Back to The Fusion: Mitofusin-2 in Alzheimer's Disease

Mitochondria are dynamic organelles that undergo constant fission and fusion. Mitochondria dysfunction underlies several human disorders, including Alzheimer's disease (AD). Preservation of mitochondrial dynamics is fundamental for regulating the organelle's functions. Several proteins participate in the regulation of mitochondrial morphology and networks, and among these, Mitofusin 2 (Mfn2) has been extensively studied. This review focuses on the role of Mfn2 in mitochondrial dynamics and in the crosstalk between mitochondria and the endoplasmic reticulum, in particular in AD. Understanding how this protein may be related to AD pathogenesis will provide essential information for the development of therapies for diseases linked to disturbed mitochondrial dynamics, as in AD

Isothiocyanates Are Promising Compounds against Oxidative Stress, Neuroinflammation and Cell Death that May Benefit Neurodegeneration in Parkinson's Disease

Parkinson's disease (PD) is recognized as the second most common neurodegenerative disorder and is characterized by a slow and progressive degeneration of dopaminergic neurons in the substantia nigra. Despite intensive research, the mechanisms involved in neuronal loss are not completely understood yet; however, misfolded proteins, oxidative stress, excitotoxicity and inflammation play a pivotal role in the progression of the pathology. Neuroinflammation may have a greater function in PD pathogenesis than initially believed, taking part in the cascade of events that leads to neuronal death. To date, no efficient therapy, able to arrest or slow down PD, is available. In this context, the need to find novel strategies to counteract neurodegenerative progression by influencing diseases' pathogenesis is becoming increasingly clear. Isothiocyanates (ITCs) have already shown interesting properties in detoxification, inflammation, apoptosis and cell cycle regulation through the induction of phase I and phase II enzyme systems. Moreover, ITCs may be able to modulate several key points in oxidative and inflammatory evolution. In view of these considerations, the aim of the present review is to describe ITCs as pleiotropic compounds capable of preventing and modulating the evolution of PD

A pro longevity role for cellular senescence

Cellular senescence is a fundamental process that may play positive or detrimental roles for the organism. It is involved in tissue development and in tumor prevention although during aging is becoming a detrimental process contributing to the decline of tissue functions. In previous investigations, we have uncovered a better capacity to detect DNA damage in cells from long-lived mammals. Here, we report that cultured cells derived from long-lived species have a higher propensity to undergo senescence when challenged with DNA damage than cells derived from short-lived species. Using a panel of cells derived from six mammals, which range in lifespan from 3-4 years up to 120 years, we examined cell cycle response, induction of apoptosis and of cellular senescence. All species exhibited a cell cycle arrest while induction of apoptosis was variable. However, a significant positive correlation was found between the relative percent of cells, within a population which entered senescence following damage, and the lifespan of the species. We suggest that cellular senescence may have a positive role during development allowing it to contribute to the evolution of longevity

Comparison of Adaptive Neuroprotective Mechanisms of Sulforaphane and its Interconversion Product Erucin in in Vitro and in Vivo Models of Parkinson's Disease

Several studies suggest that an increase of glutathione (GSH) through activation of the transcriptional nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in the dopaminergic neurons may be a promising neuroprotective strategy in Parkinson's disease (PD). Among Nrf2 activators, isothiocyanate sulforaphane (SFN), derived from precursor glucosinolate present in Brassica vegetables, has gained attention as a potential neuroprotective compound. Bioavailability studies also suggest the contribution of SFN metabolites, including erucin (ERN), to the neuroprotective effects of SFN. Therefore, we compared the in vitro neuroprotective effects of SFN and ERN at the same dose level (5 \u3bcM) and oxidative treatment with 6-hydroxydopamine (6-OHDA) in SH-SY5Y cells. The pretreatment of SH-SY5Y cells with SFN recorded a higher (p < 0.05) active nuclear Nrf2 protein (12.0 \ub1 0.4 vs 8.0 \ub1 0.2 fold increase), mRNA Nrf2 (2.0 \ub1 0.3 vs 1.4 \ub1 0.1 fold increase), total GSH (384.0 \ub1 9.0 vs 256.0 \ub1 8.0 \u3bcM) levels, and resistance to neuronal apoptosis elicited by 6-OHDA compared to ERN. By contrast, the simultaneous treatment of SH-SY5Y cells with either SFN or ERN and 6-OHDA recorded similar neuroprotective effects with both the isothiocyanates (Nrf2 protein 2.2 \ub1 0.2 vs 2.1 \ub1 0.1 and mRNA Nrf2 2.1 \ub1 0.3 vs 1.9 \ub1 0.2 fold increase; total GSH 384.0 \ub1 4.8 vs 352.0 \ub1 6.4 \u3bcM). Finally, in vitro finding was confirmed in a 6-OHDA-PD mouse model. The metabolic oxidation of ERN to SFN could account for their similar neuroprotective effects in vivo, raising the possibility of using vegetables containing a precursor of ERN for systemic antioxidant benefits in a similar manner to SFN

Personalized Medicine in Gastrointestinal Stromal Tumor (GIST): Clinical Implications of the Somatic and Germline DNA Analysis

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. They are characterized by gain of function mutations in KIT or PDGFRA tyrosine kinase receptors, with their consequent constitutive activation. The gold standard therapy is imatinib that offers a good and stable response for approximately 18-36 months. However, resistance is very common and it is vital to identify new biomarkers. Up until now, there have been two main approaches with focus to characterize novel targets. On the one hand, the focus is on the tumor genome, as the final clinical outcome depends mainly from the cancer specific mutations/alterations patterns. However, the germline DNA is important as well, and it is inconceivable to think the patients response to the drug is not related to it. Therefore the aim of this review is to outline the state of the art of the personalized medicine in GIST taking into account both the tumor DNA (somatic) and the patient DNA (germline)

DNA Repair Gene Polymorphisms and Sensitivity to Ionising Radiation

Cilj ovog istraživanja bio je procijeniti razinu oštećenja DNA u leukocitima periferne krvi prije, neposredno nakon i 120 min nakon ozračivanja dozom zračenja od 2 Gy te usporediti razine nastalih oštećenja između kontrolne skupine i skupine medicinskih radnika izloženih niskim dozama ionizirajućeg zračenja na svojim radnim mjestima. Istražen je utjecaj polimorfi zma u genima koji sudjeluju u popravku DNA; *hOGG1, XRCC1 i MGMT na razinu izmjerenih oštećenja. Istraživanjem je obuhvaćeno 40 zdravih ispitanika obaju spolova (20 kontrola i 20 izloženih). Razina oštećenja DNA mjerena je komet-testom u alkalnim uvjetima, pri čemu su za svakog ispitanika i svaku vremensku točku analizirane vrijednosti dužine repa, % DNA u repu i repnog momenta kometa. Rezultati pokazuju da su vrijednosti % DNA u repu i repni moment kometa bili statistički značajno viši u izloženoj populaciji prije, neposredno nakon i 120 min nakon ozračivanja. Pokazano je da nosioci polimorfnih alela ovih gena u izloženoj skupini imaju statistički značajno više razine oštećenja DNA, kako naspram homozigota pripadne skupine, tako i naspram cijele kontrolne skupine te da početno oštećenje DNA značajno negativno korelira s ukupnom dozom zračenja koju su primili tijekom radnog vijeka. Dobiveni rezultati upućuju na vrijednost kombiniranja alkalnoga komet-testa i genotipizacije izloženih pojedinaca u genima za popravak DNA, što bi moglo pridonijeti prepoznavanju subpopulacija sklonijih nakupljanju oštećenja DNA, a time i sklonijih riziku od razvoja tumorskih bolesti.Increasing exposure to ionising radiation raises a great concern about potential DNA damage in occupationally exposed individuals. Polymorphisms of DNA repair genes can determine individual sensitivity and DNA damage response to low doses of ionising radiation. The objective of this study was to assess DNA damage in leukocytes at baseline, immediately after and 120 min after exposure to gamma-radiation of 2 Gy, to compare DNA damage between the control group of subjects and subjects occupationally exposed to low-dose gamma-radiation, and to determine the relationship between hOGG1 (8-oxoG specifi c DNA glycosylase/AP-Lyase, Ser326Cys), XRCC1 (X-ray repair cross-complementing protein-group 1, Arg194Trp), and MGMT(O6-methylguanine-DNA methyltransferase, Leu84Phe) gene and DNA damage. The study enrolled 40 healthy subjects (20 controls and 20 occupationally exposed subjects), whose leukocytes were exposed to ionising radiation and tested for DNA damage (tail length, percentage od DNA in comet tail, and tail moment) using the alkaline version of the comet assay. Our results show that tail DNA percentage and tail moment were signifi cantly higher in the exposed group at baseline, immediately after, and 120 min after exposure to 2 Gy. The exposed subjects carrying polymorphic alleles had signifi cantly higher DNA damage than homozygous carriers of the same gene and controls. Combined use of the alkaline comet assay and genotyping of DNA repair genes could help discover sensitive occupationally exposed individuals who can accumulate higher DNA damage and are at higher risk of developing tumours

Polimorfizmi u genima za popravak DNA: poveznica s biomarkerima mikronukleus-testa u medicinskih radnika kronično izloženih niskim dozama ionizirajućeg zračenja

Individual sensitivity to ionising radiation (IR) is the result of interaction between exposure, DNA damage, and its repair, which is why polymorphisms in DNA repair genes could play an important role. We examined the association between DNA damage, expressed as micronuclei (MNi), nuclear buds (NBs), and nucleoplasmic bridges (NPBs) and single nucleotide polymorphisms in selected DNA repair genes (APE1, hOGG1, XRCC1, XRCC3, XPD, PARP1, MGMT genes; representative of the different DNA repair pathways operating in mammals) in 77 hospital workers chronically exposed to low doses of IR, and 70 matched controls. A significantly higher MNi frequency was found in the exposed group (16.2±10.4 vs. 11.5±9.4; P=0.003) and the effect appeared to be independent from the principal confounding factor. Exposed individuals with hOGG1, XRCC1, PARP1, and MGMT wild-type alleles or APEX1, as well as XPD (rs13181) heterozygous showed a significantly higher MNi frequency than controls with the same genotypes. Genetic polymorphism analysis and cytogenetic dosimetry have proven to be a powerful tool complementary to physical dosimetry in regular health surveillance programmes.Individualna osjetljivost na ionizirajuće zračenje rezultat je međudjelovanja samog izlaganja zračenju, oštećenja DNA nastalog prilikom tog izlaganja te samog popravka nastalog oštećenja. Veliki doprinos razlikama čine i polimorfizmi u genima za popravak DNA. U ovom radu istražili smo povezanost nastalih oštećenja DNA u obliku mikronukleusa (MN), jezgrinih pupova (NB) i nukleoplazmatskih mostova (NPB) s polimorfizmima jednog nukleotida (SNP) u genima za popravak DNK (APE1, hOGG1, XRCC1, XRCC3, XPD, PARP1, MGMT) koji sudjeluju u različitim mehanizmima popravka. Rezultati skupine od 77 medicinskih radnika kronično izloženih niskim dozama ionizirajućeg zračenja uspoređeni su s rezultatima skupine od 70 odgovarajućih kontrola. Izložena skupina imala je značajno veću učestalost MN-a (16,2±10,4 vs. 11.5±9.4; P=0,003), a sama pojavnost oštećenja bila je neovisna o medijatornoj varijabli (kovarijati). Značajno više učestalosti MN nađene su u izloženoj skupini u homozigotnih nositelja divljeg tipa gena hOGG1, XRCC1, PARP1 i MGMT i u heterozigotnih nositelja gena APEX1 i XPD (rs13181) u odnosu na kontrolnu skupinu istoga genotipa. Analiza genskih polimorfizama i citogenetička dozimetrija važna su dopuna osobnom dozimetrijskom nadzoru izloženih radnika

The multifaceted landscape behind imatinib resistance in gastrointestinal stromal tumors (GISTs): A lesson from ripretinib

Gastrointestinal stromal tumors (GISTs) are rare mesenchymal sarcomas and the gold-standard treatment is rep-resented by tyrosine kinase inhibitors (TKIs). Unfortunately, first-line treatment with the TKI imatinib usually promotes partial response or stable disease rather than a complete response, and resistance appears in most pa-tients. Adaptive mechanisms are immediately relevant at the beginning of imatinib therapy, and they may rep-resent the reason behind the low complete response rates observed in GISTs. Concurrently, resistant subclones can silently continue to grow or emerge de novo, becoming the most representative populations. Therefore, a slow evolution of the primary tumor gradually occurs during imatinib treatment, enriching heterogeneous ima-tinib resistant clonal subpopulations. The identification of secondary KIT/PDGFRA mutations in resistant GISTs prompted the development of novel multi-targeted TKIs, leading to the approval of sunitinib, regorafenib, and ripretinib. Although ripretinib has broad anti-KIT and-PDGFRA activity, it failed to overcome sunitinib as second-line treatment, suggesting that imatinib resistance is more multifaceted than initially thought. The present review summarizes several biological aspects suggesting that heterogeneous adaptive and resistance mechanisms can also be driven by KIT or PDGFRA downstream mediators, alternative kinases, as well as non -coding RNAs, which are not targeted by any TKI, including ripretinib. This may explain the modest effect observed with ripretinib and all anti-GIST agents in patients.&amp; COPY; 2023 Elsevier Inc. All rights reserved