Advancements in diabetic kidney disease management: integrating innovative therapies and targeted drug development.

Diabetic kidney disease (DKD) is a leading cause of chronic kidney disease and affects approximately 40% of individuals with diabetes . Cases of DKD continue to rise globally as the prevalence of diabetes mellitus increases, with an estimated 415 million people living with diabetes in 2015 and a projected 642 million by 2040. DKD is associated with significant morbidity and mortality, representing 34% and 36% of all chronic kidney disease deaths in men and women, respectively. Common comorbidities including hypertension and ageing-related nephron loss further complicate disease diagnosis and progression. The progression of DKD involves several mechanisms including glomerular endothelial cell dysfunction, inflammation, and fibrosis. Targeting these mechanisms has formed the basis of several therapeutic agents. Renin-angiotensin-aldosterone system (RAAS) blockers, specifically angiotensin receptor blockers (ARBs), demonstrate significant reductions in macroalbuminuria. Sodium-glucose transporter type 2 (SGLT-2) inhibitors demonstrate kidney protection independent of diabetes control while also decreasing the incidence of cardiovascular events. Emerging agents including glucagon-like peptide 1 (GLP-1) agonists, anti-inflammatory agents like bardoxolone, and mineralocorticoid receptor antagonists show promise in mitigating DKD progression. Many novel therapies including monoclonal antibodies CSL346, lixudebart, and tozorakimab; mesenchymal stem/stromal cell infusion; and cannabinoid-1 receptor inverse agonism via INV-202 are currently in clinical trials and present opportunities for further drug development.

Therapeutic options for premature ovarian insufficiency: an updated review.

Primary ovarian insufficiency (POI) is a rare gynecological condition. This disease causes menstrual disturbances, infertility, and various health problems. Historically, hormone replacement therapy is the first-line treatment for this disorder. Women diagnosed with POI are left with limited therapeutic options. In order to remedy this situation, a new generation of therapeutic approaches, such as in vitro activation, mitochondrial activation technique, stem cell and exosomes therapy, biomaterials strategies, and platelet-rich plasma intra-ovarian infusion, is being developed. However, these emerging therapies are yet in the experimental stage and require precise design components to accelerate their conversion into clinical treatments. Thus, each medical practitioner bears responsibility for selecting suitable therapies for individual patients. In this article, we provide a timely analysis of the therapeutic strategies that are available for POI patients and discuss the prospects of POI therapy.

Innovative Biological Treatment Methods for Degenerative Disc Disease.

Low back pain is the leading cause of work absences and years lived with disability, and it is often associated with degenerative disc disease. In recent years, biological treatment approaches such as the use of growth factors, cell injections, annulus fibrosus (AF) repair, nucleus pulposus replacement, and tissue-engineered discs have been explored as means for preventing or reversing degenerative disc disease. Both animal and clinical studies have shown promising results for cell-based therapy on the grounds of its regenerative potential. Clinical data also indicate that stem cell injection is safe when appropriately performed, albeit its long-term safety and efficacy are yet to be explored. Numerous challenges also remain to be overcome, such as isolating, differentiating, and preconditioning the disc cells, as well as managing the nutrient-deficient and oxygen-deficient micromilieu of the intervertebral disc (IVD). AF repair methods including devices used in clinical trials have shown success in decreasing reherniation rates and improving overall clinical outcomes. In addition, recent studies that combined AF repair and nucleus pulposus replacement have shown improved biomechanical stability in IVDs after the combined treatment. Tissue-engineered IVDs for total disc replacement are still being developed, and future studies are necessary to overcome the challenges in their delivery, efficacy, and safety.

Teaming: learning, competing, and innovating in the world of reproductive medicine.

Healthcare teams must be deliberately cultivated to reach their full potential. Shifting focus from individual performance to a team's collective competence allows for targeted and evidence-based interventions that support teamwork and improve patient outcomes. We reviewed essential concepts drawn from team science and explored the practical applications of teaming. Reproductive endocrinology and infertility healthcare providers play a pivotal role by teaching, modeling, and fostering teaming attitudes and behaviors. Through teaming, we can maximize our teams' ability to learn, innovate, compete with other teams, and thrive in today's healthcare environment.

Emerging Antioxidant Paradigm of Mesenchymal Stem Cell-Derived Exosome Therapy.

Mesenchymal stem cell-derived exosomes have been under investigation as potential treatments for a diverse range of diseases, and many animal and clinical trials have achieved encouraging results. However, it is well known that the biological activity of the exosomes is key to their therapeutic properties; however, till date, it has not been completely understood. Previous studies have provided different explanations of therapeutic mechanisms of the exosomes, including anti-inflammatory, immunomodulatory, and anti-aging mechanisms. The pathological effects of oxidative stress often include organ damage, inflammation, and disorders of material and energy metabolism. The evidence gathered from research involving animal models indicates that exosomes have antioxidant properties, which can also explain their anti-inflammatory and cytoprotective effects. In this study, we have summarized the antioxidant effects of exosomes in in vivo and in vitro models, and have evaluated the anti-oxidant mechanisms of exosomes by demonstrating a direct reduction in excessive reactive oxygen species (ROS), promotion of intracellular defence of anti-oxidative stress, immunomodulation by inhibiting excess ROS, and alteration of mitochondrial performance. Exosomes exert their cytoprotective and anti-inflammatory properties by regulating the redox environment and oxidative stress, which explains the therapeutic effects of exosomes in a variety of diseases, mechanisms that can be well preserved among different species.

Effectiveness of Medical Treatment of Cushing's Disease: A Systematic Review and Meta-Analysis.

Objective: The objective of this systematic review was to evaluate the effectiveness and safety of pasireotide, cabergoline, ketoconazole, levoketoconazole, metyrapone, osilodrostat, and temozolomide for the treatment of Cushing's disease (CD). Methods: The primary outcomes were the proportion of CD control, adverse events (AE), and reduction of urinary free cortisol. Search strategies were applied to Embase, Medline, and CENTRAL. Independent reviewers assessed the study eligibility, extracted data, and evaluated risk of bias. Standardized mean difference was calculated with 95% confidence interval (CI) for continuous data (i.e., pre- and post-intervention). Random meta-analyses for the proportion of CD control and AE were conducted. Results: Twenty-nine controlled and non-controlled studies were included. No study with temozolomide and levoketoconazole and one study with osilodrostat fulfilled the inclusion criteria. The meta-analyses of proportion of CD control was 35% for cabergoline (95% CI: 27-43%, six studies, 141 participants), 44% for pasireotide (95% CI: 25-35%, eight studies, 522 participants), 41% for ketoconazole (95% CI: 36-46%, six studies, 450 participants), 66% for metyrapone (95% CI: 46-87%, four studies, 66 participants), and of 66.4% for osilodrostat (95% CI: 57.9, 74.3, 97 participants, one study). One study compared two different treatments (cabergoline vs. ketoconazole), and no statistical difference was observed in CD control (RR: 0.53, 95% CI: 0.15 to 1.87, 14 participants, very low certainty of evidence). The most frequent AE associated with pasireotide was hyperglycemia, dizziness and nausea with cabergoline and metyrapone, and elevated transaminases with ketoconazole. Conclusion: The superiority of one drug over another could not be determined due to lack of controlled studies, but the proportion of disease control identified in our meta-analysis may support clinical decision. New therapeutic options should be investigated due to the limited efficacy and tolerability of the currently available medical treatment for patients with Cushing's disease. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020205567, identifier CRD42020205567.

Monocarboxylate Transporter 8 Deficiency: From Pathophysiological Understanding to Therapy Development.

Genetic defects in the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) result in MCT8 deficiency. This disorder is characterized by a combination of severe intellectual and motor disability, caused by decreased cerebral thyroid hormone signalling, and a chronic thyrotoxic state in peripheral tissues, caused by exposure to elevated serum T3 concentrations. In particular, MCT8 plays a crucial role in the transport of thyroid hormone across the blood-brain-barrier. The life expectancy of patients with MCT8 deficiency is strongly impaired. Absence of head control and being underweight at a young age, which are considered proxies of the severity of the neurocognitive and peripheral phenotype, respectively, are associated with higher mortality rate. The thyroid hormone analogue triiodothyroacetic acid is able to effectively and safely ameliorate the peripheral thyrotoxicosis; its effect on the neurocognitive phenotype is currently under investigation. Other possible therapies are at a pre-clinical stage. This review provides an overview of the current understanding of the physiological role of MCT8 and the pathophysiology, key clinical characteristics and developing treatment options for MCT8 deficiency.

Bombesin Receptor Family Activation and CNS/Neural Tumors: Review of Evidence Supporting Possible Role for Novel Targeted Therapy.

G-protein-coupled receptors (GPCRs) are increasingly being considered as possible therapeutic targets in cancers. Activation of GPCR on tumors can have prominent growth effects, and GPCRs are frequently over-/ectopically expressed on tumors and thus can be used for targeted therapy. CNS/neural tumors are receiving increasing attention using this approach. Gliomas are the most frequent primary malignant brain/CNS tumor with glioblastoma having a 10-year survival <1%; neuroblastomas are the most common extracranial solid tumor in children with long-term survival<40%, and medulloblastomas are less common, but one subgroup has a 5-year survival <60%. Thus, there is an increased need for more effective treatments of these tumors. The Bombesin-receptor family (BnRs) is one of the GPCRs that are most frequently over/ectopically expressed by common tumors and is receiving particular attention as a possible therapeutic target in several tumors, particularly in prostate, breast, and lung cancer. We review in this paper evidence suggesting why a similar approach in some CNS/neural tumors (gliomas, neuroblastomas, medulloblastomas) should also be considered.

Novel Therapeutics in Radioactive Iodine-Resistant Thyroid Cancer.

Iodine-resistant cancers account for the vast majority of thyroid related mortality and, until recently, there were limited therapeutic options. However, over the last decade our understanding of the molecular foundation of thyroid function and carcinogenesis has driven the development of many novel therapeutics. These include FDA approved tyrosine kinase inhibitors and small molecular inhibitors of VEGFR, BRAF, MEK, NTRK and RET, which collectively have significantly changed the prognostic outlook for this patient population. Some therapeutics can re-sensitize de-differentiated cancers to iodine, allowing for radioactive iodine treatment and improved disease control. Remarkably, there is now an FDA approved treatment for BRAF-mutated patients with anaplastic thyroid cancer, previously considered invariably and rapidly fatal. The treatment landscape for iodine-resistant thyroid cancer is changing rapidly with many new targets, therapeutics, clinical trials, and approved treatments. We provide an up-to-date review of novel therapeutic options in the treatment of iodine-resistant thyroid cancer.

Targeted and Non-Targeted Mechanisms for Killing Hypoxic Tumour Cells-Are There New Avenues for Treatment?

PURPOSE: A major issue in radiotherapy is the relative resistance of hypoxic cells to radiation. Historic approaches to this problem include the use of oxygen mimetic compounds to sensitize tumour cells, which were unsuccessful. This review looks at modern approaches aimed at increasing the efficacy of targeting and radiosensitizing hypoxic tumour microenvironments relative to normal tissues and asks the question of whether non-targeted effects in radiobiology may provide a new "target". Novel techniques involve the integration of recent technological advancements such as nanotechnology, cell manipulation, and medical imaging. Particularly, the major areas of research discussed in this review include tumour hypoxia imaging through PET imaging to guide carbogen breathing, gold nanoparticles, macrophage-mediated drug delivery systems used for hypoxia-activate prodrugs, and autophagy inhibitors. Furthermore, this review outlines several features of these methods, including the mechanisms of action to induce radiosensitization, the increased accuracy in targeting hypoxic tumour microenvironments relative to normal tissue, preclinical/clinical trials, and future considerations. CONCLUSIONS: This review suggests that the four novel tumour hypoxia therapeutics demonstrate compelling evidence that these techniques can serve as powerful tools to increase targeting efficacy and radiosensitizing hypoxic tumour microenvironments relative to normal tissue. Each technique uses a different way to manipulate the therapeutic ratio, which we have labelled "oxygenate, target, use, and digest". In addition, by focusing on emerging non-targeted and out-of-field effects, new umbrella targets are identified, which instead of sensitizing hypoxic cells, seek to reduce the radiosensitivity of normal tissues.

Investigational Treatments for Epidermolysis Bullosa.

Epidermolysis bullosa (EB) is a heterogeneous group of rare inherited blistering skin disorders characterized by skin fragility following minor trauma, usually present since birth. EB can be categorized into four classical subtypes, EB simplex, junctional EB, dystrophic EB and Kindler EB, distinguished on clinical features, plane of blister formation in the skin, and molecular pathology. Treatment for EB is mostly supportive, focusing on wound care and patient symptoms such as itch or pain. However, therapeutic advances have also been made in targeting the primary genetic abnormalities as well as the secondary inflammatory footprint of EB. Pre-clinical or clinical testing of gene therapies (gene replacement, gene editing, RNA-based therapy, natural gene therapy), cell-based therapies (fibroblasts, bone marrow transplantation, mesenchymal stromal cells, induced pluripotential stem cells), recombinant protein therapies, and small molecule and drug repurposing approaches, have generated new hope for better patient care. In this article, we review advances in translational research that are impacting on the quality of life for people living with different forms of EB and which offer hope for improved clinical management.

Epigenetic inheritance of polycystic ovary syndrome - challenges and opportunities for treatment.

Polycystic ovary syndrome (PCOS) is the main cause of female infertility worldwide and is associated with a substantially increased lifetime risk of comorbidities, including type 2 diabetes mellitus, psychiatric disorders and gynaecological cancers. Despite its high prevalence (~15%) and substantial economic burden, the aetiology of PCOS remains elusive. The genetic loci linked to PCOS so far account for only ~10% of its heritability, which is estimated at 70%. However, growing evidence suggests that altered epigenetic and developmental programming resulting from hormonal dysregulation of the maternal uterine environment contributes to the pathogenesis of PCOS. Male as well as female relatives of women with PCOS are also at an increased risk of developing PCOS-associated reproductive and metabolic disorders. Although PCOS phenotypes are highly heterogenous, hyperandrogenism is thought to be the principal driver of this condition. Current treatments for PCOS are suboptimal as they can only alleviate some of the symptoms; preventative and targeted treatments are sorely needed. This Review presents an overview of the current understanding of the aetiology of PCOS and focuses on the developmental origin and epigenetic inheritance of this syndrome.

Cannabinoid Receptor 1 Inhibition in Chronic Kidney Disease: A New Therapeutic Toolbox.

Chronic kidney disease (CKD) concerns millions of individuals worldwide, with few therapeutic strategies available to date. Recent evidence suggests that the endocannabinoid system (ECS) could be a new therapeutic target to prevent CKD. ECS combines receptors, cannabinoid receptor type 1 (CB1R) and type 2 (CB2R), and ligands. The most prominent receptor within the kidney is CB1R, its endogenous local ligands being anandamide and 2-arachidonoylglycerol. Therefore, the present review focuses on the therapeutic potential of CB1R and not CB2R. In the normal kidney, CB1R is expressed in many cell types, especially in the vasculature where it contributes to the regulation of renal hemodynamics. CB1R could also participate to water and sodium balance and to blood pressure regulation but its precise role remains to decipher. CB1R promotes renal fibrosis in both metabolic and non-metabolic nephropathies. In metabolic syndrome, obesity and diabetes, CB1R inhibition not only improves metabolic parameters, but also exerts a direct role in preventing renal fibrosis. In non-metabolic nephropathies, its inhibition reduces the development of renal fibrosis. There is a growing interest of the industry to develop new CB1R antagonists without central nervous side-effects. Experimental data on renal fibrosis are encouraging and some molecules are currently under early-stage clinical phases (phases I and IIa studies). In the present review, we will first describe the role of the endocannabinoid receptors, especially CB1R, in renal physiology. We will next explore the role of endocannabinoid receptors in both metabolic and non-metabolic CKD and renal fibrosis. Finally, we will discuss the therapeutic potential of CB1R inhibition using the new pharmacological approaches. Overall, the new pharmacological blockers of CB1R could provide an additional therapeutic toolbox in the management of CKD and renal fibrosis from both metabolic and non-metabolic origin.

The role of regulated necrosis in endocrine diseases.

The death of endocrine cells is involved in type 1 diabetes mellitus, autoimmunity, adrenopause and hypogonadotropism. Insights from research on basic cell death have revealed that most pathophysiologically important cell death is necrotic in nature, whereas regular metabolism is maintained by apoptosis programmes. Necrosis is defined as cell death by plasma membrane rupture, which allows the release of damage-associated molecular patterns that trigger an immune response referred to as necroinflammation. Regulated necrosis comes in different forms, such as necroptosis, pyroptosis and ferroptosis. In this Perspective, with a focus on the endocrine environment, we introduce these cell death pathways and discuss the specific consequences of regulated necrosis. Given that clinical trials of necrostatins for the treatment of autoimmune conditions have already been initiated, we highlight the therapeutic potential of such novel therapeutic approaches that, in our opinion, should be tested in endocrine disorders in the future.