Concomitant Effects of Metformin and Vitamin C on Indomethacin-Induced Gastric Ulcer in Rats: Biochemical and Histopathological Approach.

INTRODUCTION: Gastric ulcer is one of the most common and serious conditions in the gastrointestinal tract. One of the main causes of gastric ulcers is using of non-steroidal anti-inflammatory drugs (NSAIDs) which have limited their use in clinical practice. Several studies have revealed that metformin and Vitamin C (Vit C) exhibit protective effects against gastric mucosal damage in different animal models. However, no studies indicate their combination's effect on gastric ulcer models. Therefore, this study aims to investigate the protective effects of metformin and Vit C combination on indomethacin-induced gastric ulcers. MATERIAL AND METHODS: In total, thirty rats were divided into six groups, including the control group, rats received indomethacin (50 mg/kg, i.p.), rats received indomethacin and pretreated with ranitidine (100 mg/kg), metformin (100 mg/kg, i.p.), Vit C (100 mg/kg), or metformin combined with Vit C. Four hours after indomethacin administration, rats were euthanized, and gastric tissues were removed for macroscopic, histopathologic, and biochemical examinations. RESULTS: All therapeutics used in this study were found to alleviate gastric mucosal injury caused by indomethacin, as observed in histopathologic and macroscopic evaluations. Both Vit C and metformin were observed to significantly decrease lipid peroxidation and enhance the activity of anti-oxidative enzymes, SOD, GPx, and catalase. However, a more significant effectiveness was observed in catalase and GPx activities when Vit C was co-administered with metformin. CONCLUSIONS: In conclusion, the present study revealed that metformin and Vit C combination therapy could potentially treat gastric ulcers associated with indomethacin.

STING agonists as promising vaccine adjuvants to boost immunogenicity against SARS-related coronavirus derived infection: possible role of autophagy.

As a major component of innate immunity and a positive regulator of interferons, the Stimulator of interferon gene (STING) has an immunotherapy potential to govern a variety of infectious diseases. Despite the recent advances regarding vaccines against COVID-19, nontoxic novel adjuvants with the potential to enhance vaccine efficacy are urgently desired. In this connection, it has been well-documented that STING agonists are applied to combat COVID-19. This approach is of major significance for boosting immune responses most likely through an autophagy-dependent manner in susceptible individuals against infection induced by severe acute respiratory syndrome Coronavirus (SARS­CoV­2). Given that STING agonists exert substantial immunomodulatory impacts under a wide array of pathologic conditions, these agents could be considered novel adjuvants for enhancing immunogenicity against the SARS-related coronavirus. Here, we intend to discuss the recent advances in STING agonists' recruitment to boost innate immune responses upon vaccination against SARS-related coronavirus infections. In light of the primordial role of autophagy modulation, the potential of being an antiviral vaccine adjuvant was also explored.

The interplay between the PI3K/AKT pathway and circadian clock in physiologic and cancer-related pathologic conditions.

The circadian clock is responsible for the regulation of different cellular processes, and its disturbance has been linked to the development of different diseases, such as cancer. The main molecular mechanism for this issue has been linked to the crosstalk between core clock regulators and intracellular pathways responsible for cell survival. The PI3K/AKT signalling pathway is one of the most known intracellular pathways in the case of cancer initiation and progression. This pathway regulates different aspects of cell survival including proliferation, apoptosis, metabolism, and response to environmental stimuli. Accumulating evidence indicates that there is a link between the PI3K/AKT pathway activity and circadian rhythm in physiologic and cancer-related pathogenesis. Different classes of PI3Ks and AKT isoforms are involved in regulating circadian clock components in a transcriptional and functional manner. Reversely, core clock components induce a rhythmic fashion in PI3K and AKT activity in physiologic and pathogenic conditions. The aim of this review is to re-examine the interplay between this pathway and circadian clock components in normal condition and cancer pathogenesis, which provides a better understanding of how circadian rhythms may be involved in cancer progression.

Protective effects of topiramate on acetic acid-induced colitis in rats through the inhibition of oxidative stress.

Ulcerative colitis is an intestinal inflammatory condition characterized by a rise in inflammatory mediator production and oxidative stress. Topiramate is an anticonvulsant agent with effectiveness on a wide range of seizures, which is anti-oxidative. This study aims to examine the protective effects of topiramate on acetic acid-induced ulcerative colitis in rats. Rats were randomly divided into four groups as follows: control, acetic acid, acetic acid + topiramate, and acetic acid + dexamethasone groups. Topiramate (100 mg/kg/day) or dexamethasone (2 mg/kg/day) was administered for six consecutive days, and ulcerative colitis was induced on the first day of the study by transrectal administration of 4% acetic acid. Four hours after the last dose of treatments, animals of each group were sacrificed, and colon tissues were removed for further macroscopic, histopathologic, and biochemical analyses. Treatment with topiramate markedly decreased colonic lesions and macroscopic scores as well as the improvement of histopathologic changes. Topiramate also effectively decreased the levels of malondialdehyde and upregulated the activity of anti-oxidative enzymes, including catalase, superoxide dismutase, and glutathione peroxidase. Our results reveal that the administration of topiramate ameliorates acetic acid-induced colitis in rats via anti-oxidative properties, and further studies may introduce it as an effective therapeutic candidate to decrease ulcerative colitis severity.

The pharmacological effects of Berberine and its therapeutic potential in different diseases: Role of the phosphatidylinositol 3-kinase/AKT signaling pathway.

The phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway plays a central role in cell growth and survival and is disturbed in various pathologies. The PI3K is a kinase that generates phosphatidylinositol-3,4,5-trisphosphate (PI (3-5) P3), as a second messenger responsible for the translocation of AKT to the plasma membrane and its activation. However, due to the crucial role of the PI3K/AKT pathway in regulation of cell survival processes, it has been introduced as a main therapeutic target for natural compounds during the progression of different pathologies. Berberine, a plant-derived isoquinone alkaloid, is known because of its anti-inflammatory, antioxidant, antidiabetic, and antitumor properties. The effect of this natural compound on cell survival processes has been shown to be mediated by modulation of the intracellular pathways. However, the effects of this natural compound on the PI3K/AKT pathway in various pathologies have not been reviewed so far. Therefore, this paper aims to review the PI3K/AKT-mediated effects of Berberine in different types of cancer, diabetes, cardiovascular, and central nervous system diseases.

Role of Bmal1 and Gut Microbiota in Alzheimer's Disease and Parkinson's Disease Pathophysiology: The Probable Effect of Melatonin on Their Association.

In recent years, the role of new factors in the pathophysiology of neurodegenerative diseases has been investigated. Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative diseases worldwide. Although pathological changes such as the accumulation of aggregated proteins in the brain and inflammatory responses are known as the main factors involved in the development of these diseases, new studies show the role of gut microbiota and circadian rhythm in the occurrence of these changes. However, the association between circadian rhythm and gut microbiota in AD and PD has not yet been investigated. Recent results propose that alterations in circadian rhythm regulators, mainly Bmal1, may regulate the abundance of gut microbiota. This correlation has been linked to the regulation of the expression of immune-related genes and Bmal-1 mediated oscillation of IgA and hydrogen peroxide production. These data seem to provide new insight into the molecular mechanism of melatonin inhibiting the progression of AD and PD. Therefore, this manuscript aims to review the role of the gut microbiota and circadian rhythm in health and AD and PD and also presents a hypothesis on the effect of melatonin on their communication.

Concomitant effects of paclitaxel and celecoxib on genes involved in apoptosis of triple-negative metastatic breast cancer cells.

Although triple-negative breast cancer accounts for less than one-fifth of breast cancers, it has a higher rate of metastasis and mortality. This study investigated the effects of combination treatment with paclitaxel and celecoxib on the expression of genes involved in the apoptosis of triple-negative metastatic breast cancer cells. MDA-MB-231 cells were cultured and then treated with certain concentrations of celecoxib (CLX), paclitaxel (PTX), and combination of them for 24 and 48 h. Cell viability was assessed by the MTT method. The real-time PCR method was utilized to assess the expression level of the genes involved in apoptosis. Western blotting was used for evaluating protein expression. IC50 values for CLX and PTX were 73.95 µM and 3.15 µM, respectively. The results demonstrated that PTX, CLX, and PTX + CLX significantly (p < 0.05) reduced cell viability. The comparison of combination treatment with PTX showed a significant increase in caspase 3 gene expression at both time points, in Bax gene expression after 48 h, and a remarkable decrease in Bcl-2 gene expression at both times. Western blotting results were in line with genes' expression. These findings indicate that a combination of PTX and CLX results in a significantly more reduction in cell viability of breast cancer cells. In addition, it seems CLX may be an effective agent in regulating the expression level of caspase 3, Bax, and Bcl-2 when combined with PTX.

Protective effects of empagliflozin on testicular injury induced by torsion/detorsion in adult male rats.

INTRODUCTION: Testicular torsion is a known urologic emergency condition and one of the common causes of infertility in males. Hence, prompt diagnosis and treatment play a crucial role in prevention of testicular injury. It has been observed that empagliflozin, a drug for management of hyperglycemia, has anti-oxidative properties against different pathologies, the most important of which are ischemia reperfusion related injuries. OBJECTIVE: This study aims to evaluate the protective effects of empagliflozin on a testicular torsion injury in adolescent rats followed by ischemia/reperfusion (I/R) phenomena. STUDY DESIGN: Thirty-six rats were randomly assigned into three groups including sham-operated group received all surgical procedures except testicular torsion-detorsion, torsion/detorsion + dimethyl sulfoxide (DMSO) as vehicle, and torsion/detorsion + empagliflozin (10 mg/kg). Testicular torsion was performed for 2 h through rotating right testis 720° in the clockwise direction. Thirty minutes before detorsion, a single intraperitoneal dose of empagliflozin was injected to treatment group. Four hours later, orchiectomy was conducted for histopathological and biochemical examinations of testicular tissue specimens. RESULTS: The malondialdehyde (MDA) content in the torsion/detorsion animals was markedly greater than in the animals under sham operated procedure. Moreover, the testicular MDA levels in the torsion/detorsion + empagliflozin group were significantly lower than in the torsion/detorsion group. Also, significant decreases observed in catalase, superoxide dismutase, and glutathione peroxidase activities in the torsion/detorsion group in comparison with sham operated group. These values were significantly improved in the empagliflozin group. Furthermore, histopathological examinations also revealed severe testicular injury which were improved by empagliflozin administration. DISCUSSION: Empagliflozin prevented increases in oxidative stress markers and subsequently reduced the tissue injury induced by torsion/detorsion in the current study. CONCLUSION: It can be concluded that administration of empagliflozin before prevents I/R related cellular damage in testicular torsion, possibly via oxidative stress inhibition.

Gut microbiota and circadian rhythm in Alzheimer's disease pathophysiology: a review and hypothesis on their association.

Alzheimer's disease (AD) is the most common neurodegenerative disease and the leading cause of dementia worldwide. Different pathologic changes have been introduced to be involved in its progression. Although amyloid-ß (Aß) deposition and tau hyperphosphorylation and aggregation are mainly considered the main characterizations of AD, several other processes are involved. In recent years, several other changes, including alterations in gut microbiota proportion and circadian rhythms, have been noticed due to their role in AD progression. However, the exact mechanism indicating the association between circadian rhythms and gut microbiota abundance has not been investigated yet. This paper aims to review the role of gut microbiota and circadian rhythm in AD pathophysiology and introduces a hypothesis to explain their association.

Bmal1 and Gut-lung axis in SARS-CoV-2 infection: New insight into the effects of melatonin on COVID-19 patients?

Coronavirus disease 2019 (COVID-19), is known as one of the most known challenge worldwide. Numerous studies have tried to introduce different mechanisms involved in the pathophysiology of COVID-19 and efforts in this field are also ongoing. The presence of SARS-CoV-2 RNA in feces of COVID-19 patients along with a variety of gastrointestinal symptoms may show a significant association between gut microbiota and SARS-CoV-2 infection. However, the exact mechanism indicating how SARS-CoV-2 and gut flora influence each other remains unknown. This paper aims to introduce a possible molecular mechanism based on recent findings on the association between circadian rhythm and gut flora in COVID-19 patients to express a new insight into the probable mechanism of melatonin in protection against SARS-CoV-2 infection.

Protective effects of sitagliptin on methotrexate-induced nephrotoxicity in rats.

Methotrexate (MTX), a cytotoxic chemotherapeutic and immunosuppressant agent, is widely used in the treatment of autoimmune diseases and different types of cancers. However, its use has been limited by its life-threatening side effects, including nephrotoxicity and hepatotoxicity. The purpose of this study was to investigate the protective effect of sitagliptin on methotrexate (MTX)-induced nephrotoxicity in rats. Twenty-four rats were divided into four groups: control group, which received the vehicle for 6 days; MTX group, which received a single dose of MTX, followed by five daily doses of vehicle dosing; MTX + sitagliptin group, which received a single dose of MTX 1 h after the first sitagliptin treatment and six daily doses of sitagliptin; and sitagliptin group, which received sitagliptin for 6 days. Both MTX and sitagliptin were given as intraperitoneal injections at a dose of 20 mg/kg body weight. All rats were euthanized on the seventh day of the study. Kidney tissues were harvested and blood samples were collected. Serum levels of blood urea nitrogen (BUN) and creatinine were evaluated. Furthermore, catalase, glutathione peroxidase, superoxide dismutase activities, and malondialdehyde (MDA) levels were determined in kidney tissue. In addition, histopathological analysis was conducted. Histopathological evaluation showed that MTX-induced marked kidney injury. Biochemical analysis revealed a significant increase of BUN and creatinine in the serum of the MTX group. Furthermore, oxidative stress and depressed antioxidant system of the kidney tissues were evident in the MTX group. Sitagliptin did not affect these endpoints when administered alone, but it significantly attenuated the observed MTX-induced effects. These results suggest that sitagliptin exhibits potent anti-oxidant properties against the nephrotoxicity induced by MTX in rats.

Therapeutic potential of ADAM10 modulation in Alzheimer's disease: a review of the current evidence.

Alzheimer's disease (AD), the most common neurodegenerative disease worldwide, is caused by loss of neurons and synapses in central nervous system. Several causes for neuronal death in AD have been introduced, the most important of which are extracellular amyloid ß (Aß) accumulation and aggregated tau proteins. Increasing evidence suggest that targeting the process of Aß production to reduce its deposition can serve as a therapeutic option for AD management. In this regard, therapeutic interventions shown that a disintegrin and metalloproteinase domain-containing protein (ADAM) 10, involved in non-amyloidogenic pathway of amyloid precursor protein processing, is known to be a suitable candidate. Therefore, this review aims to examine the molecular properties of ADAM10, its role in AD, and introduce it as a therapeutic target to reduce the progression of the disease. Video abstract.

The PI3K/AKT Signaling Pathway and Caspase-3 in Alzheimer's Disease: Which One Is the Beginner?

One of the main players in apoptosis during Alzheimer's disease progression are different members of caspase family of proteases. The most well-known member of this family is caspase-3, in which alterations of its levels have been detected in samples from Alzheimer's disease patients. There are numerous intracellular factors involved in regulation of cellular apoptosis through regulation of caspase-3 activity, the most important of which is the PI3K/AKT signaling pathway. This commentary tries to highlight the probable relations between PI3K/AKT signaling pathway and caspase-3 in Alzheimer's disease.

The Role of ERK1/2 Pathway in the Pathophysiology of Alzheimer's Disease: An Overview and Update on New Developments.

Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide. Several findings suggest that correcting the dysregulated signaling pathways may offer a potential therapeutic approach in this disease. Extracellular signal-regulated kinase 1/2 (ERK1/2), a member of the mitogen-activated protein kinase family, plays a major role in regulation of cell proliferation, autophagy process, and protein synthesis. The available literature suggests dysregulated ERK1/2 in AD patients with potential implications in the multifaceted underlying pathologies of AD, including amyloid-ß plaque formation, tau phosphorylation, and neuroinflammation. In this regard, in the current review, we aim to summarize the reports on the potential roles of ERK1/2 in AD pathophysiology.

The Role of Caspases in Alzheimer's Disease: Pathophysiology Implications and Pharmacologic Modulation.

Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide. Although the main cause of the onset and development of AD is not known yet, neuronal death due to pathologic changes such as amyloid-ß (Aß) deposition, tau aggregation, neuroinflammation, oxidative stress, and calcium dyshomeostasis are considered to be the main cause. At the present, there is no cure for this insidious disorder. However, accurate identification of molecular changes in AD can help provide new therapeutic goals. Caspases are a group of proteases which are known because of their role in cellular apoptosis. In addition, different caspases are involved in other cellular responses to the environment, such as induction of inflammation. Emerging evidence suggest that these proteases play a central role in AD pathophysiology due to their role in the processing of amyloid-ß protein precursor, tau cleavage, and neuroinflammation. Therefore, it seems that targeting caspases may be a suitable therapeutic option to slow the progression of AD. This review focuses on the role of caspases in AD pathophysiology and introduce results from studies targeted caspases in different models of AD.

Protective effects of metformin against aluminum phosphide-induced acute hepato-renal damage in rats: An experimental approach.

Phosphine (PH3), from hydrolysis of magnesium, zinc, and aluminum phosphide (AlP), is a rodenticide and insecticide which is used to avoid losses of the agriculture products. However, using of this agent may affect the human health, in a way that poisoning with AlP has a high rate of mortality and morbidities. This study determined the ameliorative effects of metformin (MET) on AlP-induced hepato- and nephro-toxicity in Wistar rats. Male rats were randomly divided into four experimental groups. Group I was the control group received coconut oil by oral gavage, group II was the model group received AlP (12 mg/kg) distributed in coconut oil by oral gavage, group III received MET (200 mg/kg; i.p.), and group IV received MET (200 mg/kg; i.p.) 30 min after intoxication. After 24 h, the serum, liver and kidney tissues were collected for histopathological and biochemical investigations. The levels of kidney function markers, blood urea nitrogen and creatinine, and liver function markers, ALP, AST and ALT, in the plasma were increased significantly followed by AlP intoxication. The results revealed that phosphine causes a significant enhancement of lipid peroxidation, while decreases the activity of superoxide dismutase in both liver and kidney tissues. Furthermore, phosphine significantly induced the up-regulation of TNF-α and phosphorylation of NF-κB in target tissues. Overall, treatment with MET abolished aforementioned alterations resulted by AlP intoxication. Furthermore, histological evaluation indicated a deleterious effect of AlP on the liver and kidney tissues along with marked increase in kidney and liver injury scores, which is mitigated by MET administration. According to our results, although metformin could not bring the changes to the level of the control group, it was indicated that this drug might possess a protective effect against AlP-induced hepato and nephrotoxicity by inhibiting inflammatory responses and oxidative stress.

Platelet Activation and Alzheimer's Disease: The Probable Role of PI3K/AKT Pathway.

In recent years, the association between the activity of platelets and risk of Alzheimer's disease (AD) risk has been noticed in numerous studies. However, there in no investigations on the role of specific intracellular pathways to explain this connection. The phosphatidylinositol 3 kinase (PI3K)/AKT pathway is one of the main regulators of cell survival which regulates cellular responses to environmental changes. This pathway also regulates the activity of platelets, and its aberrant activity has been linked to platelet dysfunction in different pathologies. On the other hand, the PI3K/AKT pathway regulates amyloid-ß (Aß) production through regulation of amyloid-ß protein precursor (AßPP), BACE-1, ADAMs, and γ-secretase. In addition, alterations in the activity of all of these factors in platelets has been shown in AD-related pathologies. Therefore, this paper aims to introduce the PI3K/AKT pathway as a molecular inducer of platelet dysfunction during aging and AD progression.

Icariin: A Potential Neuroprotective Agent in Alzheimer's Disease and Parkinson's Disease.

Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative diseases worldwide. They are characterized by the loss of neurons and synapses in special parts of the central nervous system (CNS). There is no definitive treatment for AD and PD, but extensive studies are underway to identify the effective drugs which can slow the progression of these diseases by affecting the factors involved in their pathophysiology (i.e., aggregated proteins, neuroinflammation, and oxidative stress). Icariin, a natural compound isolated from Epimedii herba, is known because of its anti-inflammatory and anti-oxidant properties. In this regard, there are numerous studies indicating its potential as a natural compound against the progression of CNS disorders, such as neurodegenerative diseases. Therefore, this review aims to re-examine findings on the pharmacologic effects of icariin on factors involved in the pathophysiology of AD and PD.

Potential effects of icariin, the Epimedium-derived bioactive compound in the treatment of COVID-19: a hypothesis.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected the world's health systems for more than two years. This disease causes a high mortality rate followed by cytokine storm-induced oxidative stress and acute respiratory distress syndrome (ARDS). Therefore, many drugs have been considered with emphasis on their anti-inflammatory and antioxidant effects in controlling the consequences of SARS-CoV-2 infection. Icariin is a major bioactive pharmaceutical compound derived from Epimedium plants, which is known due to its anti-inflammatory and antioxidant effects. Additionally, the protective effects of icariin have been studied in different pathologies through modulating intracellular pathways. In addition to the potential effect of this compound on inflammation and oxidative stress caused by SARS-CoV-2 infection, it appears to interfere with intracellular pathways involved in viral entry into the cell. Therefore, this paper aims to review the molecular mechanisms of anti-inflammatory and antioxidant properties of icariin, and hypothesizes its potential to inhibit SARS-CoV-2 entry into host cells through modulating the intracellular pathways.

The PI3K/AKT signaling pathway in cancer: Molecular mechanisms and possible therapeutic interventions.

The human body consists of countless cells with the possibility of excessive and uncontrolled proliferation under certain dysregulated circumstances that could cause abnormal states such as cancer. Phosphatidylinositol 3 kinase (PI3K) and its downstream target, Protein kinase B or AKT, play a critical role in cell survival, proliferation, differentiation, migration, and metabolism. Research studies have examined the aberrant expression of signaling molecules that regulate PI3K/AKT pathway with the purpose of target discovery. The present review aims to recapitulate the relationship between the PI3K/AKT signaling pathway and factors contributing to initiation and development of various cancers. In addition, therapeutic interventions regulating this signaling pathway have been summarized.