Robotic-assisted proctosigmoidectomy for Hirschsprung’s disease:A multicenter prospective study

BACKGROUND Robotic surgery is a cutting-edge minimally invasive technique that overcomes many shortcomings of laparoscopic techniques,yet few studies have evaluated the use of robotic surgery to treat Hirschsprung’s disease(HSCR).AIM To analyze the feasibility and medium-term outcomes of robotic-assisted proctosigmoidectomy(RAPS)with sphincter-and nerve-sparing surgery in HSCR patients.METHODS From July 2015 to January 2022,156 rectosigmoid HSCR patients were enrolled in this multicenter prospective study.Their sphincters and nerves were spared by dissecting the rectum completely from the pelvic cavity outside the longitudinal muscle of the rectum and then performing transanal Soave pull-through procedures.Surgical outcomes and continence function were analyzed.RESULTS No conversions or intraoperative complications occurred.The median age at surgery was 9.50 months,and the length of the removed bowel was 15.50±5.23 cm.The total operation time,console time,and anal traction time were 155.22±16.77,58.01±7.71,and 45.28±8.15 min.There were 25 complications within 30 d and 48 post-30-d complications.For children aged≥4 years,the bowel function score(BFS)was 17.32±2.63,and 90.91%of patients showed moderate-to-good bowel function.The postoperative fecal continence(POFC)score was 10.95±1.04 at 4 years of age,11.48±0.72 at 5 years of age,and 11.94±0.81 at 6 years of age,showing a promising annual trend.There were no significant differences in postoperative complications,BFS,and POFC scores related to age at surgery being≤3 mo or>3 mo.CONCLUSION RAPS is a safe and effective alternative for treating HSCR in children of all ages;it offers the advantage of further minimizing damage to sphincters and perirectal nerves and thus providing better continence function.

Literature Review of the Outcome after One-Stage Transanal Endorectal Pull-Through Procedure for Hirschsprung’s Disease in Children

Background: Transanal endorectal one-stage pull-through (TERPT) procedure in children with Hirschsprung’s disease (HD) is frequently used worldwide. In order to give the families realistic expectations and to plan the medical care for the years after TERPT, the long term outcome is of great importance. Aim: To collect information on the long term outcome reported after one stage TERPT procedure for HD in children 0 - 15 years. Method: A literature review on the outcome of planned TERPT from 2005 through 2012 was carried out. Information was collected on the number of daily stools a few months postoperatively, incontinence and constipation and the measures taken to deal with these. Results: The reports are few and prospective studies were missing. The results show an initial high frequency of daily stools, 12% had later abnormal stool patterns, 21% had fecal incontinence and 10% had problems with constipation. Conclusion: In order to compare the long term outcome, it would be desirable to have uniform regular reports on the daily frequency of passed stools, incontinence and constipation during the first years after TERPT. Such knowledge would be of importance for the information given to the guardians of children with HD preoperatively to TERPT and in the planning of the future care. The findings can, furthermore, provide a benchmark for the outcome from a single centre.

Adult patients with allied disorders of Hirschsprung’s disease in emergency department:An 11-year retrospective study

BACKGROUND In the past years,only a few studies with a limited number of adult patients analyzed clinical features of allied disorders of Hirschsprung’s disease(ADHD),most of which were individual case reports or lacked detailed clinical information.Although many studies have reported patients presenting to the emergency department(ED)with recurrent abdominal symptoms for a number of disorders,there are few data involving ADHD.However,owing to a lack of awareness of the disease,misdiagnoses and mistreatments are common.Severe complications such as perforation,bleeding,malabsorption,and even death in ADHD had been reported by many studies.AIM To assist ED clinicians in having a more comprehensive understanding of this disease and making an early suspected diagnosis of ADHD more effectively.METHODS We enrolled 53 patients who visited the ED and were eventually diagnosed with ADHD over the past 11 years in our hospital.Their basic information,clinical manifestations,and imaging findings were analyzed.Blood indices were compared between the ADHD and irritable bowel syndrome(IBS)groups.RESULTS Adult patients with ADHD had a mean age of 48.8±14.3 years,and 77.4%had been treated before admission.The transverse colon was the most common dilated part(73.6%),and constipation(67.9%)was the most common symptom.ADHD patients can present with uncommon symptoms and false-negative imaging findings.Logistic regression analysis indicated that body mass index(BMI)[odds ratio(OR)=0.786,P=0.013],cholinesterase(per 1000 units;OR=0.693,P=0.008),and blood chlorine(OR=0.816,P=0.022)were determined to be independent related factors between the ADHD and IBS groups.The area under the receiver operating characteristics curve of these three indices combined was 0.812(P<0.001).CONCLUSION Emergency physicians should be vigilant regarding patients with chronic constipation,abdominal pain,or abdominal distension,and consider the possibility of ADHD despite its rarity.Abdominal computed tomography examination is recommended as a useful tool in the suspected diagnosis of ADHD.BMI,cholinesterase,and blood chlorine have good discriminative abilities between ADHD and IBS.The nutritional status of adult patients with ADHD is worthy of further attention.Surgical treatment for adult patients with ADHD is important and inevitable.

Persistent bowel dysfunction after surgery for Hirschsprung’s disease:A neuropathological perspective

Hirschsprung’s disease(HD)is a congenital disorder,characterized by aganglionosis in the distal part of the gastrointestinal tract.Despite complete surgical resection of the aganglionic segment,both constipation and fecal incontinence persist in a considerable number of patients with limited treatment options.There is growing evidence for structural abnormalities in the ganglionic bowel proximal to the aganglionosis in both humans and animals with HD,which may play a role in persistent bowel dysfunction.These abnormalities include:(1)Histopathological abnormalities of enteric neural cells;(2)Imbalanced expression of neurotransmitters and neuroproteins;(3)Abnormal expression of enteric pacemaker cells;(4)Abnormalities of smooth muscle cells;and(5)Abnormalities within the extracellular matrix.Hence,a better understanding of these previously unrecognized neuropathological abnormalities may improve follow-up and treatment in patients with HD suffering from persistent bowel dysfunction following surgical correction.In the long term,further combination of clinical and neuropathological data will hopefully enable a translational step towards more individual treatment for HD.

Transumbilical enterostomy for Hirschsprung’s disease with a two-stage laparoscopy-assisted pull-through procedure

BACKGROUND A one-stage laparoscopic operation has recently been considered a favorable option for the management of patients with Hirschsprung's disease(HD)due to its superior cosmetic results.One-stage transanal endorectal pull-through for the treatment of rectosigmoid HD has been widely used in newborns without complications.However,enterostomy is required in some HD cases for enterocolitis and dilated colon.Our transumbilical enterostomy(TUE)and twostage laparoscopy-assisted anorectoplasty were effective and achieved a similar cosmetic effect to one-stage laparoscopy on the abdominal wall in patients with anorectal malformation,but the effect in patients with HD is unclear.AIM To evaluate the safety,efficacy and cosmetic results of TUE in two-stage laparoscopy-assisted pull-through for HD.METHODS From June 2013 to June 2018,53 patients(40 boys,13 girls;mean age at enterostomy:5.5±2.2 mo)who underwent enterostomy and two-stage laparoscopy-assisted pull-through for HD with stoma closure were reviewed at our institution.Two enterostomy approaches were used:TUE in 24 patients,and conventional abdominal enterostomy(CAE)in 29 patients.Eleven patients with rectosigmoid HD had severe preoperative enterocolitis or a dilated colon.26 patients had long-segment HD,and 16 patients had total colonic aganglionosis(TCA).The patients with left-sided HD underwent the two-stage laparoscopic Soave procedure,and the patients with right-sided HD and TCA underwent the laparoscopic Duhamel procedure.Demographics,enterostomy operative time,complications and cosmetic results were respectively evaluated.RESULTS There were no differences between the groups with respect to gender,age at enterostomy,weight and clinical type(P>0.05).No conversion to open technique was required.Two patients experienced episodes of stomal mucosal prolapse in the TUE group and 1 patient in the CAE group(8.33%vs 3.45%,P>0.05).No parastomal hernia was observed in either of the two groups.Wound infection at the stoma was seen in 1 case in the TUE group,and 2 cases in the CAE group(4.17%vs 6.90%,P>0.05).No obstruction was noted in any of the patients in the TUE group,whereas obstruction was found in 1 patient in the CAE group.Enterocolitis was observed in 3 and 5 patients in the TUE and CAE group,respectively(12.50%vs 17.24%,P>0.05).There was no significant difference between the TUE group and CAE group in terms of the incidence of soiling and constipation(P>0.05).The cosmetic result using the scar score in the TUE group was better than that in the CAE group(6.83±0.96 vs 13.32±1.57,P<0.05).CONCLUSION TUE is a safe and feasible method for the treatment of HD,and the staged enterostomy and two-stage laparoscopy-assisted pull-through achieved a similar cosmetic effect to the one-stage laparoscopic procedure.

Literature Review of the Frequency of Reoperations after One Stage Transanal Endorectal Pull-Through Procedure for Hirschsprung’s Disease in Children

Background: Transanal endorectal one-stage pull-through (TERPT) procedure in children with Hirschsprung’s disease (HD) has gained worldwide acceptance. However surgical success is often reported separately, while the necessity for true reoperation is difficult to establish. Aim: To evaluate the incidence of reoperations following TERPT procedure. The findings will be important in counseling and planning childcare for HD patients as well as providing a benchmark for single centers clinical results. Methods: A literature review of reported TERPT operations on children with HD between 1998 through 2011 was performed. Only planned TERPT operation reports were included. Information was collected with particular emphasis on reoperations and their reasons. Results: Out of 26 published articles 23 were included, reporting on 836 children, female/male ratio: 1/3.3, undergoing the TERPT procedure as the only operative intervention with described postoperative courses. The children comprised neonates, 3 years of age (12%). The average follow up was 18.5 (6 - 38) months. The resected bowel length mean was 20.5 cm. Forty-one reoperations were reported (4.9%), including 24 laparotomies, 8 laparoscopies, 6 colostomies and ileostomies in 3 children. Only 2 re-do TERPT were reported (0.2%). Seven patients were considered TERPT failures (0.8%) with 5 requiring diverting colostomies and additional transabdominal pull-through operations. Two myectomies were performed (0.2%). One child with aganglionosis underwent a Duhamel pull through. Two (0.2%) had serious damage to the urinary tract also one child with a vas deferens lesion was reoperated. Two bowel obstructions required adhesiolysis. Eight anastomotic dehiscences (0.9%) required surgery after reparation. One prolapse of the pulled through colon was reported. Six patients (0.7%) suffered anastomotic leaks. Anastomotic strictures rate was 2.8%, all repaired with anal dilatation. Conclusion: The review supports the low incidence of reported reoperations for the TERPT procedure.

The role of exosomes in adult neurogenesis:implications for neurodegenerative diseases

Exosomes are cup-shaped extracellular vesicles with a lipid bilayer that is approximately 30 to 200 nm in thickness.Exosomes are widely distributed in a range of body fluids,including urine,blood,milk,and saliva.Exosomes exert biological function by transporting factors between different cells and by regulating biological pathways in recipient cells.As an important form of intercellular communication,exosomes are increasingly being investigated due to their ability to transfer bioactive molecules such as lipids,proteins,mRNAs,and microRNAs between cells,and because they can regulate physiological and pathological processes in the central nervous system.Adult neurogenesis is a multistage process by which new neurons are generated and migrate to be integrated into existing neuronal circuits.In the adult brain,neurogenesis is mainly localized in two specialized niches:the subventricular zone adjacent to the lateral ventricles and the subgranular zone of the dentate gyrus.An increasing body of evidence indicates that adult neurogenesis is tightly controlled by environmental conditions with the niches.In recent studies,exosomes released from different sources of cells were shown to play an active role in regulating neurogenesis both in vitro and in vivo,thereby participating in the progression of neurodegenerative disorders in patients and in various disease models.Here,we provide a state-of-the-art synopsis of existing research that aimed to identify the diverse components of exosome cargoes and elucidate the therapeutic potential of exosomal contents in the regulation of neurogenesis in several neurodegenerative diseases.We emphasize that exosomal cargoes could serve as a potential biomarker to monitor functional neurogenesis in adults.In addition,exosomes can also be considered as a novel therapeutic approach to treat various neurodegenerative disorders by improving endogenous neurogenesis to mitigate neuronal loss in the central nervous system.

Antisense therapy:a potential breakthrough in the treatment of neurodegenerative diseases

Neurodegenerative diseases are a group of disorders characterized by the progressive degeneration of neurons in the central or peripheral nervous system.Currently,there is no cure for neurodegenerative diseases and this means a heavy burden for patients and the health system worldwide.Therefore,it is necessary to find new therapeutic approaches,and antisense therapies offer this possibility,having the great advantage of not modifying cellular genome and potentially being safer.Many preclinical and clinical studies aim to test the safety and effectiveness of antisense therapies in the treatment of neurodegenerative diseases.The objective of this review is to summarize the recent advances in the development of these new technologies to treat the most common neurodegenerative diseases,with a focus on those antisense therapies that have already received the approval of the U.S.Food and Drug Administration.

Sorl1 knockout inhibits expression of brain-derived neurotrophic factor:involvement in the development of late-onset Alzheimer's disease

Sortilin-related receptor 1(SORL1)is a critical gene associated with late-onset Alzheimer’s disease.SORL1 contributes to the development and progression of this neurodegenerative condition by affecting the transport and metabolism of intracellularβ-amyloid precursor protein.To better understand the underlying mechanisms of SORL1 in the pathogenesis of late-onset Alzheimer s disease,in this study,we established a mouse model of SorI1 gene knockout using cluste red regularly inters paced short palindro mic repeats-associated protein 9 technology.We found that Sorl1-knocko ut mice displayed deficits in learning and memory.Furthermore,the expression of brain-derived neurotrophic factor was significantly downregulated in the hippocampus and co rtex,and amyloidβ-protein deposits were observed in the brains of 5orl1-knockout mice.In vitro,hippocampal neuronal cell synapses from homozygous Sorl1-knockout mice were impaired.The expression of synaptic proteins,including Drebrin and NR2B,was significantly reduced,and also their colocalization.Additionally,by knocking out the Sorl1 gene in N2a cells,we found that expression of the N-methyl-D-aspartate receptor,NR2B,and cyclic adenosine monophosphate-response element binding protein was also inhibited.These findings suggest that SORL1 participates in the pathogenesis of late-onset Alzheimer s disease by regulating the N-methyl-D-aspartate receptor NR2B/cyclic adenosine monophosphate-response element binding protein signaling axis.

NADPH oxidase 4(NOX4)as a biomarker and therapeutic target in neurodegenerative diseases

Diseases like Alzheimer’s and Parkinson’s diseases are defined by inflammation and the damage neurons undergo due to oxidative stress. A primary reactive oxygen species contributor in the central nervous system, NADPH oxidase 4, is viewed as a potential therapeutic touchstone and indicative marker for these ailments. This in-depth review brings to light distinct features of NADPH oxidase 4, responsible for generating superoxide and hydrogen peroxide, emphasizing its pivotal role in activating glial cells, inciting inflammation, and disturbing neuronal functions. Significantly, malfunctioning astrocytes, forming the majority in the central nervous system, play a part in advancing neurodegenerative diseases, due to their reactive oxygen species and inflammatory factor secretion. Our study reveals that aiming at NADPH oxidase 4 within astrocytes could be a viable treatment pathway to reduce oxidative damage and halt neurodegenerative processes. Adjusting NADPH oxidase 4 activity might influence the neuroinflammatory cytokine levels, including myeloperoxidase and osteopontin, offering better prospects for conditions like Alzheimer’s disease and Parkinson’s disease. This review sheds light on the role of NADPH oxidase 4 in neural degeneration, emphasizing its drug target potential, and paving the path for novel treatment approaches to combat these severe conditions.

Mitophagy in neurodegenerative disease pathogenesis

Mitochondria are critical cellular energy resources and are central to the life of the neuron.Mitophagy selectively clears damaged or dysfunctional mitochondria through autophagic machinery to maintain mitochondrial quality control and homeostasis.Mature neurons are postmitotic and consume substantial energy,thus require highly efficient mitophagy pathways to turn over damaged or dysfunctional mitochondria.Recent evidence indicates that mitophagy is pivotal to the pathogenesis of neurological diseases.However,more work is needed to study mitophagy pathway components as potential therapeutic targets.In this review,we briefly discuss the characteristics of nonselective autophagy and selective autophagy,including ERphagy,aggrephagy,and mitophagy.We then introduce the mechanisms of Parkin-dependent and Parkin-independent mitophagy pathways under physiological conditions.Next,we summarize the diverse repertoire of mitochondrial membrane receptors and phospholipids that mediate mitophagy.Importantly,we review the critical role of mitophagy in the pathogenesis of neurodegenerative diseases including Alzheimer’s disease,Parkinson’s disease,and amyotrophic lateral sclerosis.Last,we discuss recent studies considering mitophagy as a potential therapeutic target for treating neurodegenerative diseases.Together,our review may provide novel views to better understand the roles of mitophagy in neurodegenerative disease pathogenesis.

Nanomaterials-mediated lysosomal regulation:a robust protein-clearance approach for the treatment of Alzheimer’s disease

Alzheimer’s disease is a debilitating,progressive neurodegenerative disorder characterized by the progressive accumulation of abnormal proteins,including amyloid plaques and intracellular tau tangles,primarily within the brain.Lysosomes,crucial intracellular organelles responsible for protein degradation,play a key role in maintaining cellular homeostasis.Some studies have suggested a link between the dysregulation of the lysosomal system and pathogenesis of neurodegenerative diseases,including Alzheimer’s disease.Restoring the normal physiological function of lysosomes hold the potential to reduce the pathological burden and improve the symptoms of Alzheimer’s disease.Currently,the efficacy of drugs in treating Alzheimer’s disease is limited,with major challenges in drug delivery efficiency and targeting.Recently,nanomaterials have gained widespread use in Alzheimer’s disease drug research owing to their favorable physical and chemical properties.This review aims to provide a comprehensive overview of recent advances in using nanomaterials(polymeric nanomaterials,nanoemulsions,and carbon-based nanomaterials)to enhance lysosomal function in treating Alzheimer’s disease.This review also explores new concepts and potential therapeutic strategies for Alzheimer’s disease through the integration of nanomaterials and modulation of lysosomal function.In conclusion,this review emphasizes the potential of nanomaterials in modulating lysosomal function to improve the pathological features of Alzheimer’s disease.The application of nanotechnology to the development of Alzheimer’s disease drugs brings new ideas and approaches for future treatment of this disease.

Interaction between diet and genetics in patients with inflammatory bowel disease

In this editorial,we comment on the article by Marangoni et al,published in the recent issue of the World Journal of Gastroenterology 2023;29:5618-5629,about“Diet as an epigenetic factor in inflammatory bowel disease”.The authors emphasized the role of diet,especially the interaction with genetics,in promoting the inflam-matory process in inflammatory bowel disease(IBD)patients,focusing on DNA methylation,histone modifications,and the influence of microRNAs.In this editorial,we explore the interaction between genetics,gut microbiota,and diet,in an only way.Furthermore,we provided dietary recommendations for patients with IBD.The Western diet,characterized by a low fiber content and deficiency the micronutrients,impacts short-chain fatty acids production and may be related to the pathogenesis of IBD.On the other hand,the consumption of the Mediter-ranean diet and dietary fibers are associated with reduced risk of IBD flares,particularly in Crohn’s disease(CD)patients.According to the dietary guidance from the International Organization for the Study of Inflammatory Bowel Diseases(IOIBD),the regular consumption of fruits and vegetables while reducing the consumption of saturated,trans,dairy fat,additives,processed foods rich in maltodextrins,and artificial sweeteners containing sucralose or saccharine is recommended to CD patients.For patients with ulcerative colitis,the IOIBD recommends the increased intake of natural sources of omega-3 fatty acids and follows the same restrictive recommendations aimed at CD patients,with the possible inclusion of red meats.In conclusion,IBD is a complex and hetero-geneous disease,and future studies are needed to elucidate the influence of epigenetics on diet and microbiota in IBD patients.

MicroRNAs in inflammatory bowel disease:What do we know and what can we expect?

MicroRNAs(miRNAs),small non-coding RNAs composed of 18–24 nucleotides,are potent regulators of gene expression,contributing to the regulation of more than 30%of protein-coding genes.Considering that miRNAs are regulators of inflammatory pathways and the differentiation of intestinal epithelial cells,there is an interest in exploring their importance in inflammatory bowel disease(IBD).IBD is a chronic and multifactorial disease of the gastrointestinal tract;the main forms are Crohn's disease and ulcerative colitis.Several studies have investigated the dysregulated expression of miRNAs in IBD,demonstrating their important roles as regulators and potential biomarkers of this disease.This editorial presents what is known and what is expected regarding miRNAs in IBD.Although the important regulatory roles of miRNAs in IBD are clearly established,biomarkers for IBD that can be applied in clinical practice are lacking,emphasizing the importance of further studies.Discoveries regarding the influence of miRNAs on the inflammatory process and the exploration of their role in gene regulation are expected to provide a basis for the use of miRNAs not only as potent biomarkers in IBD but also as therapeutic targets for the control of inflammatory processes in personalized medicine.

Recent trends in the epidemiology and clinical outcomes of inflammatory bowel disease in South Korea,2010-2018

BACKGROUND Inflammatory bowel disease(IBD)was previously regarded as a Western disease;however,its incidence is increasing in the East.The epidemiology of IBD in Asia differs significantly from the patterns in the West.AIM To comprehensively investigate the epidemiology of IBD in South Korea,inclu-ding its incidence,prevalence,medication trends,and outcomes.METHODS We analyzed claims data from the Health Insurance Review and Assessment Service and Rare and Intractable Diseases(RIDs),operated by the National Health Insurance Service of South Korea.Patients with IBD were identified based on the International Classification of Diseases,Tenth Revision,and RID diagnostic codes for Crohn’s disease(CD)and ulcerative colitis(UC)from 2010 to 2018.RESULTS In total,14498 and 31409 patients were newly diagnosed with CD and UC,respectively,between 2010 and 2018.The annual average incidence of CD was 3.11 cases per 105 person-years,and that of UC was 6.74 cases per 10^(5) person-years.Since 2014,the incidence rate of CD has been stable,while that of UC has steadily increased,shifting the peak age group from 50-year-olds in 2010 to 20-year-olds in 2018.The CD and UC prevalence increased consistently over the study period;the use of 5-aminosali-cylates and corticosteroids gradually decreased,while that of immunomodulators and biologics steadily increased in both CD and UC.The clinical outcomes of IBD,such as hospitalization and surgery,decreased during the study period.CONCLUSION The CD incidence has been stable since 2014,but that of UC has increased with a shift to a younger age at peak incidence between 2010 and 2018.IBD clinical outcomes improved over time,with increased use of immunomodu-lators and biologics.

Crohn’s disease as the intestinal manifestation of pan-lymphatic dysfunction:An exploratory proposal based on basic and clinical data

Crohn’s disease(CD)is caused by immune,environmental,and genetic factors.It can involve the entire gastrointestinal tract,and although its prevalence is rapidly increasing its etiology remains unclear.Emerging biological and small-molecule drugs have advanced the treatment of CD;however,a considerable proportion of patients are non-responsive to all known drugs.To achieve a breakthrough in this field,innovations that could guide the further development of effective therapies are of utmost urgency.In this review,we first propose the innovative concept of pan-lymphatic dysfunction for the general distribution of lymphatic dysfunction in various diseases,and suggest that CD is the intestinal manifestation of pan-lymphatic dysfunction based on basic and clinical preliminary data.The supporting evidence is fully summarized,including the existence of lymphatic system dysfunction,recognition of the inside-out model,disorders of immune cells,changes in cell plasticity,partial overlap of the underlying mechanisms,and common gut-derived fatty and bile acid metabolism.Another benefit of this novel concept is that it proposes adopting the zebrafish model for studying intestinal diseases,especially CD,as this model is good at presenting and mimicking lymphatic dysfunction.More importantly,the ensuing focus on improving lymphatic function may lead to novel and promising therapeutic strategies for CD.

Circadian rhythm disruption and retinal dysfunction:a bidirectional link in Alzheimer’s disease?

Dysfunction in circadian rhythms is a common occurrence in patients with Alzheimer’s disease.A predominant function of the retina is circadian synchronization,carrying information to the brain through the retinohypothalamic tract,which projects to the suprachiasmatic nucleus.Notably,Alzheimer’s disease hallmarks,including amyloid-β,are present in the retinas of Alzheimer’s disease patients,followed/associated by structural and functional disturbances.However,the mechanistic link between circadian dysfunction and the pathological changes affecting the retina in Alzheimer’s disease is not fully understood,although some studies point to the possibility that retinal dysfunction could be considered an early pathological process that directly modulates the circadian rhythm.

The autophagy protein Atg9 functions in glia and contributes to parkinsonian symptoms in a Drosophila model of Parkinson’s disease

Parkinson’s disease is a progressive neurodegenerative disease characterized by motor deficits,dopaminergic neuron loss,and brain accumulation ofα-synuclein aggregates called Lewy bodies.Dysfunction in protein degradation pathways,such as autophagy,has been demonstrated in neurons as a critical mechanism for eliminating protein aggregates in Parkinson’s disease.However,it is less well understood how protein aggregates are eliminated in glia,the other cell type in the brain.In the present study,we show that autophagy-related gene 9(Atg9),the only transmembrane protein in the autophagy machinery,is highly expressed in Drosophila glia from adult brain.Results from immunostaining and live cell imaging analysis reveal that a portion of Atg9 localizes to the trans-Golgi network,autophagosomes,and lysosomes in glia.Atg9 is persistently in contact with these organelles.Lacking glial atg9 reduces the number of omegasomes and autophagosomes,and impairs autophagic substrate degradation.This suggests that glial Atg9 participates in the early steps of autophagy,and hence the control of autophagic degradation.Importantly,loss of glial atg9 induces parkinsonian symptoms in Drosophila including progressive loss of dopaminergic neurons,locomotion deficits,and glial activation.Our findings identify a functional role of Atg9 in glial autophagy and establish a potential link between glial autophagy and Parkinson’s disease.These results may provide new insights on the underlying mechanism of Parkinson’s disease.

Therapeutic advances in neural regeneration for Huntington’s disease

Huntington’s disease is a neurodegenerative disease caused by the expansion mutation of a cytosine-adenine-guanine triplet in the exon 1 of the HTT gene which is responsible for the production of the huntingtin (Htt) protein. In physiological conditions, Htt is involved in many cellular processes such as cell signaling, transcriptional regulation, energy metabolism regulation, DNA maintenance, axonal trafficking, and antiapoptotic activity. When the genetic alteration is present, the production of a mutant version of Htt (mHtt) occurs, which is characterized by a plethora of pathogenic activities that, finally, lead to cell death. Among all the cells in which mHtt exerts its dangerous activity, the GABAergic Medium Spiny Neurons seem to be the most affected by the mHtt-induced excitotoxicity both in the cortex and in the striatum. However, as the neurodegeneration proceeds ahead the neuronal loss grows also in other brain areas such as the cerebellum, hypothalamus, thalamus, subthalamic nucleus, globus pallidus, and substantia nigra, determining the variety of symptoms that characterize Huntington’s disease. From a clinical point of view, Huntington’s disease is characterized by a wide spectrum of symptoms spanning from motor impairment to cognitive disorders and dementia. Huntington’s disease shows a prevalence of around 3.92 cases every 100,000 worldwide and an incidence of 0.48 new cases every 100,000/year. To date, there is no available cure for Huntington’s disease. Several treatments have been developed so far, aiming to reduce the severity of one or more symptoms to slow down the inexorable decline caused by the disease. In this context, the search for reliable strategies to target the different aspects of Huntington’s disease become of the utmost interest. In recent years, a variety of studies demonstrated the detrimental role of neuronal loss in Huntington’s disease condition highlighting how the replacement of lost cells would be a reasonable strategy to overcome the neurodegeneration. In this view, numerous have been the attempts in several preclinical models of Huntington’s disease to evaluate the feasibility of invasive and non-invasive approaches. Thus, the aim of this review is to offer an overview of the most appealing approaches spanning from stem cell-based cell therapy to extracellular vesicles such as exosomes in light of promoting neurogenesis, discussing the results obtained so far, their limits and the future perspectives regarding the neural regeneration in the context of Huntington’s disease.

Cath-KP,a novel peptide derived from frog skin,prevents oxidative stress damage in a Parkinson’s disease model

Parkinson’s disease(PD)is a neurodegenerative condition that results in dyskinesia,with oxidative stress playing a pivotal role in its progression.Antioxidant peptides may thus present therapeutic potential for PD.In this study,a novel cathelicidin peptide(Cath-KP;GCSGRFCNLF NNRRPGRLTLIHRPGGDKRTSTGLIYV)was identified from the skin of the Asiatic painted frog(Kaloula pulchra).Structural analysis using circular dichroism and homology modeling revealed a uniqueαββconformation for Cath-KP.In vitro experiments,including free radical scavenging and ferric-reducing antioxidant analyses,confirmed its antioxidant properties.Using the 1-methyl-4-phenylpyridinium ion(MPP^(+))-induced dopamine cell line and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced PD mice,Cath-KP was found to penetrate cells and reach deep brain tissues,resulting in improved MPP^(+)-induced cell viability and reduced oxidative stress-induced damage by promoting antioxidant enzyme expression and alleviating mitochondrial and intracellular reactive oxygen species accumulation through Sirtuin-1(Sirt1)/Nuclear factor erythroid 2-related factor 2(Nrf2)pathway activation.Both focal adhesion kinase(FAK)and p38 were also identified as regulatory elements.In the MPTP-induced PD mice,Cath-KP administration increased the number of tyrosine hydroxylase(TH)-positive neurons,restored TH content,and ameliorated dyskinesia.To the best of our knowledge,this study is the first to report on a cathelicidin peptide demonstrating potent antioxidant and neuroprotective properties in a PD model by targeting oxidative stress.These findings expand the known functions of cathelicidins,and hold promise for the development of therapeutic agents for PD.