Iranian Journal of Basic Medical Sciences
Volume:26 Issue: 9, Sep 2023

Hygrophila schulli which is known as “Neermulli’’ in the vernacular is an herbaceous plant native to Sri Lanka. Ancient medicinal literature suggests the use of H. schulli whole plant or its parts for the treatment of different communicable and non-communicable diseases including diabetes mellitus and tuberculosis. Active constituents and secondary metabolites including alkaloids, tannins, steroids, proteins, flavonoids, and glycosides are identified to possess antimicrobial, antitumor, antioxidant, hepatoprotective, anthelmintic, nephroprotective, antidiabetic, anticataract, anti-inflammatory, anti-nociceptive, hematopoietic, diuretic, antiurolithiatic, antipyretic, neuroprotection, and anti-endotoxin activities. In this review, we reviewed clinical studies, patents, and analytical studies from the earliest found examples from 1886 to the end of 2021. We critically analyzed and attempt to summarize the information based on bioactivities and chemical composition of H. schulli plant extracts which will be of future use for researchers in this field.

Cancer is a disease characterized by abnormal and uncontrolled growth of cells, leading to invasion and metastasis to other tissues. Chemotherapy drugs are some of the primary treatments for cancer, which could detrimentally affect the cancer cells by various molecular mechanisms like apoptosis and cell cycle arrest. These treatment lines have always aligned with side effects and drug resistance. Due to their anticancer effects, medicinal herbs and their active derivative compounds are being profoundly used as complementary treatments for cancer. Many studies have shown that herbal ingredients exert antitumor activities and immune-modulation effects and have fewer side effects. On the other hand, combining phytotherapy and chemotherapy, with their synergistic effects, has gained much attention across the medical community. This review article discussed the therapeutic effects of essential herbal active ingredients combined with chemotherapeutic drugs in cancer therapy. To write this article, PubMed and Scopus database were searched with the keywords “Cancer,” “Combination,” “Herbal,” “Traditional,” and “Natural.” After applying inclusion/exclusion criteria, 110 articles were considered. The study shows the anticancer effects of the active herbal ingredients by inducing apoptosis and cell cycle arrest in cancer cells, especially with a chemotherapeutic agent. This study also indicates that herbal compounds can reduce side effects and dosage, potentiate anticancer responses, and sensitize cancer cells to chemotherapy drugs.

Pulmonary fibrosis (PF) is the end stage of severe lung diseases, in which the lung parenchyma is replaced by fibrous scar tissue. The result is a remarkable reduction in pulmonary compliance, which may lead to respiratory failure and even death. Idiopathic pulmonary fibrosis (IPF) is the most prevalent form of PF, with no reasonable etiology. However, some factors are believed to be behind the etiology of PF, including prolonged administration of several medications (e.g., bleomycin and amiodarone), environmental contaminant exposure (e.g., gases, asbestos, and silica), and certain systemic diseases (e.g., systemic lupus erythematosus). Despite significant developments in the diagnostic approach to PF in the last few years, efforts to find more effective treatments remain challenging. With their immunomodulatory, anti-inflammatory, and anti-fibrotic properties, stem cells may provide a promising approach for treating a broad spectrum of fibrotic conditions. However, they may lose their biological functions after long-term in vitro culture or exposure to harsh in vivo situations. To overcome these limitations, numerous modification techniques, such as genetic modification, preconditioning, and optimization of cultivation methods for stem cell therapy, have been adopted. Herein, we summarize the previous investigations that have been designed to assess the effects of stem cell preconditioning or genetic modification on the regenerative capacity of stem cells in PF.

Seizure is a prevalent disorder reflected by powerful and sudden activity of neural networks in the brain that leads to tonic-clonic attacks. These signs may be due to an increase in excitatory/inhibitory neurotransmitters ratio. So, the current experiment aimed to examine the seizure and neurobehavioral parameters, as well as the hippocampus local electroencephalogram (EEG) after seizure with and without sesamin pretreatment.    Sesamin (15, 30, and 60 mg/kg/5 ml, intraperitoneal or IP, vehicle: dimethyl sulfoxide or DMSO, for 3 days) was administrated before pentylenetetrazol (PTZ) (60 mg/kg/10 ml, IP, vehicle: saline), which induces acute seizure in adult male Wistar rats (230 ± 20 g, six weeks old). Different phases of seizures (score, latency, duration, and frequency), behavioral parameters (passive avoidance memory, anxiety, and locomotor activity), and hippocampus local EEG were evaluated after the injections. At the end of the experiments, oxidative stress markers plus gene expression of phosphoinositide 3-kinase/protein kinase B or PI3K/Akt mRNA were measured in the hippocampus.   Pretreatment with sesamin (30 mg/kg) could significantly decrease seizure scores and oxidative stress in the hippocampus. PTZ injection induced EEG deficits and neurobehavioral impairments which were significantly decreased by sesamin, especially in Beta, Theta, and delta EEG waves.  Also, the expression of PI3K/Akt significantly increased in the sesamin (30 mg/kg) group in comparison with the PTZ group.  Sesamin could prevent seizure attacks and neurobehavioral and EEG deficits induced by pentylenetetrazol, probably through the PI3K/Akt signaling pathway.

 Acrylamide (ACR) is an environmental contaminant and neurotoxin. Telmisartan is an AT1 blocker that has neuroprotective properties basically through its anti-oxidant effect. The effect of telmisartan on ACR-induced neurotoxicity was investigated in this study.  Male Wistar rats were randomly assigned to eight groups (n=6): 1:Control (normal saline), 2:ACR (50 mg/kg, 11 days, IP), 3:ACR+vitamin E (200 mg/kg, every other day, 11 days), 4-6:ACR+telmisartan (0.6, 1.25, and 2.5 mg/kg, 11 days, IP), 7:ACR+telmisartan (0.6 mg/kg, days 3–11), 8:Telmisartan (2.5 mg/kg, 11 days). The behavioral test and blood pressure were assessed after 11 days. Then, the levels of MDA and GSH in brain tissue were measured. The MTT assay was used to evaluate the effect of telmisartan on ACR-induced cytotoxicity. Exposing PC12 cells to ACR decreased cell viability versus the control group. Pretreating PC12 cells with telmisartan (0.0125, 0.025 µM) enhanced cell viability compared with the ACR group. Compared with control samples, ACR significantly caused motor impairment, elevated MDA, and reduced GSH levels. Locomotor abnormalities were significantly ameliorated by telmisartan (0.6, 1.25 mg/kg, 11 days) and vitamin E versus the ACR group. Receiving telmisartan (0.6, 1.25, and 2.5 mg/kg) and vitamin E along with ACR decreased MDA levels and enhanced GSH content compared with the ACR group.  There was no significant difference in animal blood pressure between the groups. Oxidative stress has a chief role in the neurotoxicity of ACR. Telmisartan (in doses that do not affect blood pressure) ameliorated ACR-induced toxicity by inhibiting oxidative stress.

The present research aimed to identify the functional effects and underlying mechanisms of metformin on the rat thoracic aorta. Thoracic aorta segments of Wistar Albino rats were put in the chambers of an isolated tissue bath system. The resting tone was adjusted to 1 g. Following the equilibration time, potassium chloride or phenylephrine was used to contract the vascular segments. The vessel segments were cumulatively treated with metformin (10-7–10-3 M) when a steady contraction was achieved. The described experimental approach was repeated after incubations with signaling pathway inhibitors and selective blockers of potassium channels to identify the effect mechanisms of metformin. Metformin had a potent vasorelaxant effect in a concentration-dependent way (P<0.001). After the endothelium was removed, the vasorelaxant effect level of metformin was significantly reduced. The level of vasorelaxant effect of metformin was increased by the maintenance of perivascular adipose tissue. Following administrations of L-NAME, methylene blue, compound C, BIM-I, and potassium channel blockers, the level of vasodilatory action of metformin was significantly reduced (P<0.001). According to the results of this investigation, metformin significantly relaxes the thoracic aorta segments of rats. Metformin-mediated vasorelaxation involves the activation of numerous subtypes of potassium channels, including BKCa, IKCa, Kv, Kir, and K2p channels, as well as endothelium-dependent processes, including AMPK and eNOS/NO/sGS signaling pathways. Moreover, metformin-induced vasorelaxation is mediated through PVAT activation and the PKC signaling pathway.

This study examined the effects of melatonin treatment on steroidogenesis dysfunction and testosterone impairment, following CoCl2-induced hypoxia in TM3 Leydig cells.  The TM3 cells were divided into four groups. The first group received no treatment. The MLT group was treated with a concentration of 1 mM melatonin. In the CoCl2 group, 0.2 mM CoCl2 was added to the medium to induce Hif1α overexpression. The MLT+CoCl2 group received 0.2 mM CoCl2 and 1 mM melatonin. After 24 hr treatment, the cells and supernatants were collected and used for further determination. The MTT assay was performed to estimate the decrease in cell viability throughout the CoCl2 and melatonin treatment. The mRNA and the protein levels were evaluated using Real-time PCR and Western blot analysis. The ELISA assay kit was used to detect the testosterone content. CoCl2 treatment caused Hif1α overexpression in TM3 Leydig cells. Moreover, CoCl2 treatment of these cells led to considerable downregulation of Star, Hsd3b1, and Gata4 well as Mtnr1a and Mtnr1b mRNA/protein expression coupled with testosterone content repression in the cell culture medium. Melatonin administration in CoCl2 -treated cells decreased Hif1α mRNA/protein expression, but had no significant effect on Star, Hsd3b1, Gata4, Mtnr1a mRNA/protein expression, and the testosterone level in the cell culture medium. Melatonin caused recovery of decrease in the Mtnr1b gene and protein expression.  There was no significant effect on steroidogenesis-related genes, proteins, and testosterone synthesis in the absence of gonadotropin treatment plus melatonin following CoCl2-induced hypoxia in TM3 Leydig cells.

Liver fibrosis is a common liver disease caused by chronic liver damage. However, there are currently no approved drugs available to treat it. Therefore, the therapeutic effect of indirubin on liver fibrosis was evaluated. This study investigated the protective effect and related molecular mechanism of indirubin against CCl4-induced liver fibrosis in mice. We first detected the effect of indirubin on liver fibrosis in mice (n=8 per group, 32 mice total) by ELISA, HE, and Masson staining. Subsequently, the proliferation of activated HSCs was detected by MTT and EdU. Finally, the changes of related proteins and signaling pathways in mice treated with indirubin were investigated by qRT-PCR and Western blot. One-way ANOVA or two-tailed student’s t-test was used for comparison between groups. Firstly, we found that indirubin (25 mg/kg) therapy could attenuate liver injury and significantly down-regulate α-SMA (P=0.0038) and collagen 1 (P=0.0057) in the liver using CCl4-induced liver fibrosis in mice. Secondly, we showed that indirubin (25 μM) could significantly inhibit hepatic stellate cell (HSC) trans-differentiation into myofibroblasts and proliferation (P=0.0063) in HSC-T6 cells treated by TGF-β. Finally, we showed that indirubin could greatly reduce the protein levels of p-Smad2/3, p38, p-ERK, and p-JNK in vivo and in vitro. Our results suggested that indirubin alleviated liver fibrosis and HSC activation mainly through TGF-β-mediated signaling pathways in vivo and in vitro. In conclusion, our data showed that indirubin could be a promising clinical therapeutic drug for the prevention and treatment of liver fibrosis.

Intracerebroventricular (ICV) injections of mesenchymal stem cells (MSCs) may improve the function and structure of blood-brain barrier (BBB), possibly by preserving the BBB integrity. This study examined the impact of Wharton’s jelly (WJ)-MSCs on cognitive dysfunction and BBB disruption following a protracted hypoxic state. Twenty-four male Wistar rats were randomly studied in four groups: Control (Co): Healthy animals, Sham (Sh): Rats were placed in the cage without hypoxia induction and with ICV injection of vehicle, Hypoxic (Hx)+vehicle: Hypoxic rats with ICV injection of vehicle (5 μl of PBS), and Hx+MSCs: Hypoxic rats with ICV injection of MSCs. Spatial learning and memory were evaluated one week after WJ-MSCs injection, and then animals were sacrificed for molecular research. Hypoxia increased latency and lowered the time and distance required reaching the target quarter, according to the findings. Furthermore, hypoxic rats had lower gene expression and protein levels of hippocampus vascular endothelial (VE)-cadherin, claudin 5, and tricellulin gene expression than Co and Sh animals (P<0.05). Finally, administering WJ-MSCs after long-term hypoxia effectively reversed the cognitive deficits and prevented the BBB breakdown via the upregulation of VE-cadherin, claudin 5, and tricellulin genes (P<0.05). These findings suggest that prolonged hypoxia induces spatial learning and memory dysfunction and increases BBB disruption, the potential mechanism of which might be via reducing VE-cadherin, claudin 5, and tricellulin genes. Hence, appropriate treatment with WJ-MSCs could reverse ischemia adverse effects and protect the BBB integrity following prolonged hypoxia.

Immunotherapy has changed the landscape of oncology over the last decade and has become a standard of care for various cancers. Researchers previously demonstrated that B16-F10 melanoma in C57Bl6 mice is resistant to immune checkpoint inhibitors. The goal of this study was to investigate how anti-PD1 antibodies functioned in combination with a new antimicrobial peptide (AMP) called moronecidin-like peptide (MLP). We studied the cytotoxic effect of AMP on the B10-F16 tumor cell line with the MTT experiment. The necrotic and apoptotic cells were determined by Presidium iodide (PI) /Annexin V staining and flow cytometry-based methods. Mice were inoculated subcutaneously with B10-F16 tumor cells in the mammary gland. Each group was sacrificed two weeks after the last injection to examine tumor-specific CD8+ T cell responses using flow cytometry.  Annexin V and PI staining assay revealed that MPL significantly induces apoptosis in B16F10 cells. It should be noted that MLP in combination with anti-PD-1 improved antigen-specific T-cell responses synergistically (P=0.01) when compared with respective monotherapy. Furthermore, when compared with the respective monotherapies, combination therapy significantly controlled tumor growth in B10-F16 tumor cells and increased survival rate. Treatments with anti-PD-1 inhibitors alone had only a minor effect on tumor size, whereas combination therapy resulted in significant tumor growth control and increased animal survival. MLP therapy combined with anti-PD-1 antibody improves anti-tumor immune response in addition to inducing tumor cell apoptosis. As a result, the evidence suggests that intratumoral injection of MPL can improve anti-PD-1 antibody antitumor response.

Febrile seizures (FS) are the most common neurological disorder at a young age in humans. Animal models of hyperthermia-induced seizures provide a tool to investigate the underlying mechanisms of FS related to epilepsy development and its co-morbidities. The present study investigates the alterations in monoamine neurotransmitters in two brain areas: the cortex and the hippo-campus in animals subjected to prolonged FS at their immature age.  Experimental animals were divided into three groups: cage-control group (NHT-NFS), positive hyperthermic control group (HT-NFS), and the hyperthermia-induced febrile seizure group (HT-FS). Each group was further subdivided into young (Y) and adult (A) groups.  There were significant changes in the cortical and hippocampal serotonin neurotransmitters that were persistent until adulthood. However, the changes in the two other neurotransmitters, norepinephrine and dopamine, were transient and have been recovered in adulthood.  The present study sheds more light on the importance of monoamine neurotransmitters in epileptogenesis following FS.

Rosa × damascena Herrm. belonging to the Rosaceae family has demonstrated anti-inflammatory and anti-oxidant effects previously. Excessive production of free radicals and activation of tyrosinase enzyme caused by UV induces excessive concentration of melanin pigment and skin spots in the long term. Therefore, finding natural sources with anti-oxidant and antityrosinase effects helps to regulate the melanogenesis process.  In the current research, we investigated the antimelanogenic, anti-oxidant, and anti-tyrosinase effects of its essential oil, methanol extract (MeOH), and different fractions including n-hexane, dichloromethane (CH2Cl2), n-butanol (BuOH), ethyl acetate (EtOAc), and H2O of R. × damascena in B16F10 cell line. For this purpose, impacts of extracts and essential oil of R. × damascena were investigated on cell viability, cellular tyrosinase, melanin content, mushroom tyrosinase, reactive oxygen species (ROS) production, as well as the amount of tyrosinase protein in the B16F10 murine melanoma cell line. Essential oil, MeOH, and different fractions of R. × damascena were not cytotoxic on B16F10 cells. However, they had significant reducing effects on mushroom tyrosinase activity, melanin content, and ROS production. Also, there is a significant decrease in tyrosinase protein levels at 200 µg/ml but not at other concentrations.  Therefore, the essential oil, MeOH, and different fractions of R. × damascena had promising antimelanogenic activity via repression of mushroom tyrosinase activity and ROS production.

DNA is one of the targets of cancer-therapeutic small molecules. Cisplatin, a DNA intercalator, is one of the first-line drugs in the cancer chemo regimen which comes with health-compromising side effects during chemotherapy. The synergistic effect of natural molecules with cisplatin can help to potentiate its anti-cancer efficacy and decrease its negative effect on health. Here, we report the interaction of cisplatin with calf thymus-DNA (ct-DNA) in combination with natural molecules like apocarotenoids which are reported for their therapeutic properties. The combinatorial effect of apocarotenoids on ct-DNA was explored through various biophysical techniques such as UV-Visible spectroscopy, circular dichroism studies, DNA melt curve analysis, viscosity measurements, and an in vitro study in MCF-7 cells by cell cycle analysis. UV-Visible spectroscopy studies suggest apocarotenoids and their combination shows a non-intercalative mode of binding. Circular dichroism analysis showed no major changes in DNA form during the interaction of DNA with apocarotenoids and their respective combinations with cisplatin, which is suggestive of the groove-binding mode of apocarotenoids. DNA melt curve analysis showed a decrease in the intensity of the fluorescence for apocarotenoids with cisplatin which indicates the possibility of DNA interaction through groove binding. Viscosity studies suggested a groove binding mode of interaction of ct-DNA with apocarotenoids and their combination as there was minimal change in the viscosity measurements. The in vitro analysis exhibits that the apocarotenoids and their combination have a considerable effect on DNA synthesis. This study provides a better perspective on the possible mode of interaction between ct-DNA and natural molecules along with cisplatin.

Lithium and quetiapine are administered simultaneously as a treatment for bipolar disorder. The concurrent use of these two drugs has been observed to affect the neurobiological mechanisms underlying learning and memory. To clarify the precise mechanisms involved, we evaluated the possible role of the dorsal hippocampal CA1 NMDA receptors in the interactive effects of lithium and quetiapine in memory consolidation.  The dorsal hippocampal CA1 regions of adult male Wistar rats were bilaterally cannulated, and a single-trial step-through inhibitory avoidance apparatus was used to assess memory consolidation.  Post-training administration of certain doses of lithium (20, 30, and 40 mg/kg, IP) diminished memory consolidation. Post-training administration of higher doses of quetiapine (5, 10, and 20 mg/kg, IP) augmented memory consolidation. Post-training administration of certain doses of quetiapine (2.5, 5, 10, and 20 mg/kg) dose-dependently restored lithium-induced memory impairment. Post-training microinjection of ineffective doses of the NMDA (10-5 and 10-4 µg/rat, intra-CA1) plus an ineffective dose of quetiapine (2.5 mg/kg) restored the lithium-induced memory impairment. Post-training microinjection of ineffective doses of the noncompetitive NMDA receptor antagonist, MK-801 (0.0625 and 0.0125 μg/rat, intra-CA1), diminished the quetiapine-induced (10 mg/kg) memory improvement in lithium-induced memory impairment. These findings suggest a functional interaction between lithium and quetiapine through hippocampal CA1 NMDA receptor mechanisms in memory consolidation.

Sodium arsenite (SA) exposure is toxic to the body. Zingerone (ZNG) is a flavonoid with many biological properties found naturally in honey and plants. This study aimed to determine the effects of ZNG on SA-induced rat lung toxicity. Thirty-five male Sprague rats were divided into Control, SA, ZNG, SA+ZNG25, and SA+ZNG50 groups (n=7). SA 10 mg/kg and ZNG were administered at two doses (25 and 50 mg/kg) (orally, 14 days). Analysis of oxidative stress, inflammation damage, apoptosis damage, and autophagic damage markers in lung tissue were determined by biochemical and histological methods.  The administration of ZNG reduced oxidative stress by increasing SA-induced decreased antioxidant enzyme activities, increasing Nrf-2, HO-1, and NQO1, and decreasing MDA level. ZNG administration reduced inflammation marker levels. Anti-apoptotic Bcl-2 increased and apoptotic Bax and Caspase-3 decreased with ZNG. ZNG promoted the regression of autophagy by reducing Beclin-1, LC3A, and LC3B levels. Evaluating all data showed that SA caused toxic damage to lung tissue by increasing inflammation, apoptosis, autophagy, and oxidant levels, whereas ZNG had a protective effect by reducing this damage.