PGC-1α regulates the interplay between oxidative stress, senescence and autophagy in the ageing retina important in age-related macular degeneration.

We previously showed that mice with knockout in the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A) gene encoding the PGC-1α protein, and nuclear factor erythroid 2 like 2 (NFE2L2) gene, exhibited some features of the age-related macular degeneration (AMD) phenotype. To further explore the mechanism behind the involvement of PGC-1α in AMD pathogenesis we used young (3-month) and old (12-month) mice with knockout in the PPARGC1A gene and age-matched wild-type (WT) animals. An immunohistochemical analysis showed age-dependent different expression of markers of oxidative stress defence, senescence and autophagy in the retinal pigment epithelium of KO animals as compared with their WT counterparts. Multivariate inference testing showed that senescence and autophagy proteins had the greatest impact on the discrimination between KO and WT 3-month animals, but proteins of antioxidant defence also contributed to that discrimination. A bioinformatic analysis showed that PGC-1α might coordinate the interplay between genes encoding proteins involved in antioxidant defence, senescence and autophagy in the ageing retina. These data support importance of PGC-1α in AMD pathogenesis and confirm the utility of mice with PGC-1α knockout as an animal model to study AMD pathogenesis.

A Low FODMAP Diet Supplemented with L-Tryptophan Reduces the Symptoms of Functional Constipation in Elderly Patients.

(1) Background: The elderly suffer from functional constipation (FC), whose causes are not fully known, but nutritional factors may play a role. The aim of the present study was to assess the effect of a low FODMAP diet supplemented with L-tryptophan (TRP) on its metabolism and symptoms of functional constipation in elderly patients. (2) Methods: This study included 40 people without abdominal complaints (Group I, controls) and 60 patients with FC, diagnosed according to the Rome IV Criteria (Group II). Two groups were randomly selected: Group IIA (n = 30) was qualified for administration of the low FODMAP diet, and the diet of patients of Group IIB (n = 30) was supplemented with 1000 mg TRP per day. The severity of abdominal symptoms was assessed with an abdominal pain index ranging from 1 to 7 points (S-score). The concentration of TRP and its metabolites, 5-hydroxyindoleacetic acid (5-HIAA), kynurenine (KYN), and 3-indoxyl sulfate (3-IS) in urine were determined using the LC-MS/MS method. (3) Results: In Group II, 5-HIAA concentration in urine was lower, and KYN and 3-IS concentrations were higher than in the control group. A negative correlation was found between the S-score and urinary concentration of 5-HIAA (p < 0.001), and 3-IS concentration was positively correlated with the S-score. However, the correlation between the S-score and 3-IS concentration was negative (p < 0.01). After a dietary intervention, 5-HIAA concentration increased in both groups, and the severity of symptoms decreased, but the decrease was more pronounced in Group IIB. (4) Conclusion: A low FODMAP diet supplemented with L-tryptophan has beneficial effects in elderly patients suffering from functional constipation.

Potential of focal cortical dysplasia in migraine pathogenesis.

Focal cortical dysplasias are abnormalities of the cerebral cortex associated with an elevated risk of neurological disturbances. Cortical spreading depolarization/depression is a correlate of migraine aura/headache and a trigger of migraine pain mechanisms. However, cortical spreading depolarization/depression is associated with cortical structural changes, which can be classified as transient focal cortical dysplasias. Migraine is reported to be associated with changes in various brain structures, including malformations and lesions in the cortex. Such malformations may be related to focal cortical dysplasias, which may play a role in migraine pathogenesis. Results obtained so far suggest that focal cortical dysplasias may belong to the causes and consequences of migraine. Certain focal cortical dysplasias may lower the threshold of cortical excitability and facilitate the action of migraine triggers. Migraine prevalence in epileptic patients is higher than in the general population, and focal cortical dysplasias are an established element of epilepsy pathogenesis. In this narrative/hypothesis review, we present mainly information on cortical structural changes in migraine, but studies on structural alterations in deep white matter and other brain regions are also presented. We develop the hypothesis that focal cortical dysplasias may be causally associated with migraine and link pathogeneses of migraine and epilepsy.

A new class of polyphenolic carbosilane dendrimers binds human serum albumin in a structure-dependent fashion.

The use of dendrimers as drug and nucleic acid delivery systems requires knowledge of their interactions with objects on their way to the target. In the present work, we investigated the interaction of a new class of carbosilane dendrimers functionalized with polyphenolic and caffeic acid residues with human serum albumin, which is the most abundant blood protein. The addition of dendrimers to albumin solution decreased the zeta potential of albumin/dendrimer complexes as compared to free albumin, increased density of the fibrillary form of albumin, shifted fluorescence spectrum towards longer wavelengths, induced quenching of tryptophan fluorescence, and decreased ellipticity of circular dichroism resulting from a reduction in the albumin α-helix for random coil structural form. Isothermal titration calorimetry showed that, on average, one molecule of albumin was bound by 6-10 molecules of dendrimers. The zeta size confirmed the binding of the dendrimers to albumin. The interaction of dendrimers and albumin depended on the number of caffeic acid residues and polyethylene glycol modifications in the dendrimer structure. In conclusion, carbosilane polyphenolic dendrimers interact with human albumin changing its structure and electrical properties. However, the consequences of such interaction for the efficacy and side effects of these dendrimers as drug/nucleic acid delivery system requires further research.

A New Generation of Gene Therapies as the Future of Wet AMD Treatment.

Age-related macular degeneration (AMD) is an eye disease and the most common cause of vision loss in the Western World. In its advanced stage, AMD occurs in two clinically distinguished forms, dry and wet, but only wet AMD is treatable. However, the treatment based on repeated injections with vascular endothelial growth factor A (VEGFA) antagonists may at best stop the disease progression and prevent or delay vision loss but without an improvement of visual dysfunction. Moreover, it is a serious mental and financial burden for patients and may be linked with some complications. The recent first success of intravitreal gene therapy with ADVM-022, which transformed retinal cells to continuous production of aflibercept, a VEGF antagonist, after a single injection, has opened a revolutionary perspective in wet AMD treatment. Promising results obtained so far in other ongoing clinical trials support this perspective. In this narrative/hypothesis review, we present basic information on wet AMD pathogenesis and treatment, the concept of gene therapy in retinal diseases, update evidence on completed and ongoing clinical trials with gene therapy for wet AMD, and perspectives on the progress to the clinic of "one and done" therapy for wet AMD to replace a lifetime of injections. Gene editing targeting the VEGFA gene is also presented as another gene therapy strategy to improve wet AMD management.

The Ketogenic Diet in the Prevention of Migraines in the Elderly.

Migraines display atypical age dependence, as the peak of their prevalence occurs between the ages of 20-40 years. With age, headache attacks occur less frequently and are characterized by a lower amplitude. However, both diagnosis and therapy of migraines in the elderly are challenging due to multiple comorbidities and polypharmacy. Dietary components and eating habits are migraine triggers; therefore, nutrition is a main target in migraine prevention. Several kinds of diets were proposed to prevent migraines, but none are commonly accepted due to inconsistent results obtained in different studies. The ketogenic diet is featured by very low-carbohydrate and high-fat contents. It may replace glucose with ketone bodies as the primary source of energy production. The ketogenic diet and the actions of ketone bodies are considered beneficial in several aspects of health, including migraine prevention, but studies on the ketogenic diet in migraines are not standardized and poorly evidenced. Apart from papers claiming beneficial effects of the ketogenic diet in migraines, several studies have reported that increased levels of ketone bodies may be associated with all-cause and incident heart failure mortality in older adults and are supported by research on mice showing that the ketogenic diets and diet supplementation with a human ketone body precursor may cause life span shortening. Therefore, despite reports showing a beneficial effect of the ketogenic diet in migraines, such a diet requires further studies, including clinical trials, to verify whether it should be recommended in older adults with migraines.

The kynurenine pathway of tryptophan metabolism in abdominal migraine in children - A therapeutic potential?

BACKGROUND: Abdominal migraine (AM) is a clinical diagnosis specified by Rome IV and ICHD III as a functional gastrointestinal disease (FGID) and a migraine associated syndrome, respectively. Abdominal migraine in childhood and adolescence may continue with migraine headaches in adulthood. This disease is undiagnosed and undertreated, and thus far the FDA has not approved any drug for AM treatment. It was shown that changes in the kynurenine (KYN) pathway of tryptophan (TRP) metabolism played an important role in the pathogenesis and treatment of FIGDs and associated mood disorders. Changes in the KYN pathway were shown in migraine and therefore it may be involved in AM pathogenesis. FINDINGS: Abdominal migraine reflects an impairment in the communication within the gut-brain axis. Treatment approaches in AM are based on the experience of physicians, presenting personal rather than evidence-based practice, including efficacy of some drugs in adult migraine. Non-pharmacological treatment of AM is aimed at preventing or ameliorating AM triggers and is based on the STRESS mnemonic. Metabolic treatments with riboflavin and coenzyme Q10 were effective in several cases of pediatric migraine, but in general, results on metabolic treatment in migraine in children are scarce and nonconclusive. Modulations within the KYN pathway of TRP metabolism induced by changes in TRP content in the diet, may ameliorate FGIDs and support their pharmacological treatment. Pharmacological manipulations of brain KYNs in animals have brought promising results for clinical applications. Obese children show a higher headache prevalence and may be especially predisposed to AM, and KYN metabolites showed an alternated distribution in obese individuals as compared with their normal-weight counterparts. CONCLUSIONS: In conclusion, controlled placebo-based clinical trials with dietary manipulation to adjust the amount of the product of the KYN pathway of TRP metabolism are justified in children and adolescents with AM, especially those with coexisting obesity. Further preclinical studies are needed to establish details of these trials.

Epigallocatechin-3-Gallate, an Active Green Tea Component to Support Anti-VEGFA Therapy in Wet Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is a largely incurable disease and an emerging problem in aging societies. It occurs in two forms, dry and wet (exudative, neovascular), which may cause legal blindness and sight loss. Currently, there is not any effective treatment for dry AMD. Meanwhile, repeated intravitreal injections with antibodies effective against vascular endothelial growth factor A (VEGFA) slow down wet AMD progression but are not free from complications. (-)-Epigallocatechin-3-gallate (EGCG) is an active compound of green tea, which exerts many beneficial effects in the retinal pigment epithelium and the neural retina. It has been reported to downregulate the VEGFA gene by suppressing its activators. The inhibition of mitogen-activated protein kinases 1 and 3 (MAPK1 and MAPK3) may lie behind the antiangiogenic action of EGCG mediated by VEGFA. EGCG exerts protective effects against UV-induced damage to retinal cells and improves dysfunctional autophagy. EGCG may also interact with the mechanistic target rapamycin (MTOR) and unc-51-like autophagy activating kinase (ULK1) to modulate the interplay between autophagy and apoptosis. Several other studies report beneficial effects of EGCG on the retina that may be related to wet AMD. Therefore, controlled clinical trials are needed to verify whether diet supplementation with EGCG or green tea consumption may improve the results of anti-VEGFA therapy in wet AMD.

Autophagy may protect the brain against prolonged consequences of headache attacks: A narrative/hypothesis review.

OBJECTIVE: To assess the potential of autophagy in migraine pathogenesis. BACKGROUND: The interplay between neurons and microglial cells is important in migraine pathogenesis. Migraine-related effects, such as cortical spreading depolarization and release of calcitonin gene-related peptide, may initiate adenosine triphosphate (ATP)-mediating pro-nociceptive signaling in the meninges causing headaches. Such signaling may be induced by the interaction of ATP with purinergic receptor P2X 7 (P2X7R) on microglial cells leading to a Ca2+ -mediated pH increase in lysosomes and release of autolysosome-like vehicles from microglial cells indicating autophagy impairment. METHODS: A search in PubMed was conducted with the use of the terms "migraine," "autophagy," "microglia," and "degradation" in different combinations. RESULTS: Impaired autophagy in microglia may activate secretory autophagy and release of specific proteins, including brain-derived neurotrophic factor (BDNF), which can be also released through the pores induced by P2X7R activation in microglial cells. BDNF may be likewise released from microglial cells upon ATP- and Ca2+ -mediated activation of another purinergic receptor, P2X4R. BDNF released from microglia might induce autophagy in neurons to clear cellular debris produced by oxidative stress, which is induced in the brain as the response to migraine-related energy deficit. Therefore, migraine-related signaling may impair degradative autophagy, stimulate secretory autophagy in microglia, and degradative autophagy in neurons. These effects are mediated by purinergic receptors P2X4R and P2X7R, BDNF, ATP, and Ca2+ . CONCLUSION: Different effects of migraine-related events on degradative autophagy in microglia and neurons may prevent prolonged changes in the brain related to headache attacks.

Epigenetic Connections of the TRPA1 Ion Channel in Pain Transmission and Neurogenic Inflammation - a Therapeutic Perspective in Migraine?

Persistent reprogramming of epigenetic pattern leads to changes in gene expression observed in many neurological disorders. Transient receptor potential cation channel subfamily A member 1 (TRPA1), a member of the TRP channels superfamily, is activated by many migraine triggers and expressed in trigeminal neurons and brain regions that are important in migraine pathogenesis. TRP channels change noxious stimuli into pain signals with the involvement of epigenetic regulation. The expression of the TRPA1 encoding gene, TRPA1, is modulated in pain-related syndromes by epigenetic alterations, including DNA methylation, histone modifications, and effects of non-coding RNAs: micro RNAs (miRNAs), long non-coding RNAs, and circular RNAs. TRPA1 may change epigenetic profile of many pain-related genes as it may modify enzymes responsible for epigenetic modifications and expression of non-coding RNAs. TRPA1 may induce the release of calcitonin gene related peptide (CGRP), from trigeminal neurons and dural tissue. Therefore, epigenetic regulation of TRPA1 may play a role in efficacy and safety of anti-migraine therapies targeting TRP channels and CGRP. TRPA1 is also involved in neurogenic inflammation, important in migraine pathogenesis. The fundamental role of TRPA1 in inflammatory pain transmission may be epigenetically regulated. In conclusion, epigenetic connections of TRPA1 may play a role in efficacy and safety of anti-migraine therapy targeting TRP channels or CGRP and they should be further explored for efficient and safe antimigraine treatment. This narrative/perspective review presents information on the structure and functions of TRPA1 as well as role of its epigenetic connections in pain transmission and potential in migraine therapy.

Different Aspects of Aging in Migraine.

Migraine is a common neurological disease displaying an unusual dependence on age. For most patients, the peak intensity of migraine headaches occurs in 20s and lasts until 40s, but then headache attacks become less intense, occur less frequently and the disease is more responsive to therapy. This relationship is valid in both females and males, although the prevalence of migraine in the former is 2-4 times greater than the latter. Recent concepts present migraine not only as a pathological event, but rather as a part of evolutionary adaptive response to protect organism against consequences of stress-induced brain energy deficit. However, these concepts do not fully explain that unusual dependence of migraine prevalence on age. Many aspects of aging, both molecular/cellular and social/cognitive, are interwound in migraine pathogenesis, but they neither explain why only some persons are affected by migraine, nor suggest any causal relationship. In this narrative/hypothesis review we present information on associations of migraine with chronological aging, brain aging, cellular senescence, stem cell exhaustion as well as social, cognitive, epigenetic, and metabolic aging. We also underline the role of oxidative stress in these associations. We hypothesize that migraine affects only individuals who have inborn, genetic/epigenetic, or acquired (traumas, shocks or complexes) migraine predispositions. These predispositions weakly depend on age and affected individuals are more prone to migraine triggers than others. Although the triggers can be related to many aspects of aging, social aging may play a particularly important role as the prevalence of its associated stress has a similar age-dependence as the prevalence of migraine. Moreover, social aging was shown to be associated with oxidative stress, important in many aspects of aging. In perspective, molecular mechanisms underlying social aging should be further explored and related to migraine with a closer association with migraine predisposition and difference in prevalence by sex.

Reduced Intake of Dietary Tryptophan Improves Beneficial Action of Budesonide in Patients with Lymphocytic Colitis and Mood Disorders.

Lymphocytic colitis (LC) is a gastrointestinal (GI) tract disease with poorly known pathogenesis, but some environmental and lifestyle factors, including certain dietary components, may play a role. Tryptophan is an essential amino acid, which plays important structural and functional roles as a component of many proteins. It is important in the development and maintenance of the body, in which it is metabolized in two main pathways: kynurenine (KYN) and serotonin. In this work, we explored the effect of reducing of TRP in the diet of patients with LC with mood disorders. We enrolled 40 LC patients who had a normal diet, 40 LC patients with the 8-week diet with TRP content reduced by 25% and 40 controls. All LC patients received budesonide at 9 mg per day, and the severity of their GI symptoms was evaluated by the Gastrointestinal Symptoms Rating Scale. Mood disorders were evaluated by the Hamilton Anxiety Rating Scale (HAM-A) and the Hamilton Depression Rating Scale (HAM-D). The concentration of TRP and its metabolites, 5-hydroxyindoleacetic acid (5-HIAA), kynurenine (KYN), kynurenic acid (KYNA) and quinolinic acid (QA), in urine were determined. Budesonide improved the GI and mental states of LC patients, and the diet with reduced TRP content further amended these symptoms. Dietary intervention decreased the concentration of 5-HIAA by about 50% (3.4 vs. 6.3) and QA by about 45% (3.97 vs. 7.20). These changes were correlated with a significant improvement in the profitable action of budesonide on gastrointestinal and mental health of LC patients as they displayed significantly lower GSRS, HAM-A and HAM-B scores after than before the intervention-10.5 vs. 32, 11.0 vs. 21 and 12 vs. 18, respectively. In conclusion, a reduction in TRP intake in diet may improve GI and mental symptoms in LC patients treated with budesonide and these changes may be mediated by the products of TRP metabolism.

The Usefulness of the Low-FODMAP Diet with Limited Tryptophan Intake in the Treatment of Diarrhea-Predominant Irritable Bowel Syndrome.

(1) Background: A low-FODMAP diet is often recommended in the treatment of irritable bowel syndrome, but it does not improve abdominal symptoms in all patients, and an alternative diet is desirable. The purpose of this study was to evaluate the efficacy of a low-FODMAP diet with a concomitant reduction in tryptophan (TRP) intake in irritable bowel syndrome with diarrhea predominance (IBS-D) in relation to its metabolism via the serotonin and kynurenine pathways. (2) Methods: 40 healthy people (Group I, Controls) and 80 patients with IBS-D were included in the study. IBS-D patients were randomly divided into two groups of 40 each (Groups IIA and IIB). In Group IIA, the low-FODMAP diet was recommended, while in Group IIB, the same diet was recommended but with limited TRP intake for 8 weeks. The TRP intake was analyzed with the use of the nutritional calculator. Abdominal complaints were assessed using the Gastrointestinal Symptom Rating Scale (GSRS-IBS), and psychological status was simultaneously determined using two scales: the Hamilton Anxiety Scale (HAM-A) and the Hamilton Depression Scale (HAM-D). TRP and its metabolites: 5-hydoxyindoleacetic acid (5-HIAA), kynurenine (KYN), kynurenic acid (KYNA), and quinolinic acid (QA) were measured in urine using liquid chromatography tandem mass spectrometry (LC-MS/MS). (3) Results: The consumption of TRP per mg/kg/b.w./24 h has decreased in Group IIA from 20.9 ± 2.39 to 17.45 ± 2.41 (16.5%) and in Group IIB from 21.3 ± 2.33 to 14.32 (34.4%). Significantly greater improvement was found after nutritional treatment in patients in Group IIB as compared to Group IIA (GSRS score: 38.1% vs. 49.8%; HAM-A: 38.7% vs. 49.9%; HAM-D: 13.8% vs. 35.0%; p < 0.01). Reducing TRP intake showed a negative correlation with the degree of improvement in the GSRS score. (4) Conclusions: Lowering the TRP content in a low-FODMAP diet may be useful in treating IBS-D.

Beneficial Effect of Increased Tryptophan Intake on Its Metabolism and Mental State of the Elderly.

The elderly often suffer from sleep disorders and depression, which contribute to mood disorders. In our previous work, we showed that elderly individuals with mood disorders had a lower intake of TRP and recommended a TRP-based dietary intervention to improve the mental state of such individuals. In this work, we assessed the impact of a TRP-rich diet on the mental state of, and TRP metabolism in, elderly individuals with mood disorders. Forty elderly individuals with depression and sleep disorders and an equal number of elderly subjects without mood disorders were enrolled in this study. TRP intake was evaluated with the nutrition calculator. Patients with mood disorders had a lower TRP intake than their normal counterparts and received a TRP-rich diet with TRP content of 25 mg per kilogram of the body per day for 12 weeks. The mental state was assessed before and after this dietary intervention with the Hamilton Depression Rating Scale (HAM-D) and the Insomnia Severity Index (ISI). At those times, urinary levels of TRP and its metabolites 5-hydroxyindoleacetic acid (5-HIAA), L-kynurenine (KYN), kynurenic acid (KYNA), and quinolinic acid (QA) were determined by liquid chromatography with tandem mass spectrometry and related to creatinine level. After TRP-based dietary intervention, the score of ISI and HAM-D decreased by more than half. A correlation analysis reveals that TRP, 5-HIAA, and KYNA might have anti-depressive action, while KYN and QA-pro-depressive. The levels of TRP, 5-HIAA, and KYNA in urine of mood disorder patients increased, while the levels of KYN and QA decreased. In conclusion, dietary consumption of adequate amount of tryptophan has a beneficial effect on mental health of the elderly with mood disorders and improves metabolism of this amino acid. Therefore, a TRP-enriched diet may be considered as a component of the treatment of elderly individuals with mood disorders.

Non-Coding RNAs Regulating Mitochondrial Functions and the Oxidative Stress Response as Putative Targets against Age-Related Macular Degeneration (AMD).

Age-related macular degeneration (AMD) is an ever-increasing, insidious disease which reduces the quality of life of millions of elderly people around the world. AMD is characterised by damage to the retinal pigment epithelium (RPE) in the macula region of the retina. The origins of this multi-factorial disease are complex and still not fully understood. Oxidative stress and mitochondrial imbalance in the RPE are believed to be important factors in the development of AMD. In this review, the regulation of the mitochondrial function and antioxidant stress response by non-coding RNAs (ncRNAs), newly emerged epigenetic factors, is discussed. These molecules include microRNAs, long non-coding RNAs, and circular non-coding RNAs. They act mainly as mRNA suppressors, controllers of other ncRNAs, or by interacting with proteins. We include here examples of these RNA molecules which affect various mitochondrial processes and antioxidant signaling of the cell. As a future prospect, the possibility to manipulate these ncRNAs to strengthen mitochondrial and antioxidant response functions is discussed. Non-coding RNAs could be used as potential diagnostic markers for AMD, and in the future, also as therapeutic targets, either by suppressing or increasing their expression. In addition to AMD, it is possible that non-coding RNAs could be regulators in other oxidative stress-related degenerative diseases.

Nutrition and Calcitonin Gene Related Peptide (CGRP) in Migraine.

Targeting calcitonin gene-related peptide (CGRP) and its receptor by antibodies and antagonists was a breakthrough in migraine prevention and treatment. However, not all migraine patients respond to CGRP-based therapy and a fraction of those who respond complain of aliments mainly in the gastrointestinal tract. In addition, CGRP and migraine are associated with obesity and metabolic diseases, including diabetes. Therefore, CGRP may play an important role in the functioning of the gut-brain-microflora axis. CGRP secretion may be modulated by dietary compounds associated with the disruption of calcium signaling and upregulation of mitogen-activated kinase phosphatases 1 and 3. CGRP may display anorexigenic properties through induction of anorexigenic neuropeptides, such as cholecystokinin and/or inhibit orexigenic neuropeptides, such as neuropeptide Y and melanin-concentrating hormone CH, resulting in the suppression of food intake, functionally coupled to the activation of the hypothalamic 3',5'-cyclic adenosine monophosphate. The anorexigenic action of CGRP observed in animal studies may reflect its general potential to control appetite/satiety or general food intake. Therefore, dietary nutrients may modulate CGRP, and CGRP may modulate their intake. Therefore, anti-CGRP therapy should consider this mutual dependence to increase the efficacy of the therapy and reduce its unwanted side effects. This narrative review presents information on molecular aspects of the interaction between dietary nutrients and CGRP and their reported and prospective use to improve anti-CGRP therapy in migraine.

DNA Damage and Repair in Migraine: Oxidative Stress and Beyond.

Energy generation in the brain to ameliorate energy deficit in migraine leads to oxidative stress as it is associated with reactive oxygen species (ROS) that may damage DNA and show a pronociceptive action in meninges mediated by transient receptor potential cation channel subfamily A member 1 (TRPA1). Recent studies show high levels of single-strand breaks (SSBs) at specific sites in the genome of postmitotic neurons and point at SSB repair (SSBR) as an important element of homeostasis of the central nervous system. DNA topoisomerase 1 (TOP1) is stabilized in the DNA damage-inducing state by neuronal stimulation, including cortical spreading depression. Impairment in poly (ADP-ribose) polymerase 1 (PARP-1) and X-ray repair cross complementing 1 (XRCC1), key SSBR proteins, may be linked with migraine by transient receptor potential melastatin 2 (TRPM2). TRPM2 may also mediate the involvement of migraine-related neuroinflammation with PARP-1 activated by oxidative stress-related SSBs. In conclusion, aberrant activity of SSBR evoked by compromised PARP-1 and XRCC1 may contribute to pathological phenomena in the migraine brain. Such aberrant SSBR results in the lack of repair or misrepair of SSBs induced by ROS or resulting from impaired TOP1. Therefore, components of SSBR may be considered a prospective druggable target in migraine.

Autophagy in age-related macular degeneration.

Age-related macular degeneration (AMD) is the leading cause of visual impairment in the aging population with limited understanding of its pathogenesis and a lack of effective treatment. The progression of AMD is initially characterized by atrophic alterations in the retinal pigment epithelium, as well as the formation of lysosomal lipofuscin and extracellular drusen deposits. Damage caused by chronic oxidative stress, protein aggregation and inflammatory processes may lead to geographic atrophy and/or choroidal neovascularization and fibrosis. The role of macroautophagy/autophagy in AMD pathology is steadily emerging. This review describes selective and secretory autophagy and their role in drusen biogenesis, senescence-associated secretory phenotype, inflammation and epithelial-mesenchymal transition in the pathogenesis of AMD.Abbreviations: Aß: amyloid-beta; AMBRA1: autophagy and beclin 1 regulator 1; AMD: age-related macular degeneration; ATF6: activating transcription factor 6; ATG: autophagy related; BACE1: beta-secretase 1; BHLHE40: basic helix-loop-helix family member e40; BNIP3: BCL2 interacting protein 3; BNIP3L/NIX: BCL2 interacting protein 3 like; C: complement; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CARD: caspase recruitment domain; CDKN2A/p16: cyclin dependent kinase inhibitor 2A; CFB: complement factor B; DELEC1/Dec1; deleted in esophageal cancer 1; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 3; EMT: epithelial-mesenchymal transition; ER: endoplasmic reticulum; ERN1/IRE1: endoplasmic reticulum to nucleus signaling 1; FUNDC1: FUN14 domain containing 1; GABARAP: GABA type A receptor-associated protein; HMGB1: high mobility group box 1; IL: interleukin; KEAP1: kelch like ECH associated protein 1; LAP: LC3-associated phagocytosis; LAMP2: lysosomal associated membrane protein 2; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; NFE2L2: NFE2 like bZIP transcription factor 2; NLRP3; NLR family pyrin domain containing 3; NFKB/NFκB: nuclear factor kappa B; OPTN: optineurin; PARL: presenilin associated rhomboid like; PGAM5: PGAM family member 5, mitochondrial serine/threonine protein phosphatase; PINK1: PTEN induced kinase 1; POS: photoreceptor outer segment; PPARGC1A: PPARG coactivator 1 alpha; PRKN: parkin RBR E3 ubiquitin protein ligase; PYCARD/ASC: PYD and CARD domain containing; ROS: reactive oxygen species; RPE: retinal pigment epithelium; SA: secretory autophagy; SASP: senescence-associated secretory phenotype; SEC22B: SEC22 homolog B, vesicle trafficking protein; SNAP: synaptosome associated protein; SNARE: soluble N-ethylmaleimide-sensitive factor attachment protein receptor; SQSTM1/p62: sequestosome 1; STX: syntaxin; TGFB2: transforming growth factor beta 2; TRIM16: tripartite motif containing 16; TWIST: twist family bHLH transcription factor; Ub: ubiquitin; ULK: unc-51 like autophagy activating kinase; UPR: unfolded protein response; UPS: ubiquitin-proteasome system; V-ATPase: vacuolar-type H+-translocating ATPase; VIM: vimentin.

Tryptophan Metabolism in Postmenopausal Women with Functional Constipation.

Constipation belongs to conditions commonly reported by postmenopausal women, but the mechanism behind this association is not fully known. The aim of the present study was to determine the relationship between some metabolites of tryptophan (TRP) and the occurrence and severity of abdominal symptoms (Rome IV) in postmenopausal women with functional constipation (FC, n = 40) as compared with age-adjusted postmenopausal women without FC. All women controlled their TRP intake in their daily diet. Urinary levels of TRP and its metabolites, 5-hydroxyindoleacetic acid (5-HIAA), kynurenine (KYN), and 3-indoxyl sulfate (indican, 3-IS), were determined by liquid chromatography/tandem mass spectrometry. Dysbiosis was assessed by a hydrogen-methane breath test. Women with FC consumed less TRP and had a lower urinary level of 5-HIAA, but higher levels of KYN and 3-IS compared with controls. The severity of symptoms showed a negative correlation with the 5-HIAA level, and a positive correlation with the 3-IS level. In conclusion, changes in TRP metabolism may contribute to FC in postmenopausal women, and dysbiosis may underlie this contribution.

Secretory autophagy: a turn key for understanding AMD pathology and developing new therapeutic targets?

INTRODUCTION: Age-related macular degeneration (AMD) is an eye disease leading to vision loss with poorly known pathogenesis and limited therapeutic options. Degradative autophagy (DA) is impaired in AMD, but emerging evidence points to secretary autophagy (SA) as a key element in AMD pathogenesis. AREAS COVERED: SA may cause the release of proteins and protein aggregates, lipofuscin, beta amyloid, faulty mitochondria, pro-inflammatory and pro-angiogenic factors from the retinal pigment epithelium (RPE) that may contribute to drusen formation and choroidal neovascularization. SA may replace DA, when formation of autolysosome is impaired, and then a harmful cargo, instead of being degraded, is extruded from the RPE contributing to drusen and/or angiogenic environment. Therefore, the interplay between DA and SA may be critical for drusen formation and choroidal neovascularization, so it can be a turn key to understand AMD pathogenesis. EXPERT OPINION: Although SA fulfills some beneficial functions, it is detrimental for the retina in many cases. Therefore, inhibiting SA may be a therapeutic strategy in AMD, but it is challenged by the development of selective SA inhibitors that would not affect DA. The TRIM16, SEC22B and RAB8A proteins, specific for secretory autophagosome, may be primary candidates as therapeutic targets, but their action is not limited to autophagy and therefore requires further studies.