Iranian Journal of Basic Medical Sciences
Volume:28 Issue: 7, Jul 2025

Diosmin and hesperidin, two flavonoid glycosides derived from citrus plants, offer numerous health benefits, whether used alone or in combination. They can mitigate neurodegenerative symptoms and reduce vascular and microbial inflammations, improving cardiovascular health and modulating immunity and anti-oxidant properties. Neuroinflammation and oxidative stress are associated with numerous neurological disorders. This study aims to review the neuroprotective potentials of diosmin and hesperidin, focusing on their effects on oxidative stress and inflammatory conditions. A scientific literature search was conducted using specific keywords in various databases, including PubMed, Web of Science, Google Scholar, Embase, and Scopus.Diosmin and hesperidin demonstrated protective effects in managing a variety of neurological disorders, such as epilepsy, neuropathy, depression, anxiety, insomnia, autism, glioblastoma, traumatic brain injury, cerebral ischemia-reperfusion, Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, neurotoxicity, and multiple sclerosis through the regulation of various signaling pathways. Hesperidin and diosmin exhibit promising neuroprotective effects that underscore their potential as natural multi-targeted therapeutic agents for treating neurological disorders through diverse cascades.

Nanoparticles have emerged as a cornerstone of nanomedicine, offering transformative potential to modern healthcare through their multifunctional capabilities. Their adaptability positions them as ideal candidates for wound management, either as advanced wound dressings or as efficient drug delivery systems. With intrinsic antibacterial properties and the ability to enhance tissue repair, nanoparticles have gained significant attention in promoting effective wound healing. Biopolymer-based nanoparticles, derived from naturally sourced and synthetic materials such as proteins, polysaccharides, and polymers, including collagen, chitosan, alginate, polycaprolactone, and polylactic acid, stand out due to their unique combination of biodegradability and biocompatibility. These attributes make them particularly suited for addressing the challenges of wound care. Moreover, nanofibers incorporated with biopolymer-based nanoparticles demonstrate superior antibacterial properties and wound healing effectiveness, comparable to the performance of silver nanoparticles. These advancements signify a transformative approach in wound healing therapies, facilitating targeted and personalized treatments that expedite tissue regeneration and enhance patient recovery. This review delves into biopolymer-based nanoparticles’ advancements, applications, and potential in revolutionizing wound healing.

The relationship between exercise and mitochondrial function is unclear. This study investigated the relationship between voluntary exercise and mitochondrial dynamics in ischemic stroke model mice.

This experiment used 54 male C57BL/6 J mice to assess the therapeutic effect of voluntary exercise on ischemic stroke in a middle cerebral artery occlusion (MCAO) model. Body weight and the number of wheel turns were recorded to monitor the physiological condition of the mice. The degree of brain injury was evaluated via hematoxylin and eosin (H&E) staining and measurement of the cerebral infarction volume. Western blotting and immunofluorescence were used to measure dynein-1-like protein 1 (DRP1), mitochondrial fission protein 1 (FIS1), and optic atrophy type 1 (OPA1) levels to assess mitochondrial dynamics and analyze the degree of mitochondrial apoptosis by measuring cytochrome c (CYT-C), cleaved caspase-3, and caspase-3 expression. 

Voluntary exercise positively affected the behavioral score and infarct volume. H&E staining revealed that voluntary exercise reversed MCAO-induced cortical damage. Furthermore, voluntary exercise improved mitochondrial dynamics by inhibiting DRP1 and FIS1 expression and inducing OPA1 expression. Additionally, the mitochondrial apoptosis pathway was inhibited by down-regulating the expression of CYT-C, cleaved caspase-3, and caspase-3.

Voluntary exercise exerts a significant neuroprotective effect against MCAO-induced brain injury by regulating mitochondrial dynamics and the mitochondrial apoptotic pathway.

We investigated the effects of curcumin, nanocurcumin, and pioglitazone, a peroxisome proliferator-activated receptor gamma (PPARγ) activator, on the systemic inflammation and oxidative stress induced by inhaled paraquat (PQ). 

The experimental design included male Wistar rats divided into nine groups. Animals of the control group (Ctrl) were exposed to saline and those of other groups to 54 mg/m3 PQ aerosols 8 times on alternate days. PQ exposing groups were treated with saline (PQ group), curcumin (30 mg/kg, Cu), nanocurcumin (2 and 8 mg/kg, NC-L, and NC-H), pioglitazone (5 mg/kg, Pio), Pio+ Cu-L, Pio + NC-L, and dexamethasone (0.03 mg/kg, Dexa). Pio was administered intraperitoneally and other treating agents by gavage for 16 days during the PQ exposure period. Total and differential white blood cell (WBC) counts, malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), thiol, interleukin (IL)-10, and tumor necrosis factor-alpha (TNF-α) levels were measured. 

The inhalation of PQ increased total WBC, differential WBC, MDA, IL-10, and TNF-α blood levels. It also decreased blood levels of CAT, SOD, and thiol. The treatment groups (Cu, NC-L, NC-H, Pio+Cu, Pio+NC-L, Pio, and Dexa) ameliorated PQ-induced alterations. Furthermore, the improvements in most parameters in the Pio+Cu and NC-L-treated group were more significant than the results of the three substances individually.

The amelioration of systemic inflammation and oxidative stress caused by inhaled PQ by Cu, NC, and Pio were shown. Furthermore, the findings indicated a synergistic effect between Pio with Cu and NC, suggesting the involvement of PPARγ-mediated mechanisms in the effects of curcumin.

Chronic kidney disease (CKD) is a life-threatening condition often resulting from obesity and other pathologies. The present study assesses the nephroprotective effect of Cinnamaldehyde against high-fat diet (HFD) obesity-associated nephropathy in rodents.

The molecular docking analysis on AMPK & NF-kB was carried out to identify possible targets of Cinnamaldehyde. In preclinical study, 4-week-old C57BL/6 mice (18–20 gm) were fed a conventional diet or HFD for 12 weeks After the fifth week of HFD intervention, mice were divided into six groups (n=10): vehicle group; HFD group; HFD+CA (20 mg/kg); HFD+CA (40 mg/kg); HFD+Orlistat (10 mg/kg); and CA Perse (40 mg/kg) treated orally for 49 days. On day 84, mice were fasted overnight, and urine and blood were collected for various biochemical analyses. Animals were sacrificed, and kidneys were removed for histopathology and immunohistochemistry.

In silico studies showed strong binding of Cinnamaldehyde with AMPK and NF-kB. Cinnamaldehyde showed a significant (P<0.001) decrease in BW, BMI, blood glucose, leptin, insulin, HOMA-IR, total cholesterol, triglycerides, creatinine, albumin, TNF-α, IL-6, and IL-β in serum and urinary albumin. It also produced a significant (P<0.001) reduction in KIM-1, type-IV collagen, IL-18, and NGAL urinary levels. Further, it produced a significant (P<0.001) increase in urine creatinine, serum adiponectin, and kidney SOD, GSH, GST, and GPx. Immunohistology indicated suppressed NF-kB and activated AMPK/ACC pathways. Histopathology showed improvement in glomerular inflammation, tubular injury, and degeneration in kidney tissue. 

Cinnamaldehyde significantly protects against obesity-associated nephropathy in C57BL/6 mice by HFD via modulating the AMPK/ACC and NF-kB pathways.

Insulin therapy is critical in diabetic patients for controlling blood glucose levels. In recent years, pulmonary insulin delivery has emerged as an alternative approach for overcoming the therapeutic disadvantages of subcutaneous insulin administration, such as pain, infection risk, and needle phobia. To develop the pulmonary insulin formulation, five insulin-containing dry powder inhalers (DPIs) with different excipients were tested in diabetic rats.

Formulations were inoculated endotracheally to diabetic rats induced by streptozotocin. Insulin and glucose assays were performed on blood samples taken from the carotid artery at different intervals, including baseline and 1–4 hr after insulin administration. 

The results illustrated that five formulations (F1-F5) could gradually increase the plasma insulin level during time points of the study. The first and third formulations comprising insulin, mannitol, and sodium citrate in the absence (F1) or presence of sodium alginate (F3) also declined plasma glucose levels in animals. 

The results confirmed that the pulmonary formulations could deliver and release insulin molecules in a good manner, and the biological activity of the two formulations, including F1 and F3, is acceptable and comparable to the subcutaneous insulin. Our findings support that the mentioned DPI products could have therapeutic potential as an alternative to subcutaneous insulin. Further investigations are needed to prove the capability of F1 and F3 spray-dried products to treat diabetic individuals.

The current research was conducted to study the function of Fyn in a rat model of chronic obstructive pulmonary disease (COPD).

COPD in rats was induced by intratracheal instillation of lipopolysaccharide and long-term exposure to cigarette smoke. Subsequently, the rats were treated with the Fyn-specific inhibitor AZD0530. Pulmonary function, pathological appearance, and inflammatory factors were assessed in rats with COPD.

AZD0530 significantly ameliorated pulmonary function and improved the pathological manifestations of COPD in rats. AZD0530 decreased MCP-1 and CD68 expression in lung tissues, reduced inflammatory cell accumulation, and decreased TNF-α and IL-6 production in bronchoalveolar lavage fluid. In an in vitro study, pharmacological inhibition of Fyn or knockdown of Fyn by siRNA inhibited lipopolysaccharide- and cigarette smoke extract-induced TNF-α and IL-6 secretion in the human bronchial epithelial cell line BEAS-2B. Furthermore, inhibition of Fyn by either the inhibitor or siRNA Fyn reduced the phosphorylation of p38 MAPK- and NF-κB-related molecules, which strongly affected the occurrence of inflammatory responses.

Collectively, these data show that Fyn promotes COPD development by modulating the p38 MAPK and NF-κB signaling pathways. Fyn might be a promising therapeutic target for COPD.

Isoflavone Daidzein (DDZ) has emerged as a promising alternative to hormone replacement therapy (HRT) for ameliorating estrogen deficiency (ED). However, the stereological and molecular mechanism of its effects in the OVX-hippocampus are unclear. We studied the impact of DDZ on stereological changes, estrogen receptor (ERs) expression, BDNF, GSK-3β, and inflammatory and apoptosis-related genes in the hippocampus of ovariectomized rats, compared to 17β-estradiol (E2).

OVX rats were treated with DDZ or E2. The stereological analysis assessed the total volume and number of pyramidal and granular neurons in the hippocampus CA1 and DG subregions. Expression of proinflammatory cytokines, apoptotic-related genes, ERs, and BDNF genes was evaluated using Real-Time PCR, and the GSK-3β phosphorylation level was measured by western blot analysis.

DDZ has effectively increased the volume and total number of pyramidal neurons in the CA1 region, the expression of ERα, ERβ, BDNF, and Bcl-2 genes, and the phosphorylation rate of GSK-3β protein. However, the effect of DDZ on the DG region, ERα, and BDNF genes was not significant in comparison with E2; DDZ significantly suppressed the expression of TNF-α, IL-6, and the Bax/Bcl2 ratio compared with OVX rats.

DDZ effectively reversed the stereological changes in the CA1 region by stimulating BDNF gene expression, increasing the phosphorylation ratio of the GSK-3β protein, and modulating inflammatory and apoptotic pathways. Although its effects on the DG region, BDNF, and ERα molecules were less significant than E2, DDZ could still be a promising candidate for ameliorating ED.

Thymoquinone (TQ) is the main bioactive component of Nigella sativa L. and has anti-oxidant, anti-hepatotoxic, anti-cancer, anti-hypertensive, hypoglycemic, anti-inflammatory, and lipid-lowering properties. In this study, we investigated the protective properties of TQ on the cytochrome P450 enzyme system, peroxisome proliferator-activated receptors, and gene expressions involved in apoptosis, which are disrupted by valproic acid (VPA). 

The rats were put into control, VPA, and VPA+TQ groups. The weight of the body and liver were recorded. Liver tissue samples were evaluated for gene expressions (Bcl-2, p53, CYP2B1, CYP2B2, PPARα, and PPARγ), histopatology, and immunohistochemistry (CAS-3 and NOX-4). Additionally, serum was used to measure liver function parameters (ALT, AST, LDH, LDL, and HDL). 

The VPA+TQ group had significantly lower expression of p53 (P<0.05), CYP2B1 (P<0.05), CYP2B2 (P<0.05), PPARα (P<0.05), and PPARγ (P<0.05) genes compared to the VPA groups, while Bcl-2 (P<0.05) gene expression increased. TQ decreased CAS-3 and NOX-4 levels. Also, TQ reduced ALT (P<0.05), AST (P<0.05), LDL (P<0.01), total bilirubin (P<0.05), and LDH (P<0.05) enzyme activity while increasing HDL (P<0.0001). TQ treatment improved fresh liver weight considerably (P<0.0001). 

TQ substantially protects liver tissue by modifying gene expression, lowering oxidative stress, and increasing liver function. It significantly counteracts VPA’s toxic effects, demonstrating its promise as a hepatoprotective agent in avoiding liver damage.

This study explored the molecular mechanism by which exogenous spermine attenuates diabetic cardiomyopathy (DCM)-induced myocardial fibrosis.

db/db mice and primary neonatal mouse cardiac fibroblasts were used to conduct in vivo and in vitro experiments. The levels of total cholesterol (TC), triglycerides (TG), creatine kinase isoenzyme (CK-MB), troponin I (cTnI), and lactate dehydrogenase (LDH) were measured. Heart function and collagen deposition were assessed using echocardiographic analysis, Masson staining, and Sirius red staining. Cell proliferation and migration were analyzed using EdU and transwell assays. Relevant protein expression was evaluated by immunohistochemistry and western blot.

After 12 weeks, the mice in the type 2 diabetes (T2D) group exhibited increased blood glucose, TG, TC, and serum myocardial marker enzyme levels. Ejection fraction (EF) and left ventricular fractional shortening left ventricular fractional shortening (FS) decreased, while LVIDs and LVIDd increased. Significant collagen fiber deposition and increased HW/TL ratio, SSAT, α-SMA, TGF-β1, and Collagen-I/III expression was observed in myocardial tissue. Conversely, ODC expression was down-regulated. In the T2D + spermine (SP) group, these trends were reversed. In vitro, high glucose conditions led to increased proliferation of cardiac fibroblasts. SSAT, α-SMA, TGF-β1, Collagen-I/III, MMP-2, MMP-9, p-Smad-2, TβRI, and TβRII were up-regulated, while ornithine decarboxylase (ODC) expression was down-regulated. Interestingly, these changes were reversed in the HG + SP group.

Our findings demonstrate that SP reduces collagen synthesis and secretion by inhibiting the TGF-β1/Smads signaling pathway. These results provide new insights into potential therapeutic approaches for DCM.

Substrate engineering is one of the attractive fields of changing cell behavior and fate, especially for stem cell (SC) therapies. The SC pool is an essential factor in transplantation outcomes. Here, the objective was to preserve the stemness of the cornea’s limbal epithelial stem cell (LESC) using naturally biomimicking corneal cell topography.

A cell-imprinted substrate was prepared using the natural topography of rabbit cornea’s LESC. The LESC cells were characterized by immunostaining (ABCG2 and Cytokeratin-12), then re-cultivated on a topography mold (imprinted PDMS), on FLAT PDMS (without any pattern), and the control group (tissue culture plate). Ultimately, an alkaline burn model was created on a rabbit’s cornea, and the effectiveness of cell-imprinted molds as implants for healing corneal wounds was examined in vivo.  

The in vitro results showed that imprinted PDMS kept LESC cells in a state of stemness with high expression of ∆NP63 and ABCG2 genes (stemness-associated genes) compared to the other two groups and low Cytokeratin-3 and -12 expression (as differentiation-related genes). In vivo studies showed a more significant number of cells and the expression of the ABCG2 gene in the imprinted PDMS group. In contrast, higher expressions of the ∆Np63 gene and more stratification were observed in the control group (no treatment). Histological studies showed that the imprinted PDMS group had normal morphology with fully organized collagens. 

The results of LESC cultured on imprinted PDMS suggested that LESC cell imprinting could be an excellent substrate for LESC expansion and preserve their stemness for cell therapy.

Deltamethrin (DLM) is a widely used insecticide in agriculture; however, exposure to it can lead to serious health problems. This study aimed to evaluate the protective effects of hesperidin (HSP), a natural antioxidant, against DLM-induced liver toxicity.

Thirty-two male Wistar Albino rats (250–300 g, 4 months old) were divided into four groups. The control group received 1 ml of corn oil via oral gavage for 30 days. The DLM group received 1.28 mg/kg DLM in corn oil for 30 days. The DLM+HSP 100 mg/kg and DLM+HSP 300 mg/kg groups received 1.28 mg/kg DLM followed by 100 mg/kg or 300 mg/kg HSP in distilled water, respectively, 30 min after DLM administration for 30 days. Liver tissues were examined histopathologically. Masson’s trichrome staining and PCR assessed fibrosis. Caspase 3 and 9 expressions in liver tissues were determined by immunohistochemistry and PCR. Biochemical analyses were conducted on serum samples.

HSP supplementation led to a dose-dependent decrease in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. DLM exposure decreased antioxidant capacity, while HSP supplementation increased it dose-dependently. Histopathological evaluations showed increased liver damage in the DLM group, while HSP administration reduced liver toxicity. Masson’s trichrome staining and analysis of collagen I (COL1A1) and collagen III (COL3A1) gene expression revealed increased fibrosis in the DLM group, which was attenuated with HSP treatment.

The potential prevention of DLM-induced liver toxicity and apoptosis by HSP may be an alternative protective strategy.

Premature ovarian failure (POF) is a common cause of women’s infertility. Cyclophosphamide (CP) is one of the most important gonadotoxic agents that lead to POF. This study aimed to evaluate the potential therapeutic effect of chitosan nanoparticles loaded with platelet lysate (PLCH NPs) on in vitro fertilization (IVF) outcome and early embryo development in a model of CP-induced POF.

In this study, synthesized nanoparticles were developed based on the ionic gelation method and characterized by the physicochemical properties of particle size, zeta potential, FTIR, microscopic studies, drug encapsulation, and in vitro drug release. Sixty female BALB/c mice were randomly assigned into six groups: Control, sham, POF, POF-PL, POF-CH, and POF-PLCH. Finally, the PLCH NPs were examined for their therapeutic potential against CP-induced POF by evaluating Anti-Müllerian hormone (AMH) levels, malondialdehyde (MDA) levels, total anti-oxidant capacity (TAC), fertilization rate, and embryo development.

The results showed that PL’s in vitro release profile has a sustained release pattern. The treatment of PLCH NPs in POF mice increased AMH and TAC and decreased MDA levels compared to the control group (P<0.05). The mean number of retrieved oocytes, cleavage and fertilization rates, and blastocyst formation rates were significantly increased in the POF-PLCH group compared with the POF group (P<0.05).

This study proposes a novel PLCH NP-mediated combination therapy for the clinical treatment of POF and shows that PLCH NPs are superior to free PL in terms of effectiveness.

Schisandrin B (SchB), extracted from Schisandra chinensis, has antimicrobial and anti-inflammatory effects. The study aimed to investigate SchB’s possible defense against angiotensin II (Ang II)-infused cardiac fibrosis and its molecular processes.

An equivalent volume of saline or Ang II (2.0 mg/kg/day, HY-13948, MedChemExpress) was administered subcutaneously to male C57BL/6 mice aged between 8 and 10 weeks. SchB (30 mg/kg/day, HY-N0089, MedChemExpress) was given via intraperitoneal injection two hours before Ang II infusion for 28 days. Comprehensive morphological, histological, and biochemical analyses were conducted. We evaluated the mRNA and protein expression levels using western blot and RT-qPCR techniques.

SchB treatment improves heart disease in Ang II-induced mice. SchB markedly lowered serum levels of cardiac fibrosis-related markers, including cTnI, cTnT, ANP, and BNP. In addition, SchB elevated sirtuin 1 (SIRT1) expression while reducing α-SMA, TGF-β1, collagen I, collagen III, and CTGF in vivo. Furthermore, SchB inhibited the migration of Ang II-infused rat cardiac fibroblasts. SchB increased SIRT1 expression while decreasing TGF-β1, α-SMA, collagen I, and collagen III, whereas EX-527, an inhibitor of SIRT1, recovered their activities in vitro. Furthermore, SchB elevated SIRT1 expression while lowering the expressions of p-PI3K (p85, Tyr458) and p-Akt (Ser473) proteins.

Our results suggest that SchB regulates the SIRT1/PI3K/Akt pathway to prevent Ang II-infused cardiac fibrosis.

Troxerutin (TRX) is a natural bioflavonoid with several medicinal properties. We assessed its protective effect on carbon tetrachloride-related hepatorenal damage in male mice.

Male mice were assigned to five groups: Control, TRX, CCL4, CCL4 + TRX 75 mg/kg, CCL4 + TRX 150 mg/kg. Animals received oral TRX (75 and 150 mg/kg) daily for four weeks. After treatments, serum liver enzymes aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Serum blood urine nitrogen (BUN), and creatinine (Cr) levels were assessed. Malondialdehyde (MDA, the primary lipid peroxidation product), activity of anti-oxidant enzymes glutathione peroxidase (GPX), superoxide dismutase (SOD), and total anti-oxidant capacity (TAC) were determined. Using the immunoblotting method, Bax, Bcl-2, cleaved caspase-3, and cytochrome-c protein concentrations were evaluated in the kidney and liver tissues. The Hematoxylin and Eosin (H&E) staining were used to assess the kidney and liver histopathological changes.

CCl4 caused a significant increase in the concentrations of liver and kidney indices such as ALT (P<0.05), Cr (P<0.01), AST (P<0.001), and BUN (P<0.001). Furthermore, CCl4 significantly increased the MDA level in the liver (P<0.01) and kidney (P<0.001) tissues while decreasing anti-oxidant status. TRX could significantly decrease ALT, AST, Cr, BUN, and MDA concentrations and increase SOD, GPx, and TAC activities in comparison to the CCl4-damaged control group. In addition, TRX caused an attenuation in the pro and anti-apoptotic markers in the kidney and liver tissues. 

TRX displayed liver and kidney protection, possibly by its free radical scavenging and anti-oxidant effects.