The TRPM2 ion channel regulates metabolic and thermogenic adaptations in adipose tissue of cold-exposed mice.

Introduction: During thermogenesis, adipose tissue (AT) becomes more active and enhances oxidative metabolism. The promotion of this process in white AT (WAT) is called "browning" and, together with the brown AT (BAT) activation, is considered as a promising approach to counteract obesity and metabolic diseases. Transient receptor potential cation channel, subfamily M, member 2 (TRPM2), is an ion channel that allows extracellular Ca influx into the cytosol, and is gated by adenosine diphosphate ribose (ADPR), produced from NAD degradation.

New Analogues of the Nicotinamide Phosphoribosyltransferase Inhibitor FK866 as Potential Anti-Pancreatic Cancer Agents.

Background: During the past two decades, many nicotinamide phosphoribosyltransferase (NAMPT) inhibitors were prepared and tested because this enzyme is overexpressed in pancreatic cancer. Although FK866 is a well-known, strong NAMPT inhibitor, it suffers severe drawbacks.

Objective: Our work aimed to synthesize efficient NAMPT inhibitors featuring better pharmacokinetic properties than the pyridine-containing FK866.

PLX4032 resistance of patient-derived melanoma cells: crucial role of oxidative metabolism.

Background: Malignant melanoma is the most lethal form of skin cancer which shows BRAF mutation in 50% of patients. In this context, the identification of BRAF mutation led to the development of specific inhibitors like PLX4032. Nevertheless, although its initial success, its clinical efficacy is reduced after six-months of therapy leading to cancer relapse due to the onset of drug resistance.

Iminosugar-Based Nicotinamide Phosphoribosyltransferase (NAMPT) Inhibitors as Potential Anti-Pancreatic Cancer Agents.

The nicotinamide phosphoribosyltransferase (NAMPT) is considered a very promising therapeutic target because it is overexpressed in pancreatic cancer. Although many inhibitors have been prepared and tested, clinical trials have shown that NAMPT inhibition may result in severe haematological toxicity. Therefore, the development of conceptually new inhibitors is an important and challenging task.

Sirtuin 6 Regulates the Activation of the ATP/Purinergic Axis in Endothelial Cells.

Sirtuin 6 (SIRT6) is a member of the mammalian NAD-dependent deac(et)ylase sirtuin family. SIRT6's anti-inflammatory roles are emerging increasingly often in different diseases and cell types, including endothelial cells. In this study, the role of SIRT6 in pro-inflammatory conditions was investigated by engineering human umbilical vein endothelial cells to overexpress SIRT6 (SIRT6+ HUVECs).

Aberrant Adenosine Triphosphate Release and Impairment of P2Y2-Mediated Signaling in Sarcoglycanopathies.

Sarcoglycanopathies, limb-girdle muscular dystrophies (LGMD) caused by genetic loss-of-function of the membrane proteins sarcoglycans (SGs), are characterized by progressive degeneration of skeletal muscle. In these disorders, muscle necrosis is associated with immune-mediated damage, whose triggering and perpetuating molecular mechanisms are not fully elucidated yet. Extracellular adenosine triphosphate (eATP) seems to represent a crucial factor, with eATP activating purinergic receptors.

CD38-Induced Metabolic Dysfunction Primes Multiple Myeloma Cells for NAD-Lowering Agents.

Cancer cells fuel growth and energy demands by increasing their NAD biosynthesis dependency, which therefore represents an exploitable vulnerability for anti-cancer strategies. CD38 is a NAD-degrading enzyme that has become crucial for anti-MM therapies since anti-CD38 monoclonal antibodies represent the backbone for treatment of newly diagnosed and relapsed multiple myeloma patients. Nevertheless, further steps are needed to enable a full exploitation of these strategies, including deeper insights of the mechanisms by which CD38 promotes tumorigenesis and its metabolic additions that could be selectively targeted by therapeutic strategies.

Role of Liver CD38 in the Regulation of Metabolic Pathways during Cold-Induced Thermogenesis in Mice.

Boosting NAD levels are considered a promising means to promote healthy aging and ameliorate dysfunctional metabolism. The expression of CD38, the major NAD-consuming enzyme, is downregulated during thermogenesis in both brown and white adipose tissues (BAT and WAT). Moreover, BAT activation and WAT "browning" were enhanced in mice.

The ABA-LANCL1/2 Hormone-Receptors System Protects H9c2 Cardiomyocytes from Hypoxia-Induced Mitochondrial Injury via an AMPK- and NO-Mediated Mechanism.

Abscisic acid (ABA) regulates plant responses to stress, partly via NO. In mammals, ABA stimulates NO production by innate immune cells and keratinocytes, glucose uptake and mitochondrial respiration by skeletal myocytes and improves blood glucose homeostasis through its receptors LANCL1 and LANCL2. We hypothesized a role for the ABA-LANCL1/2 system in cardiomyocyte protection from hypoxia via NO.

Paracrine ADP Ribosyl Cyclase-Mediated Regulation of Biological Processes.

ADP-ribosyl cyclases (ADPRCs) catalyze the synthesis of the Ca-active second messengers Cyclic ADP-ribose (cADPR) and ADP-ribose (ADPR) from NAD as well as nicotinic acid adenine dinucleotide phosphate (NAADP) from NADP. The best characterized ADPRC in mammals is CD38, a single-pass transmembrane protein with two opposite membrane orientations. The first identified form, type II CD38, is a glycosylated ectoenzyme, while type III CD38 has its active site in the cytosol.

Neuroprotective Potential of Dendritic Cells and Sirtuins in Multiple Sclerosis.

Myeloid cells, including parenchymal microglia, perivascular and meningeal macrophages, and dendritic cells (DCs), are present in the central nervous system (CNS) and establish an intricate relationship with other cells, playing a crucial role both in health and in neurological diseases. In this context, DCs are critical to orchestrating the immune response linking the innate and adaptive immune systems. Under steady-state conditions, DCs patrol the CNS, sampling their local environment and acting as sentinels.

P2X7 Receptor Antagonist Reduces Fibrosis and Inflammation in a Mouse Model of Alpha-Sarcoglycan Muscular Dystrophy.

Limb-girdle muscular dystrophy R3, a rare genetic disorder affecting the limb proximal muscles, is caused by mutations in the α-sarcoglycan gene (Sgca) and aggravated by an immune-mediated damage, finely modulated by the extracellular (e)ATP/purinoceptors axis. Currently, no specific drugs are available. The aim of this study was to evaluate the therapeutic effectiveness of a selective P2X7 purinoreceptor antagonist, A438079.

Role of CD38 in Adipose Tissue: Tuning Coenzyme Availability?

Nicotinamide adenine dinucleotide (NAD) is a fundamental molecule in the regulation of energy metabolism, representing both a coenzyme and a substrate for different NAD degrading enzymes. Among these enzymes, CD38 can be seen under two perspectives: as the enzyme synthesizing Ca-mobilizing second messenger, starting from NAD, and as the major NAD-consumer, to be inhibited to increase NAD levels. Indeed, the regulation of NAD availability is a key event during different processes.

CD38 downregulation modulates NAD and NADP(H) levels in thermogenic adipose tissues.

Different strategies to boost NAD levels are considered promising means to promote healthy aging and ameliorate dysfunctional metabolism. CD38 is a NAD-dependent enzyme involved in the regulation of different cell functions. In the context of systemic energy metabolism, it has been demonstrated that brown adipocytes, the parenchymal cells of brown adipose tissue (BAT) as well as beige adipocytes that emerge in white adipose tissue (WAT) depots in response to catabolic conditions, are important to maintain metabolic homeostasis.

Sirt6 inhibition delays the onset of experimental autoimmune encephalomyelitis by reducing dendritic cell migration.

Background: Experimental autoimmune encephalomyelitis (EAE) is the most common animal model of multiple sclerosis (MS), a neuroinflammatory and demyelinating disease characterized by multifocal perivascular infiltrates of immune cells. Although EAE is predominantly considered a T helper 1-driven autoimmune disease, mounting evidence suggests that activated dendritic cells (DC), which are the bridge between innate and adaptive immunity, also contribute to its pathogenesis. Sirtuin 6 (SIRT6), a NAD-dependent deacetylase involved in genome maintenance and in metabolic homeostasis, regulates DC activation, and its pharmacological inhibition could, therefore, play a role in EAE development.

Differential modulation of SIRT6 deacetylase and deacylase activities by lysine-based small molecules.

Sirtuin 6 (SIRT6) is an NAD-dependent deacetylase regulating important functions: modulators of its enzymatic activity have been considered as possible therapeutic agents. Besides the deacetylase activity, SIRT6 also has NAD-dependent deacylase activity, whereby it regulates the secretion of cytokines and proteins. We identified novel SIRT6 modulators with a lysine-based structure: compound 1 enhances SIRT6 deacylase while inhibiting the deacetylase activity.

Survivorship and clinical outcomes of 147 consecutive isolated or combined arthroscopic bone plug free meniscal allograft transplantation.

Purpose: To present the results of a survival analysis of a series of 147 arthroscopic MAT procedures.

Methods: One-hundred and forty-seven patients (117 males and 30 females) underwent arthroscopic MAT without bone plugs (82 medial MAT and 65 lateral MAT) using fresh-frozen, non-irradiated grafts. They were retrospectively reviewed at a mean of 4.

Is Sport Activity Possible After Arthroscopic Meniscal Allograft Transplantation? Midterm Results in Active Patients.

Background: Meniscal allograft transplantation (MAT) has produced good to excellent results in the general population; however, few investigations have examined MAT in athletes and sport-related outcomes.

Purpose: To report midterm clinical outcomes of MAT and the rate of return to sport in a physically active population.

Study Design: Case series; Level of evidence, 4.

Anterior cruciate ligament reconstruction with a novel porcine xenograft: the initial Italian experience.

At the current state of the art in anterior cruciate ligament (ACL) reconstruction, multiple techniques have been presented but none has given clearly defined and improved results. One of the main issues concerns the choice of graft. The concept of using xenograft tissue, defined as a graft tissue from one species and destined for implantation in an unlike species, was introduced in order to try to overcome the mechanical and biological concerns associated with synthetic materials and the safety and quality concerns and availability problems of allograft tissue.

Long-term clinical outcomes of combined BPTB ACL reconstruction and popliteus tendon plasty.

Purpose: A deficiency of posterolateral structures significantly increases the varus load on the ACL, while a chronic ACL lesion, the increased tibial rotation and the repetitive non-physiological knee motion, could affect and damage the integrity of the popliteus tendon. Therefore, the aim of the present study was to report the very long clinical outcomes of a combined single-bundle BPTB ACL reconstruction and popliteus plasty according to Bousquets technique, for the treatment of combined chronic anterior and posterolateral laxities.

Methods: Fifteen patients that underwent combined ACL reconstruction and popliteal plasty according to Bousquets technique were available at mean 26.

Clinical outcomes and complications of a collagen meniscus implant: a systematic review.

Purpose: The purpose of this systematic review was to summarise and evaluate the clinical outcomes of the collagen meniscus implant (CMI) and its complication and failure rates. These data were then used to evaluate the results of the CMI at different follow-up time periods and investigate possible differences in the behaviour of lateral and medial CMI.

Methods: A comprehensive search was performed in PubMed, MEDLINE, CINAHL, Cochrane, EMBASE and Google Scholar databases using various combinations of the following keywords: "collagen meniscus implant" or "collagen meniscal implant".

Medial patellotibial ligament (MPTL) reconstruction for patellar instability.

Purpose: To evaluate mid-term clinical and radiographic outcomes after an original medial patellotibial ligament reconstruction in patients with patellar dislocation.

Methods: Twenty-nine knees (27 patients, 8 males and 19 females) treated for patellar dislocation with medialization of the patellar tendon medial third combined with medial and lateral release were evaluated clinically and radiographically at a mean follow-up of 6.1±2.

Patellofemoral anatomy and biomechanics: current concepts.

The patellofemoral joint, due to its particular bone anatomy and the numerous capsuloligamentous structures and muscles that act dynamically on the patella, is considered one of the most complex joints in the human body from the biomechanical point of view. The medial patellofemoral ligament (MPFL) has been demonstrated to contribute 60% of the force that opposes lateral displacement of the patella, and MPFL injury results in an approximately 50% reduction in the force needed to dislocate the patella laterally with the knee extended. For this reason, recent years have seen a growing interest in the study of this important anatomical structure, whose aponeurotic nature has thus been demonstrated.