Rethinking de novo immune hepatitis,an old concept for liver allograft rejection:relevance of glutathione S-transferase T1 mismatch

Antibody-mediated rejection(AMR) in liver transplantation has long been underestimated. The concept of the liver as an organ susceptible to AMR has emerged in recent years, not only in the context of the major histocompatibility complex with the presence of HLA donor-specific antibodies, but also with antigens regarded as "minor", whose role in AMR has been demonstrated. Among them, antibodies against glutathione S-transferase T1 have been found in 100% of patients with de novo autoimmune hepatitis(dn AIH) when studied. In its latest update, the Banff Working Group for liver allograft pathology proposed replacing the term dn AIH with plasma cell(PC)-rich rejection. Antibodies to glutathione S-transferase T1(GSTT1) in null recipients of GSTT1 positive donors have been included as a contributory but nonessential feature of the diagnosis of PC-rich rejection. Also in this update, non-organ-specific anti-nuclear or smooth muscle autoantibodies are no longer included as diagnostic criteria. Although initially found in a proportion of patients with PC-rich rejection, the presence of autoantibodies is misleading since they are not diseasespecific and appear in many different contexts as bystanders. The cellular types and proportions of the inflammatory infiltrates in diagnostic biopsies have been studied in detail very recently. PC-rich rejection biopsies present a characteristic cellular profile with a predominance of T lymphocytes and a high proportion of PCs, close to 30%, of which 16.48% are Ig G4+. New data on the relevance of GSTT1-specific T lymphocytes to PC-rich rejection will be discussed in this review.

Evidences of hydroxytyrosol as an anti-inflammatory agent in Parkinson’s disease:insights into the mechanisms of action

Neuroinflammation in neurodegenerative diseases:Inflammatory processes play a critical role in neurodegenerative diseases,such as Parkinson’s disease(PD).Thus,neuroinflammation is involved in the progression and development of these diseases,becoming an important pathological hallmark.Microglial cells,the“macrophages”from central nervous system,are the initiating cells of the innate immune response against different stimuli in the brain.

Presynaptic endoplasmic reticulum architecture and hereditary spastic paraplegia

Hereditary spastic paraplegia(HSP)is a clinically and genetically heterogeneous neurodegenerative disorder,characterized primarily by progressive spasticity and weakness in the lower limbs.Pat ients can also experience peripheral neuropathy,cognitive impairment,and other neurological symptoms.To date,more than 80 genes have been implicated in HSP,encompassing various cellular components,although mutations in genes encoding endoplasmic reticulum(ER)-shaping proteins are the most prevalent(Parodi et al.,2017).ER-shaping proteins are generally known for regulating the tubulation and curvation of the ER,but most of them show additional functions,including fusion of ER tubules,microtubule-severing,ER autophagy,lipid droplet synthesis,contact sites with other organelles(Öztürk et al.,2020).This highlights the complexity of studying the role of these proteins and the link between ER function and HSP.

A new treatment for sarcoma extracted from combination of miRNA deregulation and gene association rules

Dear Editor Sarcomas are a group of heterogeneous mesodermic rare tumors with high incidence in children,reaching up to 20%of neoplasms.Standard treatment for sarcomas is surgical resection,and only some patients are treated with chemotherapy and/or radiation therapy.The 5-year relative survival rate for patients with metastatic sarcoma is only 15%.

Inflammasome activation under high cholesterol load triggers a protective microglial phenotype while promoting neuronal pyroptosis

Background Persistent inflammatory response in the brain can lead to tissue damage and neurodegeneration.In Alzheimer’s disease(AD),there is an aberrant activation of inflammasomes,molecular platforms that drive inflammation through caspase-1-mediated proteolytic cleavage of proinflammatory cytokines and gasdermin D(GSDMD),the executor of pyroptosis.However,the mechanisms underlying the sustained activation of inflammasomes in AD are largely unknown.We have previously shown that high brain cholesterol levels promote amyloid-β(Aβ)accumulation and oxidative stress.Here,we investigate whether these cholesterol-mediated changes may regulate the inflam-masome pathway.Methods SIM-A9 microglia and SH-SY5Y neuroblastoma cells were cholesterol-enriched using a water-soluble cholesterol complex.After exposure to lipopolysaccharide(LPS)plus muramyl dipeptide or Aβ,activation of the inflammasome pathway was analyzed by immunofluorescence,ELISA and immunoblotting analysis.Fluorescently-labeled Aβwas employed to monitor changes in microglia phagocytosis.Conditioned medium was used to study how microglia-neuron interrelationship modulates the inflammasome-mediated response.Results In activated microglia,cholesterol enrichment promoted the release of encapsulated IL-1βaccompanied by a switch to a more neuroprotective phenotype,with increased phagocytic capacity and release of neurotrophic factors.In contrast,in SH-SY5Y cells,high cholesterol levels stimulated inflammasome assembly triggered by both bacterial toxins and Aβpeptides,resulting in GSDMD-mediated pyroptosis.Glutathione(GSH)ethyl ester treatment,which recovered the cholesterol-mediated depletion of mitochondrial GSH levels,significantly reduced the Aβ-induced oxidative stress in the neuronal cells,resulting in lower inflammasome activation and cell death.Furthermore,using conditioned media,we showed that neuronal pyroptosis affects the function of the cholesterol-enriched microglia,lowering its phagocytic activity and,therefore,the ability to degrade extracellular Aβ.Conclusions Changes in intracellular cholesterol levels differentially regulate the inflammasome-mediated immune response in microglia and neuronal cells.Given the microglia-neuron cross-talk in the brain,cholesterol modulation should be considered a potential therapeutic target for AD treatment,which may help to block the aberrant and chronic inflammation observed during the disease progression.

Wilson's disease:Revisiting an old friend

Wilson's disease(WD)is a rare condition caused by copper accumulation primarily in the liver and secondly in other organs,such as the central nervous system.It is a hereditary autosomal recessive disease caused by a deficiency in the ATP7B transporter.This protein facilitates the incorporation of copper into ceruloplasmin.More than 800 mutations associated with WD have been described.The onset of the disease frequently includes manifestations related to the liver(as chronic liver disease or acute liver failure)and neurological symptoms,although it can sometimes be asymptomatic.Despite it being more frequent in young people,WD has been described in all life stages.Due to its fatal prognosis,WD should be suspected in all patients with unexplained biochemical liver abnormalities or neurological or psychiatric symptoms.The diagnosis is established with a combination of clinical signs and tests,including the measurement of ceruloplasmin,urinary copper excretion,copper quantification in liver biopsy,or genetic assessment.The pharmacological therapies include chelating drugs,such as D-penicillamine or trientine,and zinc salts,which are able to change the natural history of the disease,increasing the survival of these patients.In some cases of end-stage liver disease or acute liver failure,liver transplantation must be an option to increase survival.In this narrative review,we offer an overview of WD,focusing on the importance of clinical suspicion,the correct diagnosis,and treatment.

Outlook on the neuroprotective effect of estrogen

Epidemiologic studies often consider gender differences in a particular pathology, and constantly observe variations between men and wom- en. Indeed, a remarkable sexual dimorphism exists in the epidemiology of neurological conditions and brain diseases. Physiologically, males and females differ by their levels of circulating hormones that drive sexual behavioral, as well as endocrine functions. Estrogen is the pri- mary female sex hormonal group that enwraps estradiol, estrone and estriol, and which are the major naturally occurring hormones preva- lent in women. Their role in the reproductive function has long been established, although the ubiquitous expression of its receptors （alpha, beta and G protein-coupled, GPR30） presumes a broader spectrum of action. This short review will summarize the current knowledge in estrogen therapy with particular focus on some of the recent work that might lead to new neuroprotective treatments.

Magnetofection as a new tool to study microglia biology

Microglia are the resident macrophages of the brain,originally described by Pio del Rio-Hortega(a student of Santiago Ramon y Cajal)in a series of studies in 1919.Since those pioneering studies,many others have followed to describe microglia as complex and multitasking cells with many diverse roles under physiological(e.g.their key role in synapse pruning during development)or diseased conditions.Microglia exist as sentinels or surveyors of the environment that surround neurons,becoming reactive upon a wide array of stimuli and consequently developing an appropriate inflammatory response.In fact,a neuroinflammatory response driven by microglia is found in virtually every disease process that occurs within the central nervous system.Therefore,a better understanding of the mechanisms governing the microglia response is the key to improving the outcome of neurodegenerative conditions.

TET2, an “ambiguous” player in inflammation

Microglial cells,the“macrophages”from the central nervous system(CNS),perform a variety of roles necessary to keep the homeostasis in the healthy brain.However,microglial cells are best known for their role as“first responders”through initiation of an innate immune response against a wide variety of deleterious stimuli in the brain.This controlled inflammatory response is beneficial and disappears once the deleterious stimuli are gone.

β-淀粉样蛋白损害星形胶质细胞在阿尔茨海默病中对营养不良突触的吞噬作用

摘要在阿尔茨海默病(AD)中,在β-淀粉样蛋白斑块周围发现了反应性星形胶质细胞和营养不良的神经突(异常的突触前元件)。笔者的前期研究已经表明,反应性星形胶质细胞会包裹、吞噬和降解APP小鼠以及AD患者海马中营养不良的突触,但仅波及不到7%的营养不良神经突,这表明星形胶质细胞在AD中的吞噬能力降低。本研究旨在通过分析原代星形胶质细胞培养物对分离突触(突触神经小体,SNs)吞噬和降解的能力来深入了解其潜在机制。SNs分别来自APP(包含营养不良性突触和β淀粉样肽)小鼠、Tau(包含AT8-和AT100-阳性磷酸化Tau)小鼠以及WT(对照)小鼠。我们发现与SNs-WT相比,星形胶质细胞的吞噬和降解能力在SNs-APP大大降低,但在AT8/AT100阳性的SNs-Tau却没有。在12月大的APP小鼠的海马中证实了星形胶质细胞吞噬能力的降低,因为只有(1.60±3.81)%的斑块状星形胶质细胞具有吞噬结构。

The Iberian Roma Population Variant Server(IRPVS)

In recent years,the number of known disease genes has exponentially grown due to the widespread adoption of cost-effective massive parallel sequencing.To identify new disease variants,especially in monogenic disorders,a frequency-based filtering approach has proved very useful(Dopazo et al.,2016).

Phase Ⅱ trial of CDK4/6 inhibitor palbociclib in advanced sarcoma based on mRNA expression of CDK4/CDKN2A

Cyclin-dependent kinases 4 and 6(CDK4/6)inhibitors demonstrated activity in terms of progression-free survival(PFS)in advanced dedifferentiated liposarcoma(DD-LPS),a sarcoma with CDK4 amplification.CDK4 overexpression is by far more common than amplification in sarcomas and it might be a rational target for CDK inhibitors.Preclinical investigators of this study found that CDK4 overexpression,while not of CDKN2A,was the most consistent predictive factor for palbociclib efficacy in sarcomas.Advanced adult-type soft-tissue sarcoma,excluding DD-LPS,or bone sarcoma patients,progressing after at least one systemic line,whose tumors overexpressed CDK4,but not CDKN2A at baseline biopsy,were accrued in this single-arm phase II trial(EudraCT number:2016-004039-19).With the main endpoint of a 6-month PFS rate,40%was considered promising in this population.Palbociclib was administered orally at 125 mg/day for 21 days in 28-day cycles.A total of 214 patients with 236 CDK4/CDKN2A determinations were assessed for prescreening,archival material(141),and screening,baseline biopsy(95).There were 28(29%)with favorable mRNA profiles from 95 screened patients at baseline.From 23 enrolled patients,21 evaluable,the 6-month PFS rate was 29%(95%CI 9–48),and there were 6 patients out of 21 with a PFS longer than 6 months.The median PFS and overall survival were 4.2(95%CI 3.6–4.8)and 12(95%CI 8.7–15.4)months,respectively.Translational research showed a significant correlation between CDK4 mRNA and protein expression.Palbociclib was active in a variety of sarcoma subtypes,selected by CDK4/CDKN2A,and deserves further investigation in the sarcoma context.

NAD+ metabolism, sternness, the immune response, and cancer

NAD+was discovered during yeast fermentation,and since its discovery,its important roles in redox metabolism,aging,and longevity,the immune system and DNA repair have been highlighted.A deregulation of the NAD+levels has been associated with metabolic diseases and aging-related diseases,including neurodegeneration,defective immune responses,and cancer.NAD+acts as a cofactor through its interplay with NADH,playing an essential role in many enzymatic reactions of energy metabolism,such as glycolysis,oxidative phosphorylation,fatty acid oxidation,and the TCA cycle.NAD+also plays a role in deacetylation by sirtuins and ADP ribosylation during DNA damage/repair by PARP proteins.Finally,different NAD hydrolase proteins also consume NAD+while converting it into ADP-ribose or its cyclic counterpart.Some of these proteins,such as CD38,seem to be extensively involved in the immune response.Since NAD cannot be taken directly from food,NAD metabolism is essential,and NAMPT is the key enzyme recovering NAD from nicotinamide and generating most of the NAD cellular pools.Because of the complex network of pathways in which NAD+is essential,the important role of NAD+and its key ge nerating enzyme,NAMPT,in cancer is understandable.In the present work,we review the role of NAD+and NAMPT in the ways that they may influence cancer metabolism,the immune system,stemness,aging,and cancer.Finally,we review some ongoing research on therapeutic approaches.

Sarcoma stratification by combined pH2AX and MAP17(PDZK1IP1)levels for a better outcome on doxorubicin plus olaparib treatment

Sarcomas constitute a rare heterogeneous group of tumors,including a wide variety of histological subtypes.Despite advances in our understanding of the pathophysiology of the disease,first-line sarcoma treatment options are still limited and new treatment approaches are needed.Histone H2AX phosphorylation is a sensitive marker for double strand breaks and has recently emerged as biomarker of DNA damage for new drug development.In this study,we explored the role of H2AX phosphorylation at Ser139 alone or in combination with MAP17 protein,an inducer of DNA damage through ROS increase,as prognostic biomarkers in sarcoma tumors.Next,we proposed doxorubicin and olaparib combination as potential therapeutic strategies against sarcomas displaying high level of both markers.We evaluate retrospectively the levels of pH2AX(Ser139)and MAP17 in a cohort of 69 patients with different sarcoma types and its relationship with clinical and pathological features.We found that the levels of pH2AX and MAP17 were related to clinical features and poor survival.Next,we pursued PARP1 inhibition with olaparib to potentiate the antitumor effect of DNA damaging effect of the DNA damaging agent doxorubicin to achieve an optimal synergy in sarcoma.We demonstrated that the combination of olaparib and doxorubicin was synergistic in vitro,inhibiting cell proliferation and enhancing pH2AX intranuclear accumulation,as a result of DNA damage.The synergism was corroborated in patient-derived xenografts(PDX)where the combination was effective in tumors with high levels of pH2AX and MAP17,suggesting that both biomarkers might potentially identify patients who better benefit from this combined therapy.

Internal anal sphincter augmentation and substitution

There is an increasing recognition of the importance of internal anal sphincter(IAS)dysfunction presenting as passive faecal incontinence.This problem may manifest after anal sphincterotomy or following the more minimally invasive operations for haemorrhoids,as well as with advancing age.Because of the poor results of IAS plication and the beneficial outcomes with peri-urethral bulking agents in urology,these materials have been developed for use in IAS dysfunction.This review outlines the basic purported mechanisms of action,defining the materials in clinical use,their methods of deployment,complications and reported outcomes.There is still much that is unknown concerning the ideal agent or the volume and the technique of deployment,which will only be answered by powerful,prospective,randomized,controlled trials.The specific role of autologous stem cells designed to regenerate the sphincters in cases of functional impairment or muscle loss is yet to be seen.