moufida ben nasr - Profile on Academia.edu (original) (raw)
Papers by moufida ben nasr
Glucagon-like peptide 1 receptor is a T cell-negative costimulatory molecule
Cell metabolism, Jun 1, 2024
Frontiers in Endocrinology, Jan 21, 2024
Pancreatic beta cells replenishment is considered the next therapeutic option for type 1 diabetes... more Pancreatic beta cells replenishment is considered the next therapeutic option for type 1 diabetes; while stimulating endogenous beta cells proliferation is the "holy grail" for those patients with exhausted beta cell mass. Here we are demonstrating that the pro-apoptotic receptor TMEM219 is expressed in fetal pancreas, in beta cell precursors and in in vitro embryonic-derived endocrine progenitors. TMEM219 signaling negatively regulates beta cells at early stages and induces Caspase 8-mediated cell death. Pharmacological blockade of TMEM219 further rescued beta cell precursor and proliferation markers, and decreased cell death, both in islets and in in vitro-derived endocrine progenitors, allowing for beta cell preservation. While addressing the upstream controlling TMEM219 expression, we determined the TMEM219 miRNet; indeed, one of those miRNAs, miR-129-2, is highly expressed in human islets, particularly in patients at risk or with established type 1 diabetes. miR-129-2 mimic downregulated TMEM219 expression in islets, in in vitro embryonic-derived endocrine progenitors and in highly proliferating insulinoma-derived cells. Moreover, miR-129-2 inhibitor induced a TMEM219 overexpression in insulinoma-derived cells, which restored cell proliferation and functional markers, thus acting as endogenous regulator of TMEM219 expression. The TMEM219 upstream regulator miR129-2 controls the fate of beta cell precursors and may unleash their regenerative potentials to replenish beta cells in type 1 diabetes.
Type 2 diabetes mellitus pharmacological remission with dapagliflozin plus oral semaglutide
Pharmacological Research, Dec 31, 2023
Daytime hypoglycemic episodes during the use of an advanced hybrid closed loop system
Diabetes Research and Clinical Practice
Expert Opinion on Biological Therapy, Apr 17, 2020
Introduction: Type 1 diabetes (T1D) is a lifelong condition resulting from autoimmune destruction... more Introduction: Type 1 diabetes (T1D) is a lifelong condition resulting from autoimmune destruction of insulin-producing β-cells. Islet or whole-pancreas transplantation is limited by the shortage of donors and need for chronic immune suppression. Novel strategies are needed to prevent β-cell loss and to rescue production of endogenous insulin. Areas covered: This review covers the latest advances in cell-based therapies for the treatment and prevention of T1D. Topics include adoptive transfer of cells with increased immunoregulatory potential for β-cell protection, and β-cell replacement strategies such as generation of insulin-producing β-like cells from unlimited sources. Expert opinion: Cell therapy provides an opportunity to prevent or reverse T1D. Adoptive transfer of autologous cells having enhanced immunomodulatory properties can suppress autoimmunity and preserve β-cells. Such therapies have been made possible by a combination of genome-editing techniques and transplantation of tolerogenic cells. In-vitro modified autologous hematopoietic stem cells and tolerogenic dendritic cells may protect endogenous and newly generated β-cells from a patient's autoimmune response without hampering immune surveillance for infectious agents and malignant cellular transformations. However, methods to generate cells that meet quality and safety standards for clinical applications require further refinement.
Frontiers in Immunology, Nov 12, 2021
Extracellular (e)ATP, a potent pro-inflammatory molecule, is released by dying/damaged cells at t... more Extracellular (e)ATP, a potent pro-inflammatory molecule, is released by dying/damaged cells at the site of inflammation and it is degraded by the membrane ectonucleotidases CD39 and CD73. In this study, we sought to unveil the role of eATP degradation in autoimmune diabetes, we then assessed the effect of soluble CD39 (sCD39) administration in prevention and reversal studies in NOD mice as well as in mechanistic studies. Our data showed that eATP levels were increased in hyperglycemic NODs as compared to pre-diabetic NODs. CD39 and CD73 were found expressed by both α- and β-cells and by different subsets of T-cells. Importantly, pre-diabetic NOD mice displayed increased frequencies of CD3+CD73+CD39+ cells within their pancreata, pLNs and spleens. The administration of sCD39 into pre-diabetic NODs reduced their eATP levels, abrogated the proliferation of CD4+- and CD8+-autoreactive T-cells and increased the frequency of Tregs; while delaying the onset of T1D. Notably, concomitant ad...
Nano‐Targeted Delivery of Immune Therapeutics in type 1 Diabetes
Advanced Materials
Broadening horizons in mechanisms, management, and treatment of diabetic kidney disease
Pharmacological Research
eATP and autoimmune diabetes
Pharmacological Research
Stem Cells Translational Medicine
Insulin represents a life-saving treatment in patients with type 1 diabetes, and technological ad... more Insulin represents a life-saving treatment in patients with type 1 diabetes, and technological advancements have improved glucose control in an increasing number of patients. Despite this, adequate control is often still difficult to achieve and insulin remains a therapy and not a cure for the disease. β-cell replacement strategies can potentially restore pancreas endocrine function and aim to maintain normoglycemia; both pancreas and islet transplantation have greatly progressed over the last decades and, in subjects with extreme glycemic variability and diabetes complications, represent a concrete and effective treatment option. Some issues still limit the adoption of this approach on a larger scale. One is represented by the strict selection criteria for the recipient who can benefit from a transplant and maintain the lifelong immunosuppression necessary to avoid organ rejection. Second, with regard to islet transplantation, up to 40% of islets can be lost during hepatic engraftm...
BMJ Open Diabetes Research & Care
IntroductionGestational diabetes mellitus (GDM) is the most frequent metabolic complication durin... more IntroductionGestational diabetes mellitus (GDM) is the most frequent metabolic complication during pregnancy and is associated with development of short-term and long-term complications for newborns, with large-for-gestational-age (LGA) being particularly common. Interestingly, the mechanism behind altered fetal growth in GDM is only partially understood.Research design and methodsA proteomic approach was used to analyze placental samples obtained from healthy pregnant women (n=5), patients with GDM (n=12) and with GDM and LGA (n=5). Effects of altered proteins on fetal development were tested in vitro in human embryonic stem cells (hESCs).ResultsHere, we demonstrate that the placental proteome is altered in pregnant women affected by GDM with LGA, with at least 37 proteins differentially expressed to a higher degree (p<0.05) as compared with those with GDM but without LGA. Among these proteins, 10 are involved in regulating tissue differentiation and/or fetal growth and developm...
Pharmacologically Enhanced Regulatory Hematopoietic Stem Cells Revert Experimental Autoimmune Diabetes and Mitigate Other Autoimmune Disorders
The Journal of Immunology
Type 1 diabetes (T1D) is characterized by the loss of immune self-tolerance, resulting in an aber... more Type 1 diabetes (T1D) is characterized by the loss of immune self-tolerance, resulting in an aberrant immune responses against self-tissue. A few therapeutics have been partially successful in reverting or slowing down T1D progression in patients, and the infusion of autologous hematopoietic stem cells (HSCs) is emerging as an option to be explored. In this study, we proposed to pharmacologically enhance by ex vivo modulation with small molecules the immunoregulatory and trafficking properties of HSCs to provide a safer and more efficacious treatment option for patients with T1D and other autoimmune disorders. A high-throughput targeted RNA sequencing screening strategy was used to identify a combination of small molecules (16,16-dimethyl PGE2 and dexamethasone), which significantly upregulate key genes involved in trafficking (e.g., CXCR4) and immunoregulation (e.g., programmed death ligand 1). The pharmacologically enhanced, ex vivo–modulated HSCs (regulatory HSCs [HSC.Regs]) have...
Acta Diabetologica
Aims Abnormalities in the oculomotor system may represent an early sign of diabetic neuropathy an... more Aims Abnormalities in the oculomotor system may represent an early sign of diabetic neuropathy and are currently poorly studied. We designed an eye-tracking-based test to evaluate oculomotor function in patients with type 1 diabetes. Methods We used the SRLab—Tobii TX300 Eye tracker®, an eye-tracking device, coupled with software that we developed to test abnormalities in the oculomotor system. The software consists of a series of eye-tracking tasks divided into 4 classes of parameters (Resistance, Wideness, Pursuit and Velocity) to evaluate both smooth and saccadic movement in different directions. We analyzed the oculomotor system in 34 healthy volunteers and in 34 patients with long-standing type 1 diabetes. Results Among the 474 parameters analyzed with the eye-tracking-based system, 11% were significantly altered in patients with type 1 diabetes (p < 0.05), with a higher proportion of abnormalities observed in the Wideness (24%) and Resistance (10%) parameters. Patients with...
Indirect and Direct Effects of SARS-CoV-2 on Human Pancreatic Islets
Diabetes
Recent studies have shown that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infec... more Recent studies have shown that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may induce metabolic distress, leading to hyperglycemia in patients affected by coronavirus disease 19 (COVID-19). We investigated the potential indirect and direct effects of SARS-CoV-2 on human pancreatic islets in 10 patients who became hyperglycemic after COVID-19. Although there was no evidence of peripheral anti-islet autoimmunity, the serum of these patients displayed toxicity on human pancreatic islets, which could be abrogated by the use of anti–interleukin-1β (IL-1β), anti–IL-6, and anti–tumor necrosis factor α, cytokines known to be highly upregulated during COVID-19. Interestingly, the receptors of those aforementioned cytokines were highly expressed on human pancreatic islets. An increase in peripheral unmethylated INS DNA, a marker of cell death, was evident in several patients with COVID-19. Pathology of the pancreas from deceased hyperglycemic patients who had COVID-...
Patients with type 1 diabetes (T1D) may develop severe outcomes during COVID-19 disease, but thei... more Patients with type 1 diabetes (T1D) may develop severe outcomes during COVID-19 disease, but their ability to generate an immune response against the SARS-CoV-2 messenger RNA (mRNA) vaccines remains to be established. Here we evaluated the safety, immunogenicity and glycometabolic effects of the SARS-CoV-2 mRNA vaccines in patients with T1D. A total of 375 patients, 326 with T1D and 49 non-diabetics, who received two doses of the SARS-CoV-2 mRNA vaccines (mRNA-1273, BNT162b2) between March and April 2021 at the ASST FBF-Sacco Milan, Italy, were included in this monocentric observational study (NCT04905823). Local and systemic adverse events were reported in both groups after SARS-CoV-2 mRNA vaccination without statistical differences between them. While both T1D patients and non-diabetic subjects exhibited a parallel increase in anti-SARS-CoV-2S titers after vaccination, the vast majority of T1D patients (70% and 78% respectively) did not show any increase in the SARS-CoV-2-specific...
The IL-8-CXCR1/2 axis contributes to diabetic kidney disease
Metabolism, 2021
AIMS/HYPOTHESIS Inflammation has a major role in diabetic kidney disease. We thus investigated th... more AIMS/HYPOTHESIS Inflammation has a major role in diabetic kidney disease. We thus investigated the role of the IL-8-CXCR1/2 axis in favoring kidney damage in diabetes. METHODS Urinary IL-8 levels were measured in 1247 patients of the Joslin Kidney Study in type 2 diabetes (T2D). The expression of IL-8 and of its membrane receptors CXCR1/CXCR2 was quantified in kidney tissues in patients with T2D and in controls. The effect of CXCR1/2 blockade on diabetic kidney disease was evaluated in db/db mice. RESULTS IL-8 urinary levels were increased in patients with T2D and diabetic kidney disease, with the highest urinary IL-8 levels found in the patients with the largest decline in glomerular filtration rate, with an increased albumin/creatine ratio and the worst renal outcome. Moreover, glomerular IL-8 renal expression was increased in patients with T2D, as compared to controls. High glucose elicits abundant IL-8 secretion in cultured human immortalized podocytes in vitro. Finally, in diabetic db/db mice and in podocytes in vitro, CXCR1/2 blockade mitigated albuminuria, reduced mesangial expansion, decreased podocyte apoptosis and reduced DNA damage. CONCLUSIONS/INTERPRETATION The IL-8- CXCR1/2 axis may have a role in diabetic kidney disease by inducing podocyte damage. Indeed, targeting the IL-8-CXCR1/2 axis may reduce the burden of diabetic kidney disease.
Hyperglycaemia occurring in diabetes is responsible for accelerated arterial remodeling and ather... more Hyperglycaemia occurring in diabetes is responsible for accelerated arterial remodeling and atherosclerosis, affecting the macroand the microcirculatory system. Vessel injury is mainly related to deregulation of glucose homeostasis and insulin/insulinprecursors production, generation of advanced glycation end-products, reduction in nitric oxide synthesis, and oxidative and reductive stress. It occurs both at extracellular level with increased calcium and matrix proteins deposition and at intracellular level, with abnormalities of intracellular pathways and increased cell death. Peripheral arterial disease, coronary heart disease, and ischemic stroke are the main causes of morbidity/mortality in diabetic patients representing a major clinical and economic issue. Pharmacological therapies, administration of growth factors, and stem cellular strategies are the most effective approaches and will be discussed in depth in this comprehensive review covering the regenerative therapies of diabetic microangiopathy.
Frontiers in Immunology, 2021
Despite the increasing knowledge of pathophysiological mechanisms underlying the onset of type 1 ... more Despite the increasing knowledge of pathophysiological mechanisms underlying the onset of type 1 diabetes (T1D), the quest for therapeutic options capable of delaying/reverting the diseases is still ongoing. Among all strategies currently tested in T1D, the use of hematopoietic stem cell (HSC)-based approaches and of teplizumab, showed the most encouraging results. Few clinical trials have already demonstrated the beneficial effects of HSCs in T1D, while the durability of the effect is yet to be established. Investigators are also trying to understand whether the use of selected and better-characterized HSCs subsets may provide more benefits with less risks. Interestingly, ex vivo manipulated HSCs showed promising results in murine models and the recent introduction of the humanized mouse models accelerated the translational potentials of such studies and their final road to clinic. Indeed, immunomodulatory as well as trafficking abilities can be enhanced in genetically modulated HS...
Glucagon-like peptide 1 receptor is a T cell-negative costimulatory molecule
Cell metabolism, Jun 1, 2024
Frontiers in Endocrinology, Jan 21, 2024
Pancreatic beta cells replenishment is considered the next therapeutic option for type 1 diabetes... more Pancreatic beta cells replenishment is considered the next therapeutic option for type 1 diabetes; while stimulating endogenous beta cells proliferation is the "holy grail" for those patients with exhausted beta cell mass. Here we are demonstrating that the pro-apoptotic receptor TMEM219 is expressed in fetal pancreas, in beta cell precursors and in in vitro embryonic-derived endocrine progenitors. TMEM219 signaling negatively regulates beta cells at early stages and induces Caspase 8-mediated cell death. Pharmacological blockade of TMEM219 further rescued beta cell precursor and proliferation markers, and decreased cell death, both in islets and in in vitro-derived endocrine progenitors, allowing for beta cell preservation. While addressing the upstream controlling TMEM219 expression, we determined the TMEM219 miRNet; indeed, one of those miRNAs, miR-129-2, is highly expressed in human islets, particularly in patients at risk or with established type 1 diabetes. miR-129-2 mimic downregulated TMEM219 expression in islets, in in vitro embryonic-derived endocrine progenitors and in highly proliferating insulinoma-derived cells. Moreover, miR-129-2 inhibitor induced a TMEM219 overexpression in insulinoma-derived cells, which restored cell proliferation and functional markers, thus acting as endogenous regulator of TMEM219 expression. The TMEM219 upstream regulator miR129-2 controls the fate of beta cell precursors and may unleash their regenerative potentials to replenish beta cells in type 1 diabetes.
Type 2 diabetes mellitus pharmacological remission with dapagliflozin plus oral semaglutide
Pharmacological Research, Dec 31, 2023
Daytime hypoglycemic episodes during the use of an advanced hybrid closed loop system
Diabetes Research and Clinical Practice
Expert Opinion on Biological Therapy, Apr 17, 2020
Introduction: Type 1 diabetes (T1D) is a lifelong condition resulting from autoimmune destruction... more Introduction: Type 1 diabetes (T1D) is a lifelong condition resulting from autoimmune destruction of insulin-producing β-cells. Islet or whole-pancreas transplantation is limited by the shortage of donors and need for chronic immune suppression. Novel strategies are needed to prevent β-cell loss and to rescue production of endogenous insulin. Areas covered: This review covers the latest advances in cell-based therapies for the treatment and prevention of T1D. Topics include adoptive transfer of cells with increased immunoregulatory potential for β-cell protection, and β-cell replacement strategies such as generation of insulin-producing β-like cells from unlimited sources. Expert opinion: Cell therapy provides an opportunity to prevent or reverse T1D. Adoptive transfer of autologous cells having enhanced immunomodulatory properties can suppress autoimmunity and preserve β-cells. Such therapies have been made possible by a combination of genome-editing techniques and transplantation of tolerogenic cells. In-vitro modified autologous hematopoietic stem cells and tolerogenic dendritic cells may protect endogenous and newly generated β-cells from a patient's autoimmune response without hampering immune surveillance for infectious agents and malignant cellular transformations. However, methods to generate cells that meet quality and safety standards for clinical applications require further refinement.
Frontiers in Immunology, Nov 12, 2021
Extracellular (e)ATP, a potent pro-inflammatory molecule, is released by dying/damaged cells at t... more Extracellular (e)ATP, a potent pro-inflammatory molecule, is released by dying/damaged cells at the site of inflammation and it is degraded by the membrane ectonucleotidases CD39 and CD73. In this study, we sought to unveil the role of eATP degradation in autoimmune diabetes, we then assessed the effect of soluble CD39 (sCD39) administration in prevention and reversal studies in NOD mice as well as in mechanistic studies. Our data showed that eATP levels were increased in hyperglycemic NODs as compared to pre-diabetic NODs. CD39 and CD73 were found expressed by both α- and β-cells and by different subsets of T-cells. Importantly, pre-diabetic NOD mice displayed increased frequencies of CD3+CD73+CD39+ cells within their pancreata, pLNs and spleens. The administration of sCD39 into pre-diabetic NODs reduced their eATP levels, abrogated the proliferation of CD4+- and CD8+-autoreactive T-cells and increased the frequency of Tregs; while delaying the onset of T1D. Notably, concomitant ad...
Nano‐Targeted Delivery of Immune Therapeutics in type 1 Diabetes
Advanced Materials
Broadening horizons in mechanisms, management, and treatment of diabetic kidney disease
Pharmacological Research
eATP and autoimmune diabetes
Pharmacological Research
Stem Cells Translational Medicine
Insulin represents a life-saving treatment in patients with type 1 diabetes, and technological ad... more Insulin represents a life-saving treatment in patients with type 1 diabetes, and technological advancements have improved glucose control in an increasing number of patients. Despite this, adequate control is often still difficult to achieve and insulin remains a therapy and not a cure for the disease. β-cell replacement strategies can potentially restore pancreas endocrine function and aim to maintain normoglycemia; both pancreas and islet transplantation have greatly progressed over the last decades and, in subjects with extreme glycemic variability and diabetes complications, represent a concrete and effective treatment option. Some issues still limit the adoption of this approach on a larger scale. One is represented by the strict selection criteria for the recipient who can benefit from a transplant and maintain the lifelong immunosuppression necessary to avoid organ rejection. Second, with regard to islet transplantation, up to 40% of islets can be lost during hepatic engraftm...
BMJ Open Diabetes Research & Care
IntroductionGestational diabetes mellitus (GDM) is the most frequent metabolic complication durin... more IntroductionGestational diabetes mellitus (GDM) is the most frequent metabolic complication during pregnancy and is associated with development of short-term and long-term complications for newborns, with large-for-gestational-age (LGA) being particularly common. Interestingly, the mechanism behind altered fetal growth in GDM is only partially understood.Research design and methodsA proteomic approach was used to analyze placental samples obtained from healthy pregnant women (n=5), patients with GDM (n=12) and with GDM and LGA (n=5). Effects of altered proteins on fetal development were tested in vitro in human embryonic stem cells (hESCs).ResultsHere, we demonstrate that the placental proteome is altered in pregnant women affected by GDM with LGA, with at least 37 proteins differentially expressed to a higher degree (p<0.05) as compared with those with GDM but without LGA. Among these proteins, 10 are involved in regulating tissue differentiation and/or fetal growth and developm...
Pharmacologically Enhanced Regulatory Hematopoietic Stem Cells Revert Experimental Autoimmune Diabetes and Mitigate Other Autoimmune Disorders
The Journal of Immunology
Type 1 diabetes (T1D) is characterized by the loss of immune self-tolerance, resulting in an aber... more Type 1 diabetes (T1D) is characterized by the loss of immune self-tolerance, resulting in an aberrant immune responses against self-tissue. A few therapeutics have been partially successful in reverting or slowing down T1D progression in patients, and the infusion of autologous hematopoietic stem cells (HSCs) is emerging as an option to be explored. In this study, we proposed to pharmacologically enhance by ex vivo modulation with small molecules the immunoregulatory and trafficking properties of HSCs to provide a safer and more efficacious treatment option for patients with T1D and other autoimmune disorders. A high-throughput targeted RNA sequencing screening strategy was used to identify a combination of small molecules (16,16-dimethyl PGE2 and dexamethasone), which significantly upregulate key genes involved in trafficking (e.g., CXCR4) and immunoregulation (e.g., programmed death ligand 1). The pharmacologically enhanced, ex vivo–modulated HSCs (regulatory HSCs [HSC.Regs]) have...
Acta Diabetologica
Aims Abnormalities in the oculomotor system may represent an early sign of diabetic neuropathy an... more Aims Abnormalities in the oculomotor system may represent an early sign of diabetic neuropathy and are currently poorly studied. We designed an eye-tracking-based test to evaluate oculomotor function in patients with type 1 diabetes. Methods We used the SRLab—Tobii TX300 Eye tracker®, an eye-tracking device, coupled with software that we developed to test abnormalities in the oculomotor system. The software consists of a series of eye-tracking tasks divided into 4 classes of parameters (Resistance, Wideness, Pursuit and Velocity) to evaluate both smooth and saccadic movement in different directions. We analyzed the oculomotor system in 34 healthy volunteers and in 34 patients with long-standing type 1 diabetes. Results Among the 474 parameters analyzed with the eye-tracking-based system, 11% were significantly altered in patients with type 1 diabetes (p < 0.05), with a higher proportion of abnormalities observed in the Wideness (24%) and Resistance (10%) parameters. Patients with...
Indirect and Direct Effects of SARS-CoV-2 on Human Pancreatic Islets
Diabetes
Recent studies have shown that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infec... more Recent studies have shown that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may induce metabolic distress, leading to hyperglycemia in patients affected by coronavirus disease 19 (COVID-19). We investigated the potential indirect and direct effects of SARS-CoV-2 on human pancreatic islets in 10 patients who became hyperglycemic after COVID-19. Although there was no evidence of peripheral anti-islet autoimmunity, the serum of these patients displayed toxicity on human pancreatic islets, which could be abrogated by the use of anti–interleukin-1β (IL-1β), anti–IL-6, and anti–tumor necrosis factor α, cytokines known to be highly upregulated during COVID-19. Interestingly, the receptors of those aforementioned cytokines were highly expressed on human pancreatic islets. An increase in peripheral unmethylated INS DNA, a marker of cell death, was evident in several patients with COVID-19. Pathology of the pancreas from deceased hyperglycemic patients who had COVID-...
Patients with type 1 diabetes (T1D) may develop severe outcomes during COVID-19 disease, but thei... more Patients with type 1 diabetes (T1D) may develop severe outcomes during COVID-19 disease, but their ability to generate an immune response against the SARS-CoV-2 messenger RNA (mRNA) vaccines remains to be established. Here we evaluated the safety, immunogenicity and glycometabolic effects of the SARS-CoV-2 mRNA vaccines in patients with T1D. A total of 375 patients, 326 with T1D and 49 non-diabetics, who received two doses of the SARS-CoV-2 mRNA vaccines (mRNA-1273, BNT162b2) between March and April 2021 at the ASST FBF-Sacco Milan, Italy, were included in this monocentric observational study (NCT04905823). Local and systemic adverse events were reported in both groups after SARS-CoV-2 mRNA vaccination without statistical differences between them. While both T1D patients and non-diabetic subjects exhibited a parallel increase in anti-SARS-CoV-2S titers after vaccination, the vast majority of T1D patients (70% and 78% respectively) did not show any increase in the SARS-CoV-2-specific...
The IL-8-CXCR1/2 axis contributes to diabetic kidney disease
Metabolism, 2021
AIMS/HYPOTHESIS Inflammation has a major role in diabetic kidney disease. We thus investigated th... more AIMS/HYPOTHESIS Inflammation has a major role in diabetic kidney disease. We thus investigated the role of the IL-8-CXCR1/2 axis in favoring kidney damage in diabetes. METHODS Urinary IL-8 levels were measured in 1247 patients of the Joslin Kidney Study in type 2 diabetes (T2D). The expression of IL-8 and of its membrane receptors CXCR1/CXCR2 was quantified in kidney tissues in patients with T2D and in controls. The effect of CXCR1/2 blockade on diabetic kidney disease was evaluated in db/db mice. RESULTS IL-8 urinary levels were increased in patients with T2D and diabetic kidney disease, with the highest urinary IL-8 levels found in the patients with the largest decline in glomerular filtration rate, with an increased albumin/creatine ratio and the worst renal outcome. Moreover, glomerular IL-8 renal expression was increased in patients with T2D, as compared to controls. High glucose elicits abundant IL-8 secretion in cultured human immortalized podocytes in vitro. Finally, in diabetic db/db mice and in podocytes in vitro, CXCR1/2 blockade mitigated albuminuria, reduced mesangial expansion, decreased podocyte apoptosis and reduced DNA damage. CONCLUSIONS/INTERPRETATION The IL-8- CXCR1/2 axis may have a role in diabetic kidney disease by inducing podocyte damage. Indeed, targeting the IL-8-CXCR1/2 axis may reduce the burden of diabetic kidney disease.
Hyperglycaemia occurring in diabetes is responsible for accelerated arterial remodeling and ather... more Hyperglycaemia occurring in diabetes is responsible for accelerated arterial remodeling and atherosclerosis, affecting the macroand the microcirculatory system. Vessel injury is mainly related to deregulation of glucose homeostasis and insulin/insulinprecursors production, generation of advanced glycation end-products, reduction in nitric oxide synthesis, and oxidative and reductive stress. It occurs both at extracellular level with increased calcium and matrix proteins deposition and at intracellular level, with abnormalities of intracellular pathways and increased cell death. Peripheral arterial disease, coronary heart disease, and ischemic stroke are the main causes of morbidity/mortality in diabetic patients representing a major clinical and economic issue. Pharmacological therapies, administration of growth factors, and stem cellular strategies are the most effective approaches and will be discussed in depth in this comprehensive review covering the regenerative therapies of diabetic microangiopathy.
Frontiers in Immunology, 2021
Despite the increasing knowledge of pathophysiological mechanisms underlying the onset of type 1 ... more Despite the increasing knowledge of pathophysiological mechanisms underlying the onset of type 1 diabetes (T1D), the quest for therapeutic options capable of delaying/reverting the diseases is still ongoing. Among all strategies currently tested in T1D, the use of hematopoietic stem cell (HSC)-based approaches and of teplizumab, showed the most encouraging results. Few clinical trials have already demonstrated the beneficial effects of HSCs in T1D, while the durability of the effect is yet to be established. Investigators are also trying to understand whether the use of selected and better-characterized HSCs subsets may provide more benefits with less risks. Interestingly, ex vivo manipulated HSCs showed promising results in murine models and the recent introduction of the humanized mouse models accelerated the translational potentials of such studies and their final road to clinic. Indeed, immunomodulatory as well as trafficking abilities can be enhanced in genetically modulated HS...