The Role of Local Angiotensin II/Angiotensin Type 1-receptor Mechanisms in Adipose Tissue Dysfunction to Promote Pancreatic Cancer.

Obesity and adipose tissue dysfunction are important risk factors for pancreatic cancer. Pancreatic cancer is one of the most lethal cancers globally. The renin-angiotensin system (RAS) is expressed in many tissues, including adipose tissue. Dysregulation of angiotensin II and angiotensin II receptors in adipose tissue through the activation of different signaling pathways leads to adipose tissue dysfunction, including insulin resistance, adipose tissue inflammation, adipocytokines secretion, and metabolic alterations. The pathogenesis of pancreatic cancer remains uncertain. However, there is evidence that dysregulation of local angiotensin II in adipose tissue that occurs in association with obesity is, in part, responsible for the initiation and progression of pancreatic cancer. Due to the role of local angiotensin II in the dysfunction of adipose tissue, angiotensin receptor blockers may be considered a new therapeutic strategy in the amelioration of the complications related to adipose tissue dysfunction and prevention of pancreatic cancer. This review aims to consider the biological roles of local angiotensin II and angiotensin II receptors in adipose tissue dysfunction to promote pancreatic cancer progression with a focus on adipose tissue inflammation and metabolic reprogramming.

Elucidating the Role of Pro-renin Receptors in Pancreatic Ductal Adenocarcinoma Progression: A Novel Therapeutic Target in Cancer Therapy.

Pancreatic cancer is a highly aggressive malignancy with a very poor prognosis. The 5- year survival in these patients is very low, and most patients develop drug resistance to current therapies, so additional studies are needed to identify the potential role of new drug targets for the treatment of pancreatic cancer. Recent investigations have been performed regarding the roles of pro-renin receptors (PRR) in the initiation and development of cancers. PRR is a component of the local renin-angiotensin system (RAS). Local tissue RAS has been known in diverse organ systems, including the pancreas. Various investigations have implicated that PRRs are associated with the upregulation of various signaling pathways, like the renin-angiotensin system pathway, PI3K/Akt/mTOR, and the Wnt-signaling pathways, to contribute to pathological conditions, including cancer. In this review, we presented an overview of the role of PRR in the progression of pancreatic adenocarcinoma.

Evaluation of the diagnostic value of Sentinel Lymph Node in patients with gastric adenocarcinoma.

Objectives: Sentinel lymph node biopsy (SLNB) has been proven as a safe and efficient procedure in some cancers like breast cancer and melanoma with a reduction of complications and side effects of unnecessary lymphadenectomy in many patients. However, the diagnostic value of SLNB in gastric cancer is a point of debate. This study evaluated the diagnostic value of SLNB using radiotracer and isosulphan blue dye injection in patients with Gastric Adenocarcinomas (GA). Methods: This descriptive study was performed at Imam-Reza HOSPITAL on 39 patients diagnosed with GA with no lymphatic metastasis using two methods: the combination of radionuclide with isosulphan together (R&I) method compared with the isosulphan alone method. Lymphatic dissection was performed in all patients. The pathological results were compared between the sentinel lymph nodes (SLN) and other lymph nodes and their accordance rate was calculated. Results: In the T1 group, the sentinel lymph node biopsy detection rate was 100% for the combination of the R&I method and 60% for the isosulphan method and the false negative rate was zero. These values respectively were 88.8% and 88.8% in the T2 group with a false negative rate of 75%. In the T3 group, the values were 100% for the combination of the R&I method and 93.7% for the isosulphan method with a false negative rate of 40%. In the combination of the R&I method, the sensitivity, specificity, and positive and negative predictive values were 57.9, 100, 100, and 69.2 percent respectively. Conclusion: Based on the false negative rate (47.4%), SLNB by injection of isosulphan blue dye alone is not a diagnostic enough value for predicting lymph node metastasis in GA. Although, SLNB by combination of the R&I had better accuracy compared to the isosulphan alone, more studies with larger samples are needed to prove this result.

Targeting Lysyl Oxidase as a Potential Therapeutic Approach to Reducing Fibrotic Scars Post-operatively: Its Biological Role in Post-Surgical Scar Development.

Abdominal and pelvic surgery, or any surgical injury of the peritoneum, often leads to chronic abdominal adhesions that may lead to bowel obstruction, infertility, and pain. Current therapeutic strategies are usually ineffective, and the pathological mechanisms of the disease are unclear. Excess collagen cross-linking is a key mediator for extra-cellular matrix deposition and fibrogenesis. Lysyl oxidase is a key enzyme that catalyzes the formation of stabilizing cross-links in collagen. Dysregulation of Lysyl oxidase (Lox) expressing upregulates collagen cross-linking, leading ECM deposition. Tissue hypoxia during surgery induces molecular mechanisms and active transcription factors to promote the expression of several genes related to inflammation, oxidative stress, and fibrosis, such as transforming growth factor beta, and Lox. Studies have shown that targeting Lox improves clinical outcomes and fibrotic parameters in liver, lung, and myocardial fibrosis, therefore, Lox may be a potential drug target in the prevention of postsurgical adhesion.

Review the Role of Metabolism Reprogramming in the Pathogenesis of Post-surgical Adhesion: A New Therapeutic Strategy.

Metabolic reprogramming is defined as the skill of cells to change their metabolism to support the induced energy demand due to continuous growth. Metabolic reprogramming is a well- known occurrence in the progression of neoplastic cells, although, evidence has shown that it is present in fibrotic disorders. Post-surgical adhesion as a fibrotic disorder is a medical challenge and is defined by fibrotic bands connected between organs with the abdominal wall. Despite many investigations carried out about the pathogenesis of the disorder but there are many unknowns, therefore, targeting special pathways may have the potential to prevent the formation of fibrotic bands post-operative. Glycolysis is a necessary metabolic pathway in living cells. In hypoxic conditions, it is the dominant pathway in the production of energy for different types of cells such as fibroblasts, immune cells, and endothelial cells. Also, glycolysis is a main downstream target for transforming growth factor ß (TGF-ß) and upregulates during fibrotic conditions. Furthermore, this is noteworthy that hypoxia induces factor 1 alpha (HIF-1α) as a transcription factor, elevated during the hypoxia condition stimulates different signaling pathways such as TGF-ß/SMAD, nuclear factor kappa B (NF-kB), and mTOR pathway to control glycolytic metabolism and T-cell trafficking for immune cell migration. Different evidence has indicated that the administration of glycolytic inhibitors has the potential to prevent the development of fibrotic markers. In this review, we pointed out the role of the glycolysis pathway and its connection to profibrotic cytokines to promote inflammatory and fibrotic pathways. Based on the results of studies related to fibrotic disorders we hypothesized that targeting glycolysis may have therapeutic potential in the prevention of postoperative adhesions.

The Association between Circulating Adipocytokine Omentin Levels and Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-analysis.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver condition worldwide. NAFLD is often associated with features of Metabolic Syndrome such as obesity and insulin resistance. METHOD: The current comprehensive meta-analysis was performed to evaluate the association between circulating Omentin levels and NAFLD. A systematic search in Scopus, Web of Science, PubMed, and Google Scholar databases was conducted to identify relevant studies up until 5th May 2022. The standard mean difference (SMD) values and 95% confidence intervals (CIs) were computed for the association of Omentin levels with NAFLD risk in a random effect model. RESULT: The meta-analysis involved 6 case-control studies with a total of 371 cases and 269 controls. Pooled SMD showed no significant difference in serum Omentin between NAFLD and healthy groups (SMD= -0.047 and 95% CI -0.957_0.862 P=0.91). Subgroup analysis based on sample size showed that the average Omentin levels were significantly higher in NAFLD patients in studies with sample size ≥70 (SMD=0.356 CI 0.056_0.655 P=0.02). CONCLUSION: Additional well-designed studies with more sample sizes are essential to clarify the potential role of Omentin as a risk marker of NAFLD.

The association between Vitamin D deficiency and fibrocystic breast disorder.

BACKGROUND: The role of deficiency of vitamin D in a wide range of human cancer, including breast cancer, has been proven, but its role in benign breast diseases remains unknown. This study aimed to determine the prevalence of vitamin D deficiency in patients with fibrocystic breast (FB) disease. METHODS: First, the hospital prevalence of fibrocystic breast was determined by a cross-sectional study. Then, patients were divided into two groups by a case-control study; women with confirmed fibrocystic breasts based on breast pain, physical examination, and ultrasonography were included as a case group (N=48) and age-matched women without fibrocystic breasts were also included as a control group (N=48). After recording the demographic and gynecological characteristics and exposure to the sun, gynecological records, and family history of fibrocystic breast, the blood sample was taken to determine vitamin D. Data were analyzed by Stata software. RESULTS: The result indicated that the studied groups had significant differences in regards to weight, breast pain, the severity of breast pain, breast heaviness, family history of fibrocystic breast, history of breast disease, caffeine consumption, and exposure to sunlight (p <0.05), but did not show significant differences based on age, occupation, education, gynecological history, diabetes mellitus, hypertension, obesity and hypothyroidism, vegetable, fast food, and dairy products consumption. The frequency of vitamin D deficiency in the case group was 45.8%, and in the control group, it was 20.8%, and there was a statistically significant difference (p <0.05). CONCLUSION: Vitamin D deficiency is more common in women with fibrocystic breast disease and may play a role in the development of the disease.

Bacterial Ocular Infections in Iran: A Systematic Review and Meta-analysis.

Objectives: Eye infections can be caused by several microorganisms and the most common causative bacterial agents are staphylococci, streptococci, and Pseudomonas aeruginosa. This study aimed to estimate the prevalence of Staphylococcus aureus, Staphylococcus epidermidis, viridans group streptococci, and P. aeruginosa as the cause of ocular infections in Iran. Methods: We conducted a systematic search on the studies published by Iranian authors from January 2000 to December 2020 in Web of Science, PubMed, Scopus, and Embase. Eligible studies were selected according to the defined inclusion/exclusion criteria. Statistical heterogeneity between and within groups was estimated by the Q-statistic and I2 index. The funnel plots, Duval and Tweedie trim, and fill methods were obtained to evaluate the evidence of publication bias. Results: Twenty-seven studies were included in this review. According to the meta-analysis results, the prevalence of S.epidermidis was 19.1% (95% CI: 12.5-28.1). It was estimated 6.9% (95% CI: 4.4-10.6), 6.7% (95% CI: 4.6-9.6), and 3.3% (95% CI: 1.8-5.8) for P.aeruginosa, S. aureus, and viridans streptococci, respectively. Conclusions: S. epidermidis is the prevalent bacterial agents responsible for eye-associated infections in Iran.

A meta-analysis of the relationship between serums metrnl-like protein/subfatin and risk of type 2 diabetes mellitus and coronary artery disease.

There have been inconsistent reports that Metrnl-like protein, a new adipokine, is associated with the risk of metabolic syndrome (MetS), type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD). A systematic search in PubMed, Scopus, Web of Science, and Google scholar databases were conducted up until 24 November 2020. Ten eligible studies were included in this meta-analysis. The overall results showed that there was no significant association between serum Metrnl levels and risk of T2DM and CAD in patients compared with healthy control (SMD= -0.717 and 95%CI -1.572_0.139, p = .1). However, in subgroup analysis, there was a significant association between a BMI ≥ 25 and the serum level of Metrnl-like protein (SMD= -0.688 and 95%CI -1.348_-0.028 p = .041), indicating a potential inverse connection between serum Metrnl and the adiposity. Further well-designed studies are needed to explain the more subtle roles of Metrnl in metabolic disorders like T2DM and CAD.

The potential association between metabolic syndrome and risk of post-surgical adhesion.

Metabolic syndrome (MetS) is defined by the clustering of several associated with a group of disorders that include: obesity, dyslipidemia, hypertension, and insulin resistance. The incidence of MetS is increasing globally around the world. Indeed the rates of different types of surgery in older or younger patients with Mets are increasing and they are exposed to a wide range of operations including abdominal, pelvic, urologic, or any invasive procedures. Post-surgical adhesion is a common problem and is a challenge for the surgeon. Despite many studies on its pathogenesis, there remain many un-answered questions about it, for example why certain tissues and patients are more at higher risk of post-surgical adhesions. Many studies have suggested that MetS is associated with up-regulating molecular mechanisms leading to chronic inflammation and hypercoagulability. In this review, we discuss some of the molecular mechanisms by MetS may enhance post-surgical adhesion, and particularly regarding those involved in coagulation and inflammation.

Prognostic value of HIF-1α in digestive system malignancies: evidence from a systematic review and meta-analysis.

Aim: This meta-analysis aimed to evaluate the association of HIF-1α expression with clinicopathological features and overall survival (OS) of patients with digestive system malignancies. Background: Numerous studies have demonstrated that hypoxia-inducible factor-1α (HIF-1α) is abnormally expressed in various solid tumors. However, the clinicopathological features and prognostic value of HIF-1α expression in patients with digestive system malignancies remain controversial. Methods: A literature search in PubMed, Web of Science, and Scopus databases was performed to identify all relevant studies published in English until 15 October 2020. The pooled effect was calculated to evaluate the association between HIF-1α expression and clinicopathological features and overall survival in cancer patients. Pooled odds ratios (ORs) or hazard ratios (HRs) with a 95% confidence interval (CI) were calculated using fixed- or random-effects model based on between-study heterogeneity. Results: A total of 44 eligible studies with 5,964 patients were included. The pooled results indicated a positive association of HIF-1α overexpression with poor overall survival (OS) (HR=1.990, 95% CI: 1.615-2.453, p<0.001) and disease-free survival (DFS) (HR=1.90, 95% CI: 1.084-3.329, p=0.043). Meta-analysis results showed that HIF-1α level expression was significantly associated with positive lymph node metastasis (OR=1.869, 95% CI: 1.488-2.248, p<0.001), distance metastasis (OR=2.604, 95% CI: 1.500-4.519, p<0.001), tumor stage (OR=1.801, 95% CI: 1.437-2.257, p<0.001) and tumor size (OR=1.392. 95% CI: 1.068-1.815, p=0.014). Conclusion: This meta-data suggest that HIF-1α expression might serve as an independent prognostic marker and a promising therapeutic target in patients with digestive system malignancies.

Local renin-angiotensin system molecular mechanisms in intrauterine adhesions formation following gynecological operations, new strategy for novel treatment.

It has recently been proposed that local tissue renin-angiotensin system activation has a role in post-surgical adhesion. Intrauterine adhesions are scar tissues that form in the endometrial cavity causing the walls of the uterine to adhere together. Women, undergoing major gynecological surgery, are exposed to a high risk of adhesion formation. Post-operative uterine adhesion is associated with chronic pain and infertility that are important problems following post-operation uterine adhesion. A local renin-angiotensin system has been found in the organs of the female reproductive system, for example in the endometrium. Data about the physiological roles of local RAS in the gynecological tract are largely unknown, but dysfunctional local RAS in the endometrium may contribute to this pathological condition. Local AngII/AT1R may be over-activated after surgical injury or hypoxia leading to an up-regulation of the molecular mechanisms that may lead to a chronic immune response, oxidative stress, and increase the expression of fibrotic molecules like TGF-ß to induce the risk of connective fibrotic tissues. Based on AngII/AT1R pathological potential to induce pelvic and uterine adhesions, using angiotensin receptor blockers could be a therapeutic strategy for the prevention and treatment of post-surgical adhesions.IMPACT STATEMENTWhat is already known on this subject? Intrauterine adhesions are described as fibrotic scar tissues following gynecological surgeries. It's reported that 55-100% of women are at risk of intrauterine adhesion after gynecological surgeries. Injury to tissues and hypoxia during the surgery, promote molecular mechanisms to contribute post-surgical adhesion. Recently evidence supports the existence of renin-angiotensin system components in the gynecological tract. Abnormal expression of local angiotensin II and AT1R in uterus tissue following gynecological surgeries up-regulate molecular mechanisms to induce post-operative adhesions.What do the results of this study add? Recently there has been an increased focus on the role of the local renin-angiotensin system in organ fibrosis. The results of this Mini-review article refer to the pathological roles of the local renin-angiotensin system in fibrotic bands formation after gynecological operations. Over-activation of local renin-angiotensin systems up-regulate molecular mechanisms such as inflammation and the TGF-ß1 signalling pathway. TGF-ß as a profibrotic molecule strongly induces the expression of some fibrotic molecules such as PAI and TIMP to increase the risk of intrauterine adhesions.What are the implications of these findings for clinical practice and/or further research? According to the biological roles of local renin-angiotensin system and AT1R following injuries to develop post-operative adhesion, the administration of ARBs may be considered as a new therapeutic strategy for the prevention of IUA.

Procalcitonin as a Prognostic Factor in Patients with COVID-19 in Southwestern Iran.

BACKGROUND: There is increasing evidence supporting a central role of the viral-induced hyper-inflammatory immune response in the pathogenesis of COVID-19. Serum procalcitonin (PCT) is an emerging prognostic marker in coronavirus disease 2019 (COVID-19). The aim of this study was to investigate the relationship between serum procalcitonin and clinical severity and outcomes in patients with coronavirus disease 2019 (COVID-19). MATERIALS AND METHODS: Hematological and biochemical parameters were evaluated in patients with COVID-19 infection from February to April 2020 at Hajar Hospital in the Shahrekord University of Medical Science, Shahrekord, Iran. RESULTS: The results showed that total lymphocyte counts, albumin, calcium, and creatinine levels were significantly different between the two moderate and severe groups, and the mean of procalcitonin level in COVID-19 patients with severe disease was higher (0.36 ng/mL) compared with the patients with moderate disease, and its level was found to be >5 ng/mL in 14.2% of5 ng/mL in 14.2% of patients in the former group. CONCLUSION: PCT may be a marker of disease severity in COVID-19 and may contribute to determining the severity of patients infected with SARS-CoV-2. Moreover, serial PCT measurements may be beneficial in predicting the prognosis.

Hyperglycaemia and the risk of post-surgical adhesion.

Post-surgical adhesions are a major complication leading to organ dysfunctions, pain, intestinal obstruction, and infertility. The incidence of post-surgical adhesion is really high. The factors involved in the pathogenesis of post-surgical fibrosis, are largely unknown, for example why two patients with similar abdominal operation have a different risks of adhesion severity? High secretion of pro-inflammatory cytokines and growth factors, includes tumour necrosis factor α (TNF-α), interleukin 6 (IL6), and transforming growth factor ß (TGF-ß) by persistent recruitment of immune cells and the inappropriate proliferated fibroblast/mesothelial cells can stimulate signalling pathways particularly TGF-ß leads to the up-regulation of some pro-fibrotic genes that impair fibrinolytic activity and promote extracellular matrix (ECM) accumulation. In this review, we focus on the role of diabetes and hyperglycaemia on post-surgical fibrosis, including the molecular mechanisms affected by hyperglycaemia that cause inflammation, oxidative stress, and increase the expression of pro-fibrotic molecules.

The association between visceral adiposity with systemic inflammation, oxidative stress, and risk of post-surgical adhesion.

Abdominal and pelvic adhesions are common post-operative complications. Despite new medical technologies, these adhesions are appearing to be unavoidable and little is known about their causation; for example, why certain patients/or tissues are more prone to adhesions. There have been no clinical studies about increasing the risk adhesions in obese patients, but there is some evidence about the molecular mechanisms involving visceral fat (VF) that may lead to profibrotic conditions. VF is an endocrine/inflammatory organ which produces many biologically active molecules such as adipokines and inflammatory cytokines. Inflammatory conditions, oxidative stress, and the expression some fibrotic molecules in the VF may induce pathological conditions in the abdominal cavity that predispose to the formation of fibrotic bands.

The Potential Role of Changes in the Glucose and Lipid Metabolic Pathways in Gastrointestinal Cancer Progression: Strategy in Cancer Therapy.

BACKGROUND: Changes in cell metabolism are a well-known feature of some cancers, and this may be involved in the etiology of tumor formation and progression, as well as tumor heterogeneity. These changes may affect fatty acid metabolism and glycolysis and are required to provide the increase in energy necessary for the high rate of proliferation of cancer cells. Gastrointestinal cancers remain a difficult-to-treat cancer, particularly as they are usually diagnosed at a late stage of disease and are associated with poor outcomes. SUMMARY: Recently, the changes in the metabolic pathways, including the expression of the rate-limiting enzymes involved, have been considered to be a potential target for therapy for gastrointestinal tumors. KEY MESSAGE: A combination of routine chemotherapy drugs with metabolic inhibitors may improve the effectiveness of treatment.

Prognostic and Clinicopathologic Significance of Discoidin Domain Receptors in Different Human Malignancies: A Meta-Analysis.

BACKGROUND: Discoidin domain receptors (DDRs) belong to the receptor tyrosine kinases family and are activated by different types of collagens, which play roles in various physiological processes. An abnormal expression of DDRs is reported in different types of cancers. Despite many reports about the association and roles of high DDR expression levels in cancers, the prognostic values of DDRs are still unclear. This meta-analysis was performed to evaluate the prognostic effect of DDRs in different tissue cancers. METHOD: A literature search was performed in several related databases to find eligible English articles. Based on our research, 20 appropriate studies with 2,602 patients were selected till October 5, 2020. The pooled hazard ratio (HR) with a corresponding 95% confidence interval (CI) was computed to evaluate the strength of correlation between DDRs and survival of cancer patients. RESULT: Pooling results showed that a high DDR expression was significantly associated with poorer overall survival (OS) (HR = 1.304, 95% CI 1.007-1.69, p = 0.04). Subgroup analysis based on cancer type revealed a significant link between a high DDR expression level and poor OS both in gastrointestinal (pooled HR = 1.78, 95% CI 1.214-2.624, p = 0.003) and urological cancers (pooled HR = 1.42, 95% CI 1.062-1.82, p = 0.018). CONCLUSION: Our meta-analysis results suggest that high DDRs expression has the potential to be used as a biomarker of poor prognosis in cancers.

The Therapeutic Potential of MAPK/ERK Inhibitors in the Treatment of Colorectal Cancer.

The MAPK/ERK signaling pathway regulates cancer cell proliferation, apoptosis, inflammation, angiogenesis, metastasis and drug resistance. Mutations and up-regulation of components of the MAPK/ERK signaling pathway, as well as over-activation of this critical signaling pathway, are frequently observed in colorectal carcinomas. Targeting the MAPK/ERK signaling pathway, using specific pharmacological inhibitors, elicits potent anti-tumor effects, supporting the therapeutic potential of these inhibitors in the treatment of CRC. Several drugs have recently been developed for the inhibition of the MEK/ERK pathway in preclinical and clinical settings, such as MEK162 and MK-2206. MEK1/2 inhibitors demonstrate promising efficacy and anticancer activity for the treatment of this malignancy. This review summarizes the current knowledge on the role of the MAPK/ERK signaling pathway in the pathogenesis of CRC and the potential clinical value of synthetic inhibitors of this pathway in preventing CRC progression for a better understanding, and hence, better management of colorectal cancer.

Lysyl Oxidase Mechanisms to Mediate Gastrointestinal Cancer Progression.

BACKGROUND: Malignancy is a complex process resulting from different changes such as extracellular matrix (ECM) remodeling and stiffness. One of the important enzymes that contribute to ECM remodeling is lysyl oxidase (Lox) that is overexpressed in different types of human cancers. Because of the high prevalence and poor survival of gastrointestinal (GI) malignancies in this review, we discuss the association between Lox activity and the progression of GI cancers. Lox proteins are a group of extracellular enzymes that catalyzed the cross-linking of collagen and elastin, so they have important roles in the control of structure and homeostasis of ECM. Abnormal activation and expression of the Lox family of proteins lead to changes in the ECM toward increased rigidity and fibrosis. Stiffness of ECM can contribute to the pathogenesis of cancers. SUMMARY: Dysregulation of Lox expression is a factor in both fibrotic diseases and cancer. ECM stiffness by Lox overactivity creates a physical barrier against intratumoral concentration of chemotherapeutic drugs and facilitates cancer inflammation, angiogenesis, and metastasis. KEY MESSAGE: Because of the roles of Lox in GI cancers, development targeting Lox protein isotypes may be an appropriate strategy for treatment of GI cancers and improvement in survival of patients.

Metformin inhibits polyphosphate-induced hyper-permeability and inflammation.

Circulating inflammatory factor inorganic polyphosphate (polyP) released from activated platelets could enhance factor XII and bradykinin resulted in increased capillary leakage and vascular permeability. PolyP induce inflammatory responses through mTOR pathway in endothelial cells, which is being reported in several diseases including atherosclerosis, thrombosis, sepsis, and cancer. Systems and molecular biology approaches were used to explore the regulatory role of the AMPK activator, metformin, on polyP-induced hyper-permeability in different organs in three different models of polyP-induced hyper-permeability including local, systemic short- and systemic long-term approaches in murine models. Our results showed that polyP disrupts endothelial barrier integrity in skin, liver, kidney, brain, heart, and lung in all three study models and metformin abrogates the disruptive effect of polyP. We also showed that activation of AMPK signaling pathway, regulation of oxidant/anti-oxidant balance, as well as decrease in inflammatory cell infiltration constitute a set of molecular mechanisms through which metformin elicits it's protective responses against polyP-induced hyper-permeability. These results support the clinical values of AMPK activators including the FDA-approved metformin in attenuating vascular damage in polyP-associated inflammatory diseases.