PPARβ/δ: A Key Therapeutic Target in Metabolic Disorders

Research in recent years on peroxisome proliferator-activated receptor (PPAR)β/δ indicates that it plays a key role in the maintenance of energy homeostasis, both at the cellular level and within the organism as a whole. PPARβ/δ activation might help prevent the development of metabolic disorders, including obesity, dyslipidaemia, type 2 diabetes mellitus and non-alcoholic fatty liver disease. This review highlights research findings on the PPARβ/δ regulation of energy metabolism and the development of diseases related to altered cellular and body metabolism. It also describes the potential of the pharmacological activation of PPARβ/δ as a treatment for human metabolic disorder

Tissue Compatibility of SN-38-Loaded Anticancer Nanofiber Matrices

Delivery of chemotherapy in the surgical bed has shown preclinical activity to control cancer progression upon subtotal resection of pediatric solid tumors, but whether this new treatment is safe for tumor‐adjacent healthy tissues remains unknown. Here, Wistar rats are used to study the anatomic and functional impact of electrospun nanofiber matrices eluting SN‐38 a potent chemotherapeutic agent on several body sites where pediatric tumors such as neuroblastoma, Ewing sarcoma, and rhabdomyosarcoma arise. Blank and SN‐38‐loaded matrices embracing the femoral neurovascular bundle or in direct contact with abdominal viscera (liver, kidney, urinary bladder, intestine, and uterus) are placed. Foreign body tissue reaction to the implants is observed though no histologic damage in any tissue/organ. Skin healing is normal. Tissue reaction is similar for SN‐38‐loaded and blank matrices, with the exception of the hepatic capsule that is thicker for the former although within the limits consistent with mild foreign body reaction. Tissue and organ function is completely conserved after local treatments, as assessed by the rotarod test (forelimb function), hematologic tests (liver and renal function), and control of clinical signs. Overall, these findings support the clinical translation of SN‐38‐loaded nanofiber matrices to improve local control strategies of surgically resected tumors

Tissue compatibility of SN-38-loaded anticancer nanofiber matrices

Delivery of chemotherapy in the surgical bed has shown preclinical activity to control cancer progression upon subtotal resection of pediatric solid tumors, but whether this new treatment is safe for tumor-adjacent healthy tissues remains unknown. Here, Wistar rats are used to study the anatomic and functional impact of electrospun nano¿ber matrices eluting SN-38—a potent chemotherapeutic agent—on several body sites where pediatric tumors such as neuroblastoma, Ewing sarcoma, and rhabdomyosarcoma arise. Blank and SN-38-loaded matrices embracing the femoral neurovascular bundle or in direct contact with abdominal viscera (liver, kidney, urinary bladder, intestine, and uterus) are placed. Foreign body tissue reaction to the implants is observed though no histologic damage in any tissue/organ. Skin healing is normal. Tissue reaction is similar for SN-38-loaded and blank matrices, with the exception of the hepatic capsule that is thicker for the former although within the limits consistent with mild foreign body reaction. Tissue and organ function is completely conserved after local treatments, as assessed by the rotarod test (forelimb function), hematologic tests (liver and renal function), and control of clinical signs. Overall, these ¿ndings support the clinical translation of SN-38-loaded nano¿ber matrices to improve local control strategies of surgically resected tumorsPostprint (author's final draft

The Bace1 product sAPPβ induces ER stress and inflammation and impairs insulin signaling

Objective -secretase/-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) is a key enzyme involved in Alzheimer's disease that has recently been implicated in insulin-independent glucose uptake in myotubes. However, it is presently unknown whether BACE1 and the product of its activity, soluble APPsAPPcontribute to lipid-induced inflammation and insulin resistance in skeletal muscle cells. Materials/Methods Studies were conducted in mouse C2C12 myotubes, skeletal muscle from Bace1-/-mice and mice treated with sAPP and adipose tissue and plasma from obese and type 2 diabetic patients. Results We show that BACE1 inhibition or knockdown attenuates palmitate-induced endoplasmic reticulum (ER) stress, inflammation, and insulin resistance and prevents the reduction in Peroxisome Proliferator- Activated Receptor Co-activator 1 (PGC-1) and fatty acid oxidation caused by palmitate in myotubes. The effects of palmitate on ER stress, inflammation, insulin resistance, PGC-1 down-regulation, and fatty acid oxidation were mimicked by soluble APP in vitro. BACE1 expression was increased in subcutaneous adipose tissue of obese and type 2 diabetic patients and this was accompanied by a decrease in PGC-1 mRNA levels and by an increase in sAPPplasma levels of obese type 2 diabetic patients compared to obese non-diabetic subjects. Acute sAPP administration to mice reduced PGC-1 levels and increased inflammation in skeletal muscle and decreased insulin sensitivity. Conclusions Collectively, these findings indicate that the BACE1 product sAPP is a key determinant in ER stress, inflammation and insulin resistance in skeletal muscle and gluconeogenesis in liver

How future surgery will benefit from SARS-COV-2-related measures: a SPIGC survey conveying the perspective of Italian surgeons

COVID-19 negatively affected surgical activity, but the potential benefits resulting from adopted measures remain unclear. The aim of this study was to evaluate the change in surgical activity and potential benefit from COVID-19 measures in perspective of Italian surgeons on behalf of SPIGC. A nationwide online survey on surgical practice before, during, and after COVID-19 pandemic was conducted in March-April 2022 (NCT:05323851). Effects of COVID-19 hospital-related measures on surgical patients' management and personal professional development across surgical specialties were explored. Data on demographics, pre-operative/peri-operative/post-operative management, and professional development were collected. Outcomes were matched with the corresponding volume. Four hundred and seventy-three respondents were included in final analysis across 14 surgical specialties. Since SARS-CoV-2 pandemic, application of telematic consultations (4.1% vs. 21.6%; p < 0.0001) and diagnostic evaluations (16.4% vs. 42.2%; p < 0.0001) increased. Elective surgical activities significantly reduced and surgeons opted more frequently for conservative management with a possible indication for elective (26.3% vs. 35.7%; p < 0.0001) or urgent (20.4% vs. 38.5%; p < 0.0001) surgery. All new COVID-related measures are perceived to be maintained in the future. Surgeons' personal education online increased from 12.6% (pre-COVID) to 86.6% (post-COVID; p < 0.0001). Online educational activities are considered a beneficial effect from COVID pandemic (56.4%). COVID-19 had a great impact on surgical specialties, with significant reduction of operation volume. However, some forced changes turned out to be benefits. Isolation measures pushed the use of telemedicine and telemetric devices for outpatient practice and favored communication for educational purposes and surgeon-patient/family communication. From the Italian surgeons' perspective, COVID-related measures will continue to influence future surgical clinical practice

Novel potential determinants in endoplasmic reticulum stress, inflammation and insulin resistance: Apo CIII and sAPPβ

Diabetes represents one of the biggest health challenges of the 21st century. Insulin resistance is the primary defect in the most common form of diabetes, type 2 diabetes mellitus (T2D), and is defined as a failure in the capacity of insulin to drive glucose into its target tissues. This condition both predicts and precedes the development of T2D. Loss of insulin sensitivity in skeletal muscle is the major defect in T2D and is believed to be critical in the pathogenesis of this disease. Elucidating new molecular mechanisms involved in insulin resistance in skeletal muscle may lead to the development of new strategies for the prevention and treatment of T2D. Insulin resistance develops as the result of the expansion of adipose tissue in obese individuals, which releases increased amounts of fatty acids, hormones, pro-inflammatory cytokines and other factors. Most of these molecules induce the activation of a chronic low-level inflammatory process that contributes to insulin resistance and T2D. The molecular mechanisms by which these molecules induce a low-grade and chronic inflammatory process in obese patients are not completely understood. However, some studies have shown that alterations in the endoplasmic reticulum (ER) might contribute to the development of an inflammatory status and consequently to insulin resistance. Obesity and insulin resistance are also characterized by the presence of atherogenic dyslipidemia, which refers to elevated levels of triglycerides (TG) and the particles responsible for carrying these lipids in the plasma, the very low-density lipoproteins (VLDL), low levels of high-density lipoproteins (HDL), and increased levels of small, dense low-density lipoproteins (sdLDL). In addition to TG, VLDL also contain apolipoproteins, of which apolipoprotein CIII (Apo CIII) is one of the most abundant. Although plasma levels of VLDL and Apo CIII are increased in diabetic patients, little was known about whether the increase in the levels of these lipoproteins and apolipoproteins contributes to exacerbate insulin resistance and the mechanisms involved. Recent evidence indicates that subjects suffering T2D are at higher risk of developing Alzheimer’s Disease (AD). In addition, several evidences point out that the converse is also true, since cognitive impairment and Alzheimer’s dementia can induce central and peripheral insulin resistance, thus increasing the risk of T2D. The β-site Amyloid precursor protein Cleaving Enzyme 1 (BACE1) or β-secretase is a key enzyme involved in AD and is responsible for the cleavage of Amyloid Precursor Protein in the amyloidogenic pathway. It has been recently reported that BACE1 is also implicated in glucose metabolism. Thus, BACE1-deficient mice are protected against high fat diet (HFD)-induced glucose intolerance and inhibition of BACE1 activity increases insulin-independent glucose uptake. BACE1 is proteolytically active not only in the brain but also in skeletal muscle, suggesting that this enzyme might be involved in development of systemic insulin resistance. However, little was known about whether BACE1 contributes to ER stress, inflammation and insulin resistance. In this thesis, we report that the increase in the levels of VLDL can promote ER stress, inflammation, and insulin resistance in skeletal muscle through Apo CIII-mediated activation of the toll-like receptor 2. Moreover, BACE1 inhibition in myotubes results in an improvement in lipid-induced ER stress, inflammation, and insulin resistance. Further, the product of BACE1 enzymatic activity, soluble amyloid precursor protein β (sAPPβ), mimics the effects of palmitate and induces ER stress, inflammation and insulin resistance. Overall, these findings suggest that both VLDL-Apo CIII and sAPPβ are new determinants involved in ER stress, inflammation and insulin resistance in skeletal muscle

Postsurgical pain related to breast implant: reduction with lipofilling procedure

After a review of clinical cases of the Unit of Plastic Surgery of the University of Siena, Italy, we found that 22 patients undergoing lipofilling for breast recontruction needed less pain drugs compared to 18 patients which did not undergo lipofilling. In this work, the postoperative pain was analyzed in two groups of patients: a cohort treated with prosthesis and a cohort treated with prosthesis implant together with a lipofilling procedure

miR-146a targets Fos expression in human cardiac cells

miR-146a is a microRNA whose transcript levels are induced in the heart upon activation of NF-kappaB, a transcription factor induced by pro-inflammatory molecules strongly related to the pathogenesis of cardiac disorders. The main goal of this study consisted in studying new roles of miR-146a in cardiac pathological processes caused by the pro-inflammatory cytokine TNF-alpha. Our results demonstrate that miR-146a transcript levels were sharply increased in cardiac ventricular tissue of transgenic mice with specific overexpression of TNF-alpha in the heart, and also in a cardiomyocyte cell line of human origin (AC16) exposed to TNF-alpha. Among all the in silico predicted miR-146a target genes, c-Fos mRNA and protein levels notably decreased after TNF-alpha treatment or miR-146a overexpression. These changes correlated with a diminution in the DNA-binding activity of AP-1, the c-Fos-containing transcription factor complex. Interestingly, AP-1 inhibition was accompanied by a reduction in matrix metalloproteinase (MMP)-9 mRNA levels in human cardiac cells. The specific regulation of this matrix metalloproteinase by miR-146a was further confirmed at the secretion and enzymatic activity levels, as well as after anti-miR-mediated miR-146a inhibition. The results reported here demonstrate that c-Fos is a direct target of miR-146a activity and that c-Fos/AP-1 pathway downregulation by miR-146a has the capacity to inhibit MMP-9 activity. Given that MMP-9 is an AP-1 target gene involved in cardiac remodeling, myocardial dysfunction and progression of heart failure, these findings suggest that miR-146a may be a new and promising therapeutic tool for treating cardiac disorders associated with enhanced inflammation in the heart

PPARβ/δ: A Key Therapeutic Target in Metabolic Disorders

Research in recent years on peroxisome proliferator-activated receptor (PPAR)β/δ indicates that it plays a key role in the maintenance of energy homeostasis, both at the cellular level and within the organism as a whole. PPARβ/δ activation might help prevent the development of metabolic disorders, including obesity, dyslipidaemia, type 2 diabetes mellitus and non-alcoholic fatty liver disease. This review highlights research findings on the PPARβ/δ regulation of energy metabolism and the development of diseases related to altered cellular and body metabolism. It also describes the potential of the pharmacological activation of PPARβ/δ as a treatment for human metabolic disorders

VLDL and apolipoprotein CIII induce ER stress and inflammation and attenuate insulin signalling via Toll-like receptor 2 in mouse skeletal muscle cells

[Aim/hypothesis] Here, our aim was to examine whether VLDL and apolipoprotein (apo) CIII induce endoplasmic reticulum (ER) stress, inflammation and insulin resistance in skeletal muscle. [Methods] Studies were conducted in mouse C2C12 myotubes, isolated skeletal muscle and skeletal muscle from transgenic mice overexpressing apoCIII. [Results] C2C12 myotubes exposed to VLDL showed increased levels of ER stress and inflammatory markers whereas peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) and AMP-activated protein kinase (AMPK) levels were reduced and the insulin signalling pathway was attenuated. The effects of VLDL were also observed in isolated skeletal muscle incubated with VLDL. The changes caused by VLDL were dependent on extracellular signal-regulated kinase (ERK) 1/2 since they were prevented by the ERK1/2 inhibitor U0126 or by knockdown of this kinase by siRNA transfection. ApoCIII mimicked the effects of VLDL and its effects were also blocked by ERK1/2 inhibition, suggesting that this apolipoprotein was responsible for the effects of VLDL. Skeletal muscle from transgenic mice overexpressing apoCIII showed increased levels of some ER stress and inflammatory markers and increased phosphorylated ERK1/2 levels, whereas PGC-1α levels were reduced, confirming apoCIII effects in vivo. Finally, incubation of myotubes with a neutralising antibody against Toll-like receptor 2 abolished the effects of apoCIII on ER stress, inflammation and insulin resistance, indicating that the effects of apoCIII were mediated by this receptor. [Conclusions/interpretation] These results imply that elevated VLDL in diabetic states can contribute to the exacerbation of insulin resistance by activating ERK1/2 through Toll-like receptor 2.This study was partly supported by funds from the Spanish Ministerio de Economía y Competitividad (SAF2012-30708 and SAF2015-64146-R to MVC), the Generalitat de Catalunya (2014SGR0013 to MVC), NIH NIDDK (DK101663 to ABK), USDA NIFA (11874590 to ABK) and USDA NIFA Hatch Formula Funds (2015- 31200-06009 to ABK), an Instituto de Salud Carlos III grant (PI16- 00139 to JCE-G) and European Union ERDF funds. CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) is an Instituto de Salud Carlos III project (Grant CB07/08/0003 to MVC). GB was supported by an FPI grant from the Spanish Ministerio de Economía y Competitividad.Peer reviewe