by crocin. Crocin inhibited oxidative stress and ERS-induced kidney injury in db/db mice by activating the PI3K/AKT and Nrf2 pathways.

It is worthwhile to note that, some probiotics such as Lactobacilli and Bifidobacteria isolated from dairy products have significant therapeutic effects against cancer cells. Here, we evaluated anti-proliferation and the apoptotic effects of isolated Lactobacillus fermentum Ab.RS22 from traditional dairy products on the HeLa cervical cancer cells in vitro. The viability of treated HeLa cells with supernatant of Lactobacillus in 0.5, 0.75, 1, 1.5, and 2 ng/ml concentrations, and IC50 values were detected by tetrazolium bromide. The L. fermentum Ab.RS22-induced cell death by flow cytometry was confirmed through evaluation of the expression of caspase-3, P53, PTEN, and AKT genes by quantitative reverse transcription-polymerase chain reactions (qRT-PCR). Most cytotoxicity effects of Lactobacillus on HeLa cells were detected in 2 ng/ml at 24 hr (P<0.01); also, the IC50 value was measured as 1.5 ng/ml. The findings of the flow cytometry assay showed that L. fermentum Ab.RS22 in 1.5 ng/ml concentration at 24 hr increased the percentage of both apoptosis and necrosis cells. Lactobacillus-induced cell death was verified through results of Real-time PCR; where expression of caspase-3, P53, and PTEN genes was increased (P<0.01), and also expression of AKT gene (anti-apoptotic) was decreased (P<0.05).  Our findings showed that L. fermentum Ab.RS22 could dose-dependently inhibit the proliferation of the HeLa cells. Its apoptotic effect was confirmed via modulating PTEN/p53/Akt gene expression and activation of the caspase-3 mediated apoptosis pathway. Therefore, L. fermentum Ab.RS22 can be considered a valuable anticancer candidate against cervical cancer progression in subsequent studies.

Dexmedetomidine (Dex) is a potent α2-adrenergic receptor(α2-AR) agonist that has been shown to protect against sepsis-induced lung injury, however, the underlying mechanisms of this protection are not fully understood. Autophagy and the Smad2/3 signaling pathway play important roles in sepsis-induced lung injury, but the relationship between Dex and Smad2/3 is not clear. This study aimed to investigate the role of autophagy and the Smad2/3 signaling pathway in Dex-mediated treatment of sepsis-induced lung injury. Sepsis was performed using cecal ligation and puncture (CLP) in C57BL/6J mice.  Mice were randomly assigned to four groups (n=6 per group): sham, CLP, CLP-Dex, and CLP-Dex-YOH, Yohimbine hydrochloride (YOH) is an α2-AR blocker. The cecum was carefully separated to avoid blood vessel damage and was identified and punctured twice with an 18-gauge needle. The pathological changes, inflammatory factor levels, oxidative stress, autophagy, Smad2/3 signaling pathway-related protein levels in lung tissues, and the activity of superoxide dismutase (SOD) and malonaldehyde (MDA) in the serum were measured. CLP-induced lung injury was reflected by increased levels of inflammatory cytokines, apoptosis, and oxidative stress, along with an increase in the expression of autophagy and Smad2/3 signaling pathway-related proteins. Dex could reverse these changes and confer a protective effect on the lung during sepsis. However, the administration of YOH significantly reduced the positive effects of Dex in mice with sepsis. Dex exerts its beneficial effects against sepsis-induced lung injury through the regulation of autophagy and the Smad2/3 signaling pathway.

Long-term potentiation (LTP) is a kind of synaptic plasticity and has a key role in learning and memory. Endocannabinoids and orexins are the endogenous systems that can modulate synaptic plasticity. Given that new studies have shown an interaction between cannabinoid and orexin systems in the brain, we decided to examine this interaction between the two systems on LTP induction in rat’s hippocampus. Twenty-eight male Wistar rats were used for evaluating the effects of co-administrating of cannabinoid-1 receptor (CB1R) antagonist (AM251) and orexin-2 receptor (OX2R) antagonist (TCS OX2 29) on the induction of LTP in the Schaffer collateral-CA1 synapses of rat hippocampus. The drugs were microinjected into the CA1 area of rat hippocampus 30 min before inducing of LTP. Results showed that sole administration of the antagonists inhibited LTP, with respect to the control group. Also, co-administrating of them reduced LTP as compared to the control group, but not significantly more than that when the antagonists were solely microinjected into the CA1. Nonetheless, the inhibitory effect of concurrent administration of the antagonists on LTP lasted until the end of the recording.  These results propose that endogenous cannabinoids and orexins play a role in the expression of LTP, at least by CA1-CB1Rs and CA1-OX2Rs, respectively. Finally, there is no interaction between CB1R and OX2R on the induction of LTP in the Schaffer collateral-CA1 synapses; therefore, these two systems possibly act through common signaling pathways in the hippocampus’s CA1 region.

Oxaliplatin (OXL) is a platinum-based chemotherapeutic agent widely used in the treatment of colorectal cancer. Unfortunately, this important drug also causes unwanted side effects such as neuropathy, ototoxicity, and testicular toxicity. This study aimed to investigate the possible protective effects of naringin (NRG) against OXL-induced testicular toxicity in rats.  In the present study, rats were injected with OXL (4 mg/kg, b.w./day, IP) in 5% dextrose solution 30 min after oral administration of NRG (50 and 100 mg/kg, b.w./day) on the 1st, 2nd, 5th, and 6th days. Then, the rats were sacrificed on the 7th day and the testicular tissues were removed.  The results showed that NRG decreased (P<0.001) lipid peroxidation, increased (P<0.001) the activities of superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), and the levels of glutathione (GSH), and also maintained the testis histological architecture and integrity. NRG decreased the levels of apoptosis-related markers such as caspase-3, Bax, and Apaf-1 and increased Bcl2 in the OXL-induced testicular toxicity (P<0.001). In addition, NRG reversed the changes in mRNA transcript levels of oxidative stress, inflammation, and endoplasmic reticulum stress parameters such as Nrf2, HO-1, NQO1, RAGE, NLRP3, MAPK-14, STAT3, NF-κB, IL-1β, TNF-α, PERK, IRE1, ATF6, and GRP78 in OXL-induced testicular toxicity (P<0.001).  Our results demonstrated that NRG can protect against OXL-induced testicular toxicity by enhancing the anti-oxidant defense system and suppressing apoptosis, inflammation, and endoplasmic reticulum stress.

Colorectal cancer (CRC) remains a major health concern worldwide due to its high incidence, mortality rate, and resistance to conventional treatments. The discovery of new targets for cancer therapy is essential to improve the survival of CRC patients. Here, this study aims to present a finding that identifies the STAT6 oncogene as a potent therapeutic target for CRC. HT-29 CRC cells were transfected with STAT6 siRNA and treated with 5-fluorouracil (5-FU) alone and combined. Then, to evaluate cellular proliferation and apoptosis percentage, MTT assay and annexin V/PI staining were carried out, respectively. Moreover, the migration ability of HT-29 cells was followed using a wound-healing assay, and a colony formation assay was performed to explore cell stemness features. Gene expression was quantified via qRT-PCR. Afterward, functional enrichment analysis was used to learn in-depth about the STAT6 co-expressed genes and the pathways to which they belong. Our study shows that silencing STAT6 with small interfering RNA (siRNA) enhances the chemosensitivity of CRC cells to 5-FU, a commonly used chemotherapy drug, by inducing apoptosis, reducing proliferation, and inhibiting metastasis. These results suggest that combining 5-FU with STAT6-siRNA could provide a promising strategy for CRC treatment. Our study sheds light on the potential of STAT6 as a druggable target for CRC cancers, the findings offer hope for more effective treatments for CRC patients, especially those with advanced stages that are resistant to conventional therapies.

In the present study, the potential protective effects of zingerone (ZNG) against sciatic nerve damage caused by sodium arsenite (SA), a common environmental pollutant, were evaluated by various biochemical, molecular, and histological methods. In the study, SA and ZNG were given to 35 male Sprague Dawley rats for 14 days. At the end of the period, the sciatic nerve tissues were taken and the markers involved in oxidative stress, endoplasmic reticulum stress, inflammation, and apoptosis were analyzed. The data obtained showed that SA decreased glutathione (GSH) levels and increased malondialdehyde (MDA) levels in the sciatic nerve tissue. However, it was determined that these markers approached the control group levels due to the anti-oxidant properties of ZNG. While SA triggered endoplasmic reticulum stress and apoptosis pathways, ZNG suppressed them. Moreover, SA up-regulated inflammatory markers such as nuclear factor kappa-B (NF-κB), tumor necrosis factor-alpha (TNF-α), interleukin-1-beta (IL-1β), and neuronal nitric oxide synthases (nNOS) in the sciatic nerves and caused neuro-inflammation and inhibited cell survival by suppressing serine/threonine-protein kinase 2 (Akt2) and forkhead box protein O1 (FOXO1) genes. It has also been shown histopathologically that SA causes degeneration in the sciatic nerves. In contrast, ZNG suppressed neuro-inflammation, activated Akt2/FOXO1 signaling, and repaired histological irregularities. In general, SA caused oxidative stress, inflammation, ER stress, and apoptosis in the sciatic nerves of rats, causing damage to the tissues, however, ZNG suppressed these pathways and protected the sciatic nerves from the destructive effect of SA.

Luteolin is a flavone that provides defense against myocardial ischemia/reperfusion (I/R) injury. However, this compound is subjected to methylation mediated by catechol-O-methyltransferase (COMT), thus influencing its pharmacological effect. To synthesize a new flavone from luteolin that avoids COMT-catalyzed methylation and find out the protective mechanism of LUA in myocardial I/R injury. Luteolin and 2,2’-azobis (2-amidinopropane) dihydrochloride (AAPH) were used to synthesize the new flavone known as LUAAPH-1 (LUA). Then, the myocardial ischemia/reperfusion injury cell model was established using H9c2 cells to detect the effect in myocardial ischemia/reperfusion regulation and to identify the underlying mechanism.  Pretreatment with LUA (20 μmol/l) substantially increased cell viability while reducing cell apoptosis rate and caspase-3 expression induced by I/R, and the protective effect of LUA on cell viability was stronger than diosmetin, which is the major methylated metabolite of luteolin. In addition, intracellular reactive oxygen species (ROS) production and calcium accumulation were both inhibited by LUA. Furthermore, we identified that LUA markedly relieved the promotive effects of I/R stimulation upon JNK and p38 phosphorylation. LUT pretreatment conveys significant cardioprotective effects after myocardial I/R injury, and JNK and p38 MAPK signaling pathway may be involved.

Pulmonary arterial hypertension (PAH) is a severe and often fatal disease that is associated with oxidative stress and inflammation. Alamandine, a component of the renin-angiotensin system, known for its antioxidative, anti-inflammatory, and antifibrotic effects, has been investigated in this study to determine if it has protective effects against PAH induced by monocrotaline (MCT) and if these effects are associated with oxidative stress, inflammatory factors, and inducible nitric oxide synthase (iNOS). Rats were administered MCT (40 mg/kg) on day 0 and then received alamandine (50 mg/kg/day) via mini-osmotic pumps for 21 days starting one day later. Hemodynamic parameters, electrocardiograms, superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), inflammatory cytokines (TNF-α, IL-1β, and NF-κB), iNOS, and MrgD receptor expression in lung tissue were evaluated at the end of the 21-day period. The MrgD receptor was quantified through immunofluorescent staining, and the histopathology of lung tissues was evaluated using hematoxylin and eosin staining.  The results showed that alamandine treatment significantly improved hemodynamic parameters, oxidative stress markers, inflammatory factors, and electrocardiographic data. Furthermore, treatment with alamandine decreased the levels of iNOS. Additionally, alamandine treatment decreased the expression levels of MrgD receptors in the lung tissue of MCT-induced PAH.  In summary, this study indicates that alamandine has protective effects against monocrotaline-induced PAH, and these effects may be attributed to the inhibition of oxidative stress, inflammatory parameters, and iNOS.

Proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) contribute to hypoxia-induced pulmonary hypertension (HPH). The transcription factor Cbp/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 (Cited2) has been implicated in the control of tumor cells and mesenchymal stem cell (MSC) and cardiomyocyte growth or migration. Whether Cited2 is involved in the proliferation and migration of PASMCs and the underlying mechanisms deserve to be explored.  Cited2 expression was detected in rat PASMCs under hypoxia conditions and HPH rat models. The effect of Cited2 on the proliferation and migration of PASMC was detected by overexpression or knockdown of the Cited2 gene. After PAMSCs were treated with recombinant TGF-β1 and the lentivirus vector overexpressing Cited2, expression of peroxisome proliferator-activated receptor gamma (PPARγ) was examined by western blotting. We revealed that hypoxia down-regulated the expression of Cited2 in PASMCs and rat pulmonary arteries. Cited2 overexpression inhibited the proliferation and migration of PASMCs under hypoxia, while Cited2 knockdown induced the proliferation and migration of PASMCs. Cited2 inhibits the negative regulation of the TGF-β1 pathway on PPARγ to inhibit the proliferation and migration of PASMCs. These findings suggest that increased Cited2 expression contributes to the inhibition of PASMCs proliferation and migration by regulating TGF-β1-mediated target gene expression in HPH and provides a new target for molecular therapy of HPH.

During aging, cerebral structures undergo changes due to oxidative stress. The consumption of some plants seems to improve neurological health. For example, rosemary extract (RE) which is widely used as a flavoring food has anti-inflammatory and anti-oxidant activities. Therefore, we aimed to study the effect of RE on the changes related to the aging process in the prefrontal cortex (PFC).

Twenty-four male Wistar rats including young and old were purchased. Each group was divided into two subgroups: vehicle and rosemary (old vehicle (OV), old rosemary (OR), young vehicle (YV), and young rosemary (YR) groups). Then, we examined the number of intact neurons, myelin base protein (MBP), white matter (WM), levels of malondialdehyde (MDA), and glutathione peroxidase (GPx) in the PFC. 

The results showed that in the old vehicle rats compared to the young group without treatment, except for the MDA level (which increased), other variables significantly decreased (P≤0.05). Additionally, RE consumption demonstrated a significant elevation of WMA, MBP intensity, number of intact neurons, and GPx activity level, while MDA levels significantly reduced in the treated old rats compared to the old vehicle group (P≤0.05). However, there was no significant difference between the OR and YV groups (P≥0.05). 

Overall, it seems that RE can protect and improve aging damages in the PFC due to its anti-oxidant properties. So, the use of RE can be a suitable strategy to prevent aging complications in the brain.