Superoxide dismutase and neurological disorders.

Superoxide dismutase (SOD) is a common antioxidant enzyme found majorly in living cells. The main physiological role of SOD is detoxification and maintain the redox balance, acts as a first line of defence against Reactive nitrogen species (RNS), Reactive oxygen species (ROS), and other such potentially hazardous molecules. SOD catalyses the conversion of superoxide anion free radicals (O 2 -.) into molecular oxygen (O 2) and hydrogen peroxide (H 2O 2) in the cells. Superoxide dismutases (SODs) are expressed in neurons and glial cells throughout the CNS both intracellularly and extracellularly. Endogenous oxidative stress (OS) linked with enlarged production of reactive oxygen metabolites (ROMs), inflammation, deregulation of redox balance, mitochondrial dysfunction and bioenergetic crisis are found to be prerequisite for neuronal loss in neurological diseases. Clinical and genetic studies indicate a direct correlation between mutations in SOD gene and neurodegenerative diseases, like Amyotrophic Lateral Sclerosis (ALS), Huntington's disease (HD), Parkinson's Disease (PD) and Alzheimer's Disease (AD). Therefore, inhibitors of OS are considered as an optimistic approach to prevent neuronal loss. SOD mimetics like Metalloporphyrin Mn (II)-cyclic polyamines, Nitroxides and Mn (III)- Salen complexes are designed and used as therapeutic extensively in the treatment of neurological disorders. SODs and SOD mimetics are promising future therapeutics in the field of various diseases with OS-mediated pathology.

Current Technologies and Future Perspectives in Immunotherapy towards a Clinical Oncology Approach.

Immunotherapy is now established as a potent therapeutic paradigm engendering antitumor immune response against a wide range of malignancies and other diseases by modulating the immune system either through the stimulation or suppression of immune components such as CD4+ T cells, CD8+ T cells, B cells, monocytes, macrophages, dendritic cells, and natural killer cells. By targeting several immune checkpoint inhibitors or blockers (e.g., PD-1, PD-L1, PD-L2, CTLA-4, LAG3, and TIM-3) expressed on the surface of immune cells, several monoclonal antibodies and polyclonal antibodies have been developed and already translated clinically. In addition, natural killer cell-based, dendritic cell-based, and CAR T cell therapies have been also shown to be promising and effective immunotherapeutic approaches. In particular, CAR T cell therapy has benefited from advancements in CRISPR-Cas9 genome editing technology, allowing the generation of several modified CAR T cells with enhanced antitumor immunity. However, the emerging SARS-CoV-2 infection could hijack a patient's immune system by releasing pro-inflammatory interleukins and cytokines such as IL-1ß, IL-2, IL-6, and IL-10, and IFN-γ and TNF-α, respectively, which can further promote neutrophil extravasation and the vasodilation of blood vessels. Despite the significant development of advanced immunotherapeutic technologies, after a certain period of treatment, cancer relapses due to the development of resistance to immunotherapy. Resistance may be primary (where tumor cells do not respond to the treatment), or secondary or acquired immune resistance (where tumor cells develop resistance gradually to ICIs therapy). In this context, this review aims to address the existing immunotherapeutic technologies against cancer and the resistance mechanisms against immunotherapeutic drugs, and explain the impact of COVID-19 on cancer treatment. In addition, we will discuss what will be the future implementation of these strategies against cancer drug resistance. Finally, we will emphasize the practical steps to lay the groundwork for enlightened policy for intervention and resource allocation to care for cancer patients.

Formulation of fortified instant weaning food from Musa paradisiaca (banana) and Eleusine coracana.

Weaning food is a soft, easily digestible type of food other than breast milk for infants aged 6 to 24 months. The present study was conducted to develop cereal-fruit-based complementary foods for infants and evaluate the nutritional quality of such types of foods. Few researchers have focused on formulating weaning foods from locally available, nutritious, and rich ingredients without nutrient loss to reduce malnutrition and infant morbidity rates. In this study, the formulated infant food was prepared from Musa paradisiaca (Nendran banana) and Eleusine coracana (ragi). Formulated weaning food was analyzed using various standard methods, demonstrating that it could provide adequate nutrients to growing infants for their proper growth and development. The shelf life of the weaning food was also studied for a period of 3 months at ambient conditions in two different packaging materials: aluminum and plastic (low-density polyethylene or LDPE), with the aluminum foil pouch exhibiting the best shelf life. This ready-to-serve food, which is formulated and fortified with natural ingredients containing essential macronutrients and micronutrients, could be regarded as highly effective supplementary food for infants. Furthermore, this development has the potential to introduce an affordable weaning product specifically targeted at low socioeconomic groups.

Functional foods and their impact on health.

Functional foods play an important role in maintaining a healthy lifestyle and reducing the risk factors of various diseases. Most foods have a functional element which is responsible for improving the healthy state. All food substances such as fruits, vegetables, cereals, meat, fish, dairy contain functional ingredients. A wide range of naturally occurring substances from plant and animal sources having active components which play a role in physiological actions deserve attention for their optimal use in maintaining health. The market for functional food is keep on expanding, and the global market is projected to reach a value of at least 91 billion USD soon. Overwhelming evidence from preclinical (in vitro and in vivo) and clinical studies have shown that intake of functional foods could have an impact on the prevention of chronic diseases, especially cancer, cardiovascular diseases, gastrointestinal tract disorders and neurological diseases. Extensive research needs to be done to determine the potential health benefits for the proper application of these foods to improve health state and combat chronic disease progression. The aim of this review is to conduct a thorough literature survey, to understand the various classification of functional foods and their health benefits.

Effect of different drying techniques on the nutrient and physiochemical properties of Musa paradisiaca (ripe Nendran banana) powder.

Musa paradisiaca (ripe Nendran) is the staple food of south India, especially Kerala. The present study analyzed the effect of different drying techniques, namely, freeze, spray and tray drying on the retention of nutrients especially micronutrients. Mineral content was determined by using Atomic absorption spectroscopy and Vitamin content was determined through High-performance liquid chromatography. This study aimed to analyze the availability of minerals and water-soluble vitamins in dried ripe banana powder. The micronutrient content of freeze-dried banana powder was observed to be with 486.92 ± 0.12 mg/100 g of potassium, 0.60 ± 0.005 mg/100 g of calcium, 3.10 ± 0.10 mg/100 g of sodium, 3.82 ± 0.02 mg/100 g of iron, 6.28 ± 0.04 mg/100 g of vitamin C and 0.606 ± 0.005 mg/100 g of vitamin B6. Along with micronutrient analysis, proximate, and various important physiochemical properties were also analyzed. The results showed that freeze-drying was the best technique to preserve nutrients present in ripe banana. Structure analysis of dried banana was done using scanning electron microscopy indicated that remarkable changes has occurred in both tray and spray dried banana when comparing to freeze dried banana. Data was analyzed by one-way ANOVA, found significantly differ at p < 0.05 with respect to drying methods.

Role of Endogenous Lipopolysaccharides in Neurological Disorders.

Lipopolysaccharide (LPS) is a cell-wall immunostimulatory endotoxin component of Gram-negative bacteria. A growing body of evidence reveals that alterations in the bacterial composition of the intestinal microbiota (gut dysbiosis) disrupt host immune homeostasis and the intestinal barrier function. Microbial dysbiosis leads to a proinflammatory milieu and systemic endotoxemia, which contribute to the development of neurodegenerative diseases and metabolic disorders. Two important pathophysiological hallmarks of neurodegenerative diseases (NDDs) are oxidative/nitrative stress and inflammation, which can be initiated by elevated intestinal permeability, with increased abundance of pathobionts. These changes lead to excessive release of LPS and other bacterial products into blood, which in turn induce chronic systemic inflammation, which damages the blood-brain barrier (BBB). An impaired BBB allows the translocation of potentially harmful bacterial products, including LPS, and activated neutrophils/leucocytes into the brain, which results in neuroinflammation and apoptosis. Chronic neuroinflammation causes neuronal damage and synaptic loss, leading to memory impairment. LPS-induced inflammation causes inappropriate activation of microglia, astrocytes, and dendritic cells. Consequently, these alterations negatively affect mitochondrial function and lead to increases in oxidative/nitrative stress and neuronal senescence. These cellular changes in the brain give rise to specific clinical symptoms, such as impairment of locomotor function, muscle weakness, paralysis, learning deficits, and dementia. This review summarizes the contributing role of LPS in the development of neuroinflammation and neuronal cell death in various neurodegenerative diseases.

Effects of Frankincense Compounds on Infection, Inflammation, and Oral Health.

Boswellia trees, found throughout the Middle East and parts of Africa and Asia, are the source of frankincense oil. Since antiquity, frankincense has been traded as a precious commodity, but it has also been used for the treatment of chronic disease, inflammation, oral health, and microbial infection. More recently, the bioactive components of Boswellia trees have been identified and characterized for their effects on cancer, microbial infection (especially infection by oral pathogens), and inflammation. Most studies have focused on cell lines, but more recent research has also investigated effects in animal models of disease. As natural products are considered to be safer than synthetic drugs, there is growing interest in further developing the use of substances such as frankincense oil for therapeutic treatment.

Mechanistic Insights into the Link between Gut Dysbiosis and Major Depression: An Extensive Review.

Depression is a highly common mental disorder, which is often multifactorial with sex, genetic, environmental, and/or psychological causes. Recent advancements in biomedical research have demonstrated a clear correlation between gut dysbiosis (GD) or gut microbial dysbiosis and the development of anxiety or depressive behaviors. The gut microbiome communicates with the brain through the neural, immune, and metabolic pathways, either directly (via vagal nerves) or indirectly (via gut- and microbial-derived metabolites as well as gut hormones and endocrine peptides, including peptide YY, pancreatic polypeptide, neuropeptide Y, cholecystokinin, corticotropin-releasing factor, glucagon-like peptide, oxytocin, and ghrelin). Maintaining healthy gut microbiota (GM) is now being recognized as important for brain health through the use of probiotics, prebiotics, synbiotics, fecal microbial transplantation (FMT), etc. A few approaches exert antidepressant effects via restoring GM and hypothalamus-pituitary-adrenal (HPA) axis functions. In this review, we have summarized the etiopathogenic link between gut dysbiosis and depression with preclinical and clinical evidence. In addition, we have collated information on the recent therapies and supplements, such as probiotics, prebiotics, short-chain fatty acids, and vitamin B12, omega-3 fatty acids, etc., which target the gut-brain axis (GBA) for the effective management of depressive behavior and anxiety.

The Influence of Gut Dysbiosis in the Pathogenesis and Management of Ischemic Stroke.

Recent research on the gut microbiome has revealed the influence of gut microbiota (GM) on ischemic stroke pathogenesis and treatment outcomes. Alterations in the diversity, abundance, and functions of the gut microbiome, termed gut dysbiosis, results in dysregulated gut-brain signaling, which induces intestinal barrier changes, endotoxemia, systemic inflammation, and infection, affecting post-stroke outcomes. Gut-brain interactions are bidirectional, and the signals from the gut to the brain are mediated by microbially derived metabolites, such as trimethylamine N-oxide (TMAO) and short-chain fatty acids (SCFAs); bacterial components, such as lipopolysaccharide (LPS); immune cells, such as T helper cells; and bacterial translocation via hormonal, immune, and neural pathways. Ischemic stroke affects gut microbial composition via neural and hypothalamic-pituitary-adrenal (HPA) pathways, which can contribute to post-stroke outcomes. Experimental and clinical studies have demonstrated that the restoration of the gut microbiome usually improves stroke treatment outcomes by regulating metabolic, immune, and inflammatory responses via the gut-brain axis (GBA). Therefore, restoring healthy microbial ecology in the gut may be a key therapeutic target for the effective management and treatment of ischemic stroke.

Antioxidant and Antiaging Properties of Agar Obtained from Brown Seaweed Laminaria digitata (Hudson) in D-Galactose-Induced Swiss Albino Mice.

The present paper explores the antioxidant and antiaging properties of agar extracted from Laminaria digitata (L. digitata) on a D-galactose (D-Gal)-induced mouse model. Experimental mice were divided into four groups: group I comprised of control nontreated mice, group II comprised of D-Gal-induced mice, group III mice were treated with extracted agar after D-Gal induction, and group IV mice were given ascorbic acid as a positive control. Antioxidant enzymes and aging marker proteins declined significantly in group II, whereas they were normal in group III and group IV mice. Expressions of interleukin-1ß (IL-1ß) in D-Gal-induced mice were significantly enhanced in the liver and brain of the experimental mice, which were otherwise normal in agar-treated mice. Also, IL-6 levels were significantly increased in the liver and reversed in the brain of D-gal mice, while it was regularly in the agar-treated mice. The histopathological analysis of D-Gal-induced mice showed spongiosis and tangles in brain cells, increased fat and decreased collagen contents in the skin, and few dilated sinuses in the hepatic cells. The changes were under control in group III and group IV mice, suggesting the protective effects of agar extracted from L. digitata and ascorbic acid.

Gut dysbiosis, defective autophagy and altered immune responses in neurodegenerative diseases: Tales of a vicious cycle.

The human microbiota comprises trillions of symbiotic microorganisms and is involved in regulating gastrointestinal (GI), immune, nervous system and metabolic homeostasis. Recent observations suggest a bidirectional communication between the gut microbiota and the brain via immune, circulatory and neural pathways, termed the Gut-Brain Axis (GBA). Alterations in gut microbiota composition, such as seen with an increased number of pathobionts and a decreased number of symbionts, termed gut dysbiosis or microbial intestinal dysbiosis, plays a prominent role in the pathogenesis of central nervous system (CNS)-related disorders. Clinical reports confirm that GI symptoms often precede neurological symptoms several years before the development of neurodegenerative diseases (NDDs). Pathologically, gut dysbiosis disrupts the integrity of the intestinal barrier leading to ingress of pathobionts and toxic metabolites into the systemic circulation causing GBA dysregulation. Subsequently, chronic neuroinflammation via dysregulated immune activation triggers the accumulation of neurotoxic misfolded proteins in and around CNS cells resulting in neuronal death. Emerging evidence links gut dysbiosis to the aggravation and/or spread of proteinopathies from the peripheral nervous system to the CNS and defective autophagy-mediated proteinopathies. This review summarizes the current understanding of the role of gut microbiota in NDDs, and highlights a vicious cycle of gut dysbiosis, immune-mediated chronic neuroinflammation, impaired autophagy and proteinopathies, which contributes to the development of neurodegeneration in Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis and frontotemporal lobar degeneration. We also discuss novel therapeutic strategies targeting the modulation of gut dysbiosis through prebiotics, probiotics, synbiotics or dietary interventions, and faecal microbial transplantation (FMT) in the management of NDDs.

Fortification methods of coenzyme Q10 in yogurt and its health functionality-a review.

Coenzyme Q10 (CoQ10) is an antioxidant, fat-soluble component present in the mitochondrial cells. It provides beneficial results in the treatment of male infertility. In the current scenario, the sedative lifestyle, diet and stress in human lead to excessive free radicals (ROS), leading to health aliments. The review is conducted to compare the effect of different fortification methods of CoQ10 in the Yogurt. The study showed that nanoparticles form of CoQ10 in yogurt showed higher bioaccesiblity rates in humans, and the microencapsulation of CoQ10 showed a low amount of Ubiquinone released during its shelf life. The functional Yogurt produced by the Monascus-fermented soybean powder (MFSP) co-fermentation has been shown to have high free radicals scavenging activity. Thus, the review observes that each fortified sample is useful in its way as CoQ10 supplements. Further studies must be done for accurate conclusions on its effect on male infertility, and other fortification media can be explored.

Impact of Pharmacological and Non-Pharmacological Modulators on Dendritic Spines Structure and Functions in Brain.

Dendritic spines are small, thin, hair-like protrusions found on the dendritic processes of neurons. They serve as independent compartments providing large amplitudes of Ca2+ signals to achieve synaptic plasticity, provide sites for newer synapses, facilitate learning and memory. One of the common and severe complication of neurodegenerative disease is cognitive impairment, which is said to be closely associated with spine pathologies viz., decreased in spine density, spine length, spine volume, spine size etc. Many treatments targeting neurological diseases have shown to improve the spine structure and distribution. However, concise data on the various modulators of dendritic spines are imperative and a need of the hour. Hence, in this review we made an attempt to consolidate the effects of various pharmacological (cholinergic, glutamatergic, GABAergic, serotonergic, adrenergic, and dopaminergic agents) and non-pharmacological modulators (dietary interventions, enriched environment, yoga and meditation) on dendritic spines structure and functions. These data suggest that both the pharmacological and non-pharmacological modulators produced significant improvement in dendritic spine structure and functions and in turn reversing the pathologies underlying neurodegeneration. Intriguingly, the non-pharmacological approaches have shown to improve intellectual performances both in preclinical and clinical platforms, but still more technology-based evidence needs to be studied. Thus, we conclude that a combination of pharmacological and non-pharmacological intervention may restore cognitive performance synergistically via improving dendritic spine number and functions in various neurological disorders.

Mitochondria-Endoplasmic Reticulum Crosstalk in Parkinson's Disease: The Role of Brain Renin Angiotensin System Components.

The past few decades have seen an increased emphasis on the involvement of the mitochondrial-associated membrane (MAM) in various neurodegenerative diseases, particularly in Parkinson's disease (PD) and Alzheimer's disease (AD). In PD, alterations in mitochondria, endoplasmic reticulum (ER), and MAM functions affect the secretion and metabolism of proteins, causing an imbalance in calcium homeostasis and oxidative stress. These changes lead to alterations in the translocation of the MAM components, such as IP3R, VDAC, and MFN1 and 2, and consequently disrupt calcium homeostasis and cause misfolded proteins with impaired autophagy, distorted mitochondrial dynamics, and cell death. Various reports indicate the detrimental involvement of the brain renin-angiotensin system (RAS) in oxidative stress, neuroinflammation, and apoptosis in various neurodegenerative diseases. In this review, we attempted to update the reports (using various search engines, such as PubMed, SCOPUS, Elsevier, and Springer Nature) demonstrating the pathogenic interactions between the various proteins present in mitochondria, ER, and MAM with respect to Parkinson's disease. We also made an attempt to speculate the possible involvement of RAS and its components, i.e., AT1 and AT2 receptors, angiotensinogen, in this crosstalk and PD pathology. The review also collates and provides updated information on the role of MAM in calcium signaling, oxidative stress, neuroinflammation, and apoptosis in PD.

Effects of Telmisartan, an AT1 receptor antagonist, on mitochondria-specific genes expression in a mouse MPTP model of Parkinsonism.

Background: Mitochondrial dysfunction plays a crucial role in Parkinson's disease (PD) pathogenesis. The present study was undertaken to investigate the effects of Telmisartan (TEL), an angiotensin II type 1 receptor (AT1R) blocker, on the mitochondria-specific genes expression in a mouse model of Parkinsonism. Materials and methods: Mice were divided into 5 groups with 6 in each; Group I received 0.5% CMC (control) + saline, Group II received 0.5% CMC + 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (positive control), Group III & IV received MPTP + TEL 3 and 10 mg/kg, p.o. respectively, Group V received TEL 10 mg/kg, p.o. (drug control). MPTP was given 80 mg/kg intraperitoneal in two divided doses (40 mg/kg × 2 at 16 h time interval). Vehicle or TEL was administered 1 h before the MPTP injection. Motor function was assessed 48 h after the first dose of MPTP and animals were euthanized to collect brain. Results: Mice intoxicated with MPTP showed locomotor deficits and significant upregulation of α-synuclein (α-syn), downregulation of metastasis-associated protein 1 (MTA1), and Ubiquitin C-terminal hydrolase L1 (UCHL1) in the substantia nigra pars compacta (SNpc) and Striatum (STr) regions of brains. In addition, MPTP intoxication down-regulated mitochondria-specific genes such as DJ-1, PTEN-induced putative kinase 1 (PINK1), Parkin, enriched with leucine repeats kinase 2 (LRRK2) gene expfression. Pre-treatment with TEL restored locomotor functions and upregulated PINK1, Parkin, LRRK2, DJ-1, MTA1 and UCHL1. Conclusion: The present study evidences that TEL has the ability to improve mitochondrial functions in PD.

Agricultural biotechnology: Revealing insights about ethical concerns.

Genetic modification (GM) of crops is a technique that involves the transfer of a genetic material from one organism, including plants, animals, or microorganisms, into a different organism, modifying the plants' characteristics. The technology provides different approaches towards agricultural improvements (environmental, nutritional, yield increases, etc.), which maintained the global food security (quality and safety). However, the opponents have kept on fighting against the technology in a way that merely addresses the potential risks with disregard to the benefits. Some of the arguments which are commonly addressed against the agricultural biotechnology are the negative impacts of overproduction, unnatural biological diversity and the domination of multinational agribusiness corporations. Therefore, the present review reveals an insight towards the negative and positive effects of GM crops on human health and the environment including ethical concerns. The write up will also be an overview that addresses the importance of GM crops and the moral imperative including religious perspectives, thus, providing the public awareness towards accepting the biotechnology.

Mitochondrial and Organellar Crosstalk in Parkinson's Disease.

Mitochondrial dysfunction is a well-established pathological event in Parkinson's disease (PD). Proteins misfolding and its impaired cellular clearance due to altered autophagy/mitophagy/pexophagy contribute to PD progression. It has been shown that mitochondria have contact sites with endoplasmic reticulum (ER), peroxisomes and lysosomes that are involved in regulating various physiological processes. In pathological conditions, the crosstalk at the contact sites initiates alterations in intracellular vesicular transport, calcium homeostasis and causes activation of proteases, protein misfolding and impairment of autophagy. Apart from the well-reported molecular changes like mitochondrial dysfunction, impaired autophagy/mitophagy and oxidative stress in PD, here we have summarized the recent scientific reports to provide the mechanistic insights on the altered communications between ER, peroxisomes, and lysosomes at mitochondrial contact sites. Furthermore, the manuscript elaborates on the contributions of mitochondrial contact sites and organelles dysfunction to the pathogenesis of PD and suggests potential therapeutic targets.

Acetylsalicylic acid improves cognitive performance in sleep deprived adult Zebrafish (Danio rerio) model.

Sleep deprivation (SD) is commonly associated with decreased attention, reduced responsiveness to external stimuli, and impaired locomotor and cognitive performances. Strong evidence indicates that SD disrupts neuro-immuno-endocrine system which is also linked to cognitive function. Recently Zebrafish have emerged as a powerful model sharing organizational and functional characteristics with other vertebrates, providing great translational relevance with rapid and reliable screening results. In the current study, we examined the effects of acetylsalicylic acid (aspirin) on cognitive and locomotor activity in sleep deprived Zebrafish model. Learning and memory were assessed by T-maze and locomotor activity was assessed by partition preference and swimming time in spinning tasks. Furthermore, brain bioavailability of aspirin was determined by high performance liquid chromatography. Following drug exposure and tasks, histopathology of the brain was performed. It was observed that three-day SD significantly reduces learning and memory and locomotion in the Zebrafish. Aspirin was found to restore SD induced cognitive decline and improve the locomotor functions. Neuro-inflammation and impaired functional network connectivity is linked to cognitive defects, which implicate the possible benefits of immunotherapeutics. In the present study, aspirin decreased neutrophil infiltration, and increased spine density in dentate gyrus granular and shrinkage and basophil in the CA1 neurons of hippocampus. This hints the benefit of aspirin on neuroimmune functions in sleep deprived fish and warrants more studies to establish the clear molecular mechanism behind this protective effect.

Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury.

Advanced glycation end products (AGEs) are potentially harmful and heterogeneous molecules derived from nonenzymatic glycation. The pathological implications of AGEs are ascribed to their ability to promote oxidative stress, inflammation, and apoptosis. Recent studies in basic and translational research have revealed the contributing roles of AGEs in the development and progression of various aging-related pathological conditions, such as diabetes, cardiovascular complications, gut microbiome-associated illnesses, liver or neurodegenerative diseases, and cancer. Excessive chronic and/or acute binge consumption of alcohol (ethanol), a widely consumed addictive substance, is known to cause more than 200 diseases, including alcohol use disorder (addiction), alcoholic liver disease, and brain damage. However, despite the considerable amount of research in this area, the underlying molecular mechanisms by which alcohol abuse causes cellular toxicity and organ damage remain to be further characterized. In this review, we first briefly describe the properties of AGEs: their formation, accumulation, and receptor interactions. We then focus on the causative functions of AGEs that impact various aging-related diseases. We also highlight the biological connection of AGE-alcohol-adduct formations to alcohol-mediated tissue injury. Finally, we describe the potential translational research opportunities for treatment of various AGE- and/or alcohol-related adduct-associated disorders according to the mechanistic insights presented.