Selenium suppressed growth of Ehrlich solid tumor and improved health of tumor-bearing mice.

Selenium (Se) is an important micronutritional biomolecule in cancer therapy. The current work evaluated the anticancer effect of Se and its ability to improve health of mice with solid Ehrlich carcinoma implanted subcutaneously. Four groups of five female BALB/c mice each were assembled. Ehrlich tumor cells were engrafted into two of them, either with or without Se therapy. The other groups served as control groups, either with or without Se treatment. Se treatment resulted in a notable decrease in both tumor volume and animal body mass in tumor-bearing mice. Treatment with Se markedly increased oxidative stress in tumor while ameliorating oxidative stress in sera of tumors-bearing mice. Similarly, treatment with Se resulted in downregulation of inflammatory cytokines (TNF-α and IL-6) while increasing IL-10 in serum of tumor-bearing mice. Conversely, selenium increased TNF- α and IL-6 and decreased IL-10 in tumor suggesting disruption of tumor immunity. The increased oxidative stress and inflammation in tumor tissue dysregulated cell cycle phases with increase apoptotic tumor cells population in G0/G1 phase. This is supported by the increased levels apoptotic regulating proteins (Bax and caspase-3 and P-53) while decreasing Bcl-2 in the tumor tissue. Treatment with Se also resulted in increased comet parameters indicating DNA damage of tumor cells. Histopathological examination revealed a significant decrease in a number of neoplastic cells within tumor of mice that treated with Se. In conclusion, these findings suggest that Se therapy significantly suppressed solid tumor proliferation and growth while mitigating the health status of tumor-bearing mice.

Melatonin protected against kidney impairment induced by 5-fluorouracil in mice.

The utility of 5-fluorouracil (5-FU) as a successful chemotherapeutic drug for several cancers is limited by the induction of kidney injury and dysfunction due to redox imbalance, inflammation, and apoptosis. Meanwhile, melatonin (MLT) is a potent antioxidant and anti-inflammatory natural compound with a wide safety range. The current study aimed to investigate MLT's protective effect against 5-FU-induced kidney impairment. Male mice were given multiple doses of 5-FU at 25 and 100 mg/kg, as well as MLT at 20 mg/kg. MLT treatment alleviated the toxic effect of 5-FU by normalizing blood urea and creatinine levels and preserving the histological structure, indicating MLT's nephroprotective ability. This is accompanied by body weight maintenance, an increase in survival percentage, and preserved hematological parameters in comparison to the 5-FU-treated mice. MLT's renoprotective effect was explained by improvements in C-reactive protein, IL-6, and caspase-3 in kidney tissue, indicating MLT's anti-inflammatory and antiapoptotic ability. Furthermore, MLT inhibited 5-FU-induced lipid peroxidation by maintaining the activity of superoxide dismutase and catalase, as well as glutathione levels in kidney tissue from mice treated with both doses of 5-FU. The current findings show that MLT has a novel protective effect against 5-FU-induced renal injury and renal impairment.

Angiotensin converting enzyme 2 gene expression and markers of oxidative stress are correlated with disease severity in patients with COVID-19.

BACKGROUND: Oxidative stress is thought to play a significant role in the pathogenesis and severity of COVID-19. Additionally, angiotensin converting enzyme 2 (ACE2) expression may predict the severity and clinical course of COVID-19. Accordingly, the aim of the present study was to evaluate the association of oxidative stress and ACE2 expression with the clinical severity in patients with COVID-19. METHODS AND RESULTS: The present study comprised 40 patients with COVID-19 and 40 matched healthy controls, recruited between September 2021 and March 2022. ACE 2 expression levels were measured using Hera plus SYBR Green qPCR kits with GAPDH used as an internal control. Serum melatonin (MLT) levels, serum malondialdehyde (MDA) levels, and total antioxidant capacity (TAC) were estimated using ELISA. The correlations between the levels of the studied markers and clinical indicators of disease severity were evaluated. Significantly, lower expression of ACE2 was observed in COVID-19 patients compared to controls. Patients with COVID-19 had lower serum levels of TAC and MLT but higher serum levels of MDA compared to normal controls. Serum MDA levels were correlated with diastolic blood pressure (DBP), Glasgow coma scale (GCS) scores, and serum potassium levels. Serum MLT levels were positively correlated with DBP, mean arterial pressure (MAP), respiratory rate, and serum potassium levels. TAC was correlated with GCS, mean platelet volume, and serum creatinine levels. Serum MLT levels were significantly lower in patients treated with remdesivir and inotropes. Receiver operating characteristic curve analysis demonstrates that all markers had utility in discriminating COVID-19 patients from healthy controls. CONCLUSIONS: Increased oxidative stress and increased ACE2 expression were correlated with disease severity and poor outcomes in hospitalized patients with COVID-19 in the present study. Melatonin supplementation may provide a utility as an adjuvant therapy in decreasing disease severity and death in COVID-19 patients.

Utility of melatonin in mitigating ionizing radiation-induced testis injury through synergistic interdependence of its biological properties.

BACKGROUND: Ionizing radiations (IR) have widespread useful applications in our daily life; however, they have unfavorable effects on reproductive health. Maintaining testicular health following IR exposure is an important requirement for reproductive potential. The current study explored the role of melatonin (MLT) in mitigating IR-induced injury in young adult rat testis. METHODS: Rats were given daily MLT (25 mg/kg) for 3 and 14 days after receiving 4 Gy γ-radiation. RESULTS: Serum MLT levels and other antioxidants, including glutathione content, and the activity of glutathione peroxidase and glutathione reductase in the testis of the irradiated rats were remarkably maintained by MLT administration in irradiated rats. Hence, the hydrogen peroxide level declined with remarkably reduced formation of oxidative stress markers, 4-hydroxynonenal, and 8-Hydroxy-2'-deoxyguanosine in the testis of irradiated animals after MLT administration. The redox status improvement caused a remarkable regression of proapoptotic protein (p53, Cyto-c, and caspase-3) in the testis and improved inflammatory cytokines (CRP and IL-6), and anti-inflammatory cytokine (interleukin IL-10) in serum. This is associated with restoration of disturbed sex hormonal balance, androgen receptor upregulation, and testicular cell proliferation activity in irradiated rats, explaining the improvement of sperm parameters (count, motility, viability, and deformation). Consequently, spermatogenic cell depletion and decreased seminiferous tubule diameter and perimeter were attenuated by MLT treatment post irradiation. Moreover, the testis of irradiated-MLT-treated rats showed well-organized histological architecture and normal sperm morphology. CONCLUSIONS: These results show that radiation-induced testicular injury is mitigated following IR exposure through synergistic interdependence between the antioxidant, anti-inflammatory, anti-apoptotic, and anti-DNA damage actions of MLT.

Epigallocatechin-3-gallate Enhances Cognitive and Memory Performance and Protects Against Brain Injury in Methionine-induced Hyperhomocysteinemia Through Interdependent Molecular Pathways.

Brain injury and cognitive impairment are major health issues associated with neurodegenerative diseases in young and aged persons worldwide. Epigallocatechin-3-gallate (EGCG) was studied for its ability to protect against methionine (Met)-induced brain damage and cognitive dysfunction. Male mice were given Met-supplemented in drinking water to produce hyperhomocysteinemia (HHcy)-induced animals. EGCG was administered daily concurrently with Met by gavage. EGCG attenuated the rise in homocysteine levels in the plasma and the formation of amyloid-ß and tau protein in the brain. Cognitive and memory impairment in HHcy-induced mice were significantly improved by EGCG administration. These results were associated with improvement in glutamate and gamma-aminobutyric acid levels in the brain. EGCG maintained the levels of glutathione and the activity of antioxidant enzymes in the brain. As a result of the reduction of oxidative stress, EGCG protected against DNA damage in Met-treated mice. Moreover, maintaining the redox balance significantly ameliorated neuroinflammation evidenced by the normalization of IL-1ß, IL-6, tumor necrosis factor α, C-reactive protein, and IL-13 in the same animals. The decreases in both oxidative stress and inflammatory cytokines were significantly associated with upregulation of the antiapoptotic Bcl-2 protein and downregulation of the proapoptotic protein Bax, caspases 3 and 9, and p53 compared with Met-treated animals, indicating a diminution of neuronal apoptosis. These effects reflect and explain the improvement in histopathological alterations in the hippocampus of Met-treated mice. In conclusion, the beneficial effects of EGCG may be due to interconnecting pathways, including modulation of redox balance, amelioration of inflammation, and regulation of antiapoptotic proteins.

Proanthocyanidins attenuated liver damage and suppressed fibrosis in CCl4-treated rats.

Liver damage and fibrosis are serious health problems without effective treatment. Proanthocyanidins (PAs) are flavonoids with several biological effects. We investigated the potential anti-fibrotic effect of proanthocyanidins on carbon tetrachloride (CCl4)-induced liver injury and fibrosis. Liver fibrosis was induced by oral administration of CCl4 three times a week for 5 and 9 weeks. PAs were daily administered in a dose of 500 mg/kg bw. Animals were divided into five groups: control groups, olive oil-treated group, Pas-treated group, CCl4-treated animals, and PAs + CCl4-treated rats. CCl4 and PAs were administered by gavage. Administration of CCl4 caused a significant elevation in alanine aminotransferase and aspartate aminotransferase activities, the concentration of alpha-2-macroglobulin, and bilirubin concentration. In addition, the protein and apolipoprotein contents were significantly decreased in the serum of CCl4-treated rats. These results were accompanied by histopathological alterations and increased inflammation, apoptosis, and DNA damage. Treatment with PAs caused remarkable regression of fibrosis and alpha-2-macroglobulin with improvement in histological characteristics of the liver after 5 and 9 weeks of intoxication. PAs could also maintain redox balance, evidenced by the prevention of lipid peroxidation and mitigation of the decrease in antioxidants. Treatment of intoxicated rats with PAs resulted in a significant decline in pro-inflammatory cytokines, including IL-6, IL-1ß, and TNF-α in serum. This is associated with a remarkable decrease in apoptosis of hepatic cells shown by decreased levels of Bax, caspase-3, and -9, with increased Bcl-2. The protective effect of PAs was also evident by protecting DNA integrity in the intoxicated rats. PAs suppressed hepatic fibrosis, improved liver function and structure via modulating the interdependence between oxidative stress, inflammation, apoptosis, and DNA integrity in CCl4-treated rats.

Punicalagin protects against the development of pancreatic injury and insulitis in rats with induced T1DM by reducing inflammation and oxidative stress.

Pancreatic inflammation and oxidative damage remain major concerns in type 1 diabetes mellitus (T1DM). Punicalagin, a major polyphenol in pomegranates, exhibited antioxidant and protective effects on several organs in case of T1DM; however, no study has yet explored the protective effects of punicalagin on the pancreas and islets of Langerhans. T1DM was induced by injecting 40 mg/kg streptozotocin (STZ) intraperitoneally. Punicalagin (1 mg/kg ip) was injected daily for 15 days after T1DM induction. In diabetic rats, punicalagin treatment lowered the levels of inflammatory biomarkers (monocyte chemoattractant protein-1 and C-reactive protein) and adhesion molecules (E-selectin, intercellular adhesion molecule, and vascular cell adhesion molecule) while activating myeloperoxidase activity. Treatment of diabetic rats with punicalagin improved glutathione content and superoxide dismutase, catalase, and glutathione peroxidase activities; upregulated serum paraoxonase-1 activity; and prevented the elevation lipid peroxidation and protein oxidation products in the pancreas. Furthermore, punicalagin protected the pancreas against STZ-induced histopathological alterations and increased immune-reactive ß-cells while reducing leucocyte infiltration into the islets of Langerhans, leading to normalized blood glucose and insulin levels. These findings indicated that punicalagin might protect against the development of insulitis in T1DM. In conclusion, punicalagin exerts a strong protective effect on the pancreas against oxidative injury and inflammation in STZ-induced experimental T1DM. The present results recommend punicalagin as a potential adjuvant for reducing diabetes-associated insulitis.

Constant light exposure and/or pinealectomy increases susceptibility to trichloroethylene-induced hepatotoxicity and liver cancer in male mice.

Exposure to light at night, pineal gland impairment, and the environmental pollutant trichloroethylene (TCE) have serious implications for health and contribute to illness, including liver cancer. The adverse effect of the association of continuous exposure to light with decreased melatonin levels and TCE-induced toxicity is not disclosed in target organs. This work explored the role of light and pineal impairment in increasing susceptibility to liver toxicity and cancer upon exposure to TCE. Male albino mice were divided into groups as follows: control group (12-h light/12-h dark cycle), constant light (24-h light), pinealectomized (Pnx) mice, sham surgically treated group, TCE-treated groups subjected to two doses (500 and 1000 mg/kg) at two different light regimens, and combination of Pnx and TCE-treated mice kept at a 12-h light/12-h dark cycle. Melatonin levels were significantly decreased in both Pnx mice and TCE-treated animals at both light regimens. Aspartate transaminase, alanine aminotransferase, activities, and serum bilirubin levels were significantly elevated, whereas albumin levels were markedly decreased in Pnx mice, TCE-treated mice, and the combination group. Histopathological investigations reflected changes in liver function parameters indicating liver injury and induction of cancer. These effects were accompanied by significant increase of the liver cancer biomarker alpha-fetoprotein and the expression of the metastatic markers CD44, TGFß-1, and VEGF, along with increased oxidative stress indicators and inflammatory cytokines (IL-6, IL-1ß, and TNF-α) in both Pnx and TCE-treated mice and the combination group at both light regimens. Taken together, our findings indicated that low melatonin levels, exposure to constant light, and the combination of both factors increases susceptibility to the toxic and carcinogenic effects of TCE on the liver.

Thymax, a gross thymic extract, exerts cell cycle arrest and apoptosis in Ehrlich ascites carcinoma in vivo.

Thymax is a gross thymic extract that has been shown to induce apoptosis in vitro for human breast cancer cells. Here we examine Thymax's ability to induce apoptosis in animals bearing Ehrlich ascites carcinoma (EAC). Thymax was administered six days/week orally to mice (5.45 mg/kg body weight) beginning either 14 days prior to EAC inoculation or 9 days post inoculation; treatment continued for 30 days post inoculation. Pretreatment of mice with Thymax markedly delayed tumor growth and reduced tumor incidence by 38.9%, and tumor volumes relative to untreated controls were suppressed by 90.5% and 55.0% for pre- and post-inoculation groups, respectively. Treatment with Thymax inhibited cellular proliferation by decreasing the expression of tumor markers Ki-67, PCNA, and Cyclin D1 in cancer cells and increasing the expression of p21 and p27. This was associated with the ability of Thymax to arrest the cell cycle of EAC cells in the G0/G1 phase and to induce apoptosis, as indicated by a significant increase in the sub-G1 phase's percentage of hypodiploid cells and further affirmed by DNA fragmentation and Annexin V/propidium iodide staining. In addition, Thymax exerted its apoptotic effect in EAC cancer cells through a mitochondrial-dependent pathway, as evidenced by an increased Bax/Bcl-2 ratio, up-regulation of p53 expression, and activation of caspase-3. We conclude that Thymax supplementation enhances tumor cell demise by arresting the cell cycle and inducing apoptosis. These data suggest that Thymax could be a new adjuvant for breast cancer treatment.

Silymarin inhibits the progression of Ehrlich solid tumor via targeting molecular pathways of cell death, proliferation, angiogenesis, and metastasis in female mice.

BACKGROUND: Plant-derived phytochemicals have been reported to exert anticancer activity. This study investigated the antitumor role of silymarin (Silybum marianum) (SMN) and its molecular targets in Ehrlich solid tumor xenografts in vivo. METHODS AND RESULTS: Female Swiss albino mice were divided into three groups (of five animals each) that were engrafted with Ehrlich tumor (ET) cells with or without SMN treatment. The 3rd groups treated with DMSO only vehicle control group. A significant reduction in animal body mass and tumor volume/weight were observed in xenografted mice treated with SMN. SMN modulated oxidative stress in tumors while enhancing the antioxidant levels in mouse serum. SMN activated both mitochondrial and death receptor-related apoptosis pathways and induced cell cycle arrest, marked by a significant downregulation of cyclin D1 in SMN-treated tumors. Significant decreases in RNA content and protein expression levels of Ki-67 and proliferating cell nuclear antigen were observed in ET cells. Additionally, SMN downregulated vascular endothelial growth factor and nuclear factor-kappa B levels indicating anti-angiogenesis activity of this agent. SMN upregulated the expression of E-cadherin in tumor tissue suggesting, that SMN has potential ability to inhibit metastasis. Tumor tissue from SMN-treated animals showed a remarkable degeneration and reduction in the neoplastic cell density. CONCLUSIONS: The anticancer effect was associated with apparent apoptosis in neoplastic cells with abundance of multifocal necrotic areas. SMN was found to inhibit ET growth via enhancing apoptosis, inhibition of cell division and reduction in angiogenesis in vivo. Hypothetical scheme of SMN antitumor effects (mechanism of signaling) in solid ET in vivo. SMN anticancer effect may be mediated by molecular mediators that affect proliferation, cell cycle activity, apoptotic pathways, angiogenesis, and metastasis.

Melatonin is a potential oncostatic agent to inhibit HepG2 cell proliferation through multiple pathways.

CONTEXT: Chemotherapy is a cornerstone in the treatment of hepatocellular carcinoma (HCC). Melatonin is a pineal hormone that targets various cancers, however, its antitumor pathways are still not fully elucidated. OBJECTIVE: This study investigated melatonin's antitumor molecular mechanisms to inhibit the proliferation of HepG2 cells. MATERIALS AND METHODS: HepG2 Cells were classified into cells without treatment as a control group and cells treated with melatonin (5.4 mmol/L) for 48 h. Proliferating cell nuclear antigen (PCNA) and marker of proliferation Ki-67 were estimated using immunohistochemical analysis. Apoptosis and cell cycle were evaluated using flow cytometric analysis. Apoptotic markers were detected using RT-qPCR assay. Antioxidants and oxidative stress biomarkers were performed using a colorimetric assay. RESULTS: Melatonin produced a remarkable steady decrease in the viability of HepG2 cells at a concentration range between 5-20 mmol/L. Melatonin suppressed cell proliferation in the G2/M phase of the cell cycle (34.97 ± 0.92%) and induced apoptosis (12.43 ± 0.73%) through up-regulating p21 and p53 that was confirmed by the reduction of PCNA and Ki-67 expressions. Additionally, melatonin repressed angiogenesis evidenced by the down-regulation of angiopoietin-2, vascular endothelial growth factor receptor-2 expressions (0.42-fold change), and the level of CD133. Moreover, melatonin augmented the oxidative stress manifested by a marked increase of 4-hydroxynonenal levels with a reduction of glutathione content and superoxide dismutase activity. DISCUSSION AND CONCLUSION: Melatonin inhibits proliferation and angiogenesis and induced apoptosis and oxidative stress in HepG2 cells. These results indicate the oncostatic effectiveness of melatonin on liver cancer.

Utility of melatonin in mitigating ionizing radiation-induced testis injury through synergistic interdependence of its biological properties

BACKGROUND: Ionizing radiations (IR) have widespread useful applications in our daily life; however, they have unfavorable effects on reproductive health. Maintaining testicular health following IR exposure is an important requirement for reproductive potential. The current study explored the role of melatonin (MLT) in mitigating IR-induced injury in young adult rat testis. METHODS: Rats were given daily MLT (25 mg/kg) for 3 and 14 days after receiving 4 Gy γ-radiation. RESULTS: Serum MLT levels and other antioxidants, including glutathione content, and the activity of glutathione peroxidase and glutathione reductase in the testis of the irradiated rats were remarkably maintained by MLT administration in irradiated rats. Hence, the hydrogen peroxide level declined with remarkably reduced formation of oxidative stress markers, 4-hydroxynonenal, and 8-Hydroxy-2'-deoxyguanosine in the testis of irradiated animals after MLT administration. The redox status improvement caused a remarkable regression of proapoptotic protein (p53, Cyto-c, and caspase-3) in the testis and improved inflammatory cytokines (CRP and IL-6), and anti-inflammatory cytokine (interleukin IL-10) in serum. This is associated with restoration of disturbed sex hormonal balance, androgen receptor upregulation, and testicular cell proliferation activity in irradiated rats, explaining the improvement of sperm parameters (count, motility, viability, and deformation). Consequently, spermatogenic cell depletion and decreased seminiferous tubule diameter and perimeter were attenuated by MLT treatment post irradiation. Moreover, the testis of irradiated-MLT-treated rats showed well-organized histological architecture and normal sperm morphology. CONCLUSIONS: These results show that radiation-induced testicular injury is mitigated following IR exposure through synergistic interdependence between the antioxidant, anti-inflammatory, anti-apoptotic, and anti-DNA damage actions of MLT.

Melatonin protects the heart and pancreas by improving glucose homeostasis, oxidative stress, inflammation and apoptosis in T2DM-induced rats.

Cardiomyopathy and pancreatic injury are health issues associated with type 2 diabetes mellitus (T2DM) and are characterized by elevated oxidative stress, inflammation and apoptosis. Melatonin (MLT) is a hormone with multifunctional antioxidant activity. The protective effects of MLT on the heart and pancreas during the early development of diabetic cardiomyopathy and pancreatic injury were investigated in male Wistar rats with T2DM. MLT (10 mg/kg) was administered daily by gavage for 15 days after diabetic induction. Treatment of diabetic rats with MLT significantly normalized the levels of serum glucose, HbA1-c, and the lipid profile and improved the insulin levels and insulin resistance compared with diabetic rats, affirming its antidiabetic effect. MLT significantly prevented the development of oxidative stress and sustained the levels of glutathione and glutathione peroxidase activity in the heart and pancreas of diabetic animals, indicating its antioxidant capacity. Additionally, MLT prevented the increase in proinflammatory cytokines and expression of Bax, caspase-3 and P53. Furthermore, MLT enhanced the anti-inflammatory cytokine IL-10 and antiapoptotic protein Bcl-2. MLT controlled the levels of troponin T and creatine kinase-MB and lactate dehydrogenase activity, indicating its anti-inflammatory and antiapoptotic effects. Histological examinations confirmed the protective effects of MLT on T2DM-induced injury in the myocardium, pancreas and islets of Langerhans. In conclusion, the protective effects of melatonin on the heart and pancreas during the early development of T2DM are attributed to its antihyperglycemic, antilipidemic and antioxidant influences as well as its remarkable anti-inflammatory and antiapoptotic properties.

Melatonin exerts a neuroprotective effect against γ-radiation-induced brain injury in the rat through the modulation of neurotransmitters, inflammatory cytokines, oxidative stress, and apoptosis.

The current study aimed to investigate the ameliorative effect of melatonin (MLT) against brain injury in rats undergoing whole-body exposure to γ-radiation. Male Wistar rats were whole-body exposed to 4-Gy γ-radiation from a cesium-137 source. MLT (10 mg/kg) was orally administrated 30 minutes before irradiation and continued once daily for 1 and 7 days after exposure. In the irradiated rats, the plasma levels of glutamate were increased, while the gamma-aminobutyric acid (GABA) levels were decreased, and MLT improved the disturbed glutamate and GABA levels. These effects paralleled an increase in pro-inflammatory cytokines (IL-1b, IL-6, and TNF-a) and C-reactive protein as well as a decrease in IL-10 in the plasma of the irradiated rats. MLT treatment markedly reduced these effects, indicating its anti-inflammatory impact. Immunohistochemical studies demonstrated a remarkable upregulation of caspase-3 and P53 expression, indicating the increased apoptosis in the brain of irradiated rats. MLT significantly downregulated the expression of these parameters compared with that in the irradiated rats, indicating its anti-apoptotic effect. Oxidative stress is developed in the brain as evidenced by increased levels of malondialdehyde; decreased activities of superoxide dismutase, catalase, and glutathione peroxidase; and decreased content of glutathione in the brain. MLT remarkably ameliorated the development of oxidative stress in the brain of the irradiated rats indicating its antioxidant impact. The histopathological results were consistent with the biochemical and immunohistochemical results and showed that MLT remarkably protected the histological structure of brain tissue compared with that in the irradiated rats. In conclusion, MLT showed potential neuroprotective properties by increasing the release of neurotransmitters, antioxidants, and anti-inflammatory factors and reducing pro-inflammatory cytokines and apoptosis in the brain of irradiated rats. MLT can be beneficial in clinical and occupational settings requiring radiation exposure; however, additional studies are required to elucidate its neuroprotective effect in humans.

Melatonin ameliorates diabetes-induced brain injury in rats.

Diabetic brain is a serious complication of diabetes, and it is associated with oxidative stress and neuronal injury. This study investigated the protective effect of melatonin (MLT) on diabetes-induced brain injury. A rat model of type 2 diabetes mellitus was produced by intraperitoneal injection of nicotinamide 100 mg/kg, followed by intraperitoneal injection of streptozotocin 55 mg/kg. The diabetic rats were orally administered MLT 10 mg/kg of body weight for 15 days. MLT remarkably downregulated serum glucose levels. It also improved levels of the lipid peroxidation product 4-hydroxynonenal, improved levels of antioxidants including glutathione, glutathione peroxidase and glutathione reductase in the brains of the diabetic rats, and this is indicative of the antioxidant potential of MLT. MLT also prevented increase in homocysteine, amyloid-ß42 and tau levels in diabetic rats, and this suggests that it can reduce the risk of dementia. This is associated with reduction in the levels of the dopamine, serotonin, and glutamate and is indicative of the regulatory effect of MLT on neurotransmitters. Treatment with MLT improved diabetes-induced structural alteration in the hippocampus and cerebral cortex. MLT significantly reduced caspase-3 and Bax as well as significantly increase Bcl-2 protein and GFAP-positive astrocytes indicating its anti-apoptotic effect. MLT showed remarkable ameliorative effect against biochemical and molecular alterations in the brains of diabetic rats most likely through its antioxidant property.