Enhancing Precision in Photodynamic Therapy: Innovations in Light-Driven and Bioorthogonal Activation.

Over the past few decades, photodynamic therapy (PDT) has evolved as a minimally invasive treatment modality offering precise control over cancer and various other diseases. To address inherent challenges associated with PDT, researchers have been exploring two promising avenues: the development of intelligent photosensitizers activated through light-induced energy transfers, charges, or electron transfers, and the disruption of photosensitive bonds. Moreover, there is a growing emphasis on the bioorthogonal delivery or activation of photosensitizers within tumors, enabling targeted deployment and activation of these intelligent photosensitive systems in specific tissues, thus achieving highly precise PDT. This concise review highlights advancements made over the last decade in the realm of light-activated or bioorthogonal photosensitizers, comparing their efficacy and shaping future directions in the advancement of photodynamic therapy.

A first-in-class ß-glucuronidase responsive conjugate for selective dual targeted and photodynamic therapy of bladder cancer.

In this report, we present a novel prodrug strategy that can significantly improve the efficiency and selectivity of combined therapy for bladder cancer. Our approach involved the synthesis of a conjugate based on a chlorin-e6 photosensitizer and a derivative of the tyrosine kinase inhibitor cabozantinib, linked by a ß-glucuronidase-responsive linker. Upon activation by ß-glucuronidase, which is overproduced in various tumors and localized in lysosomes, this conjugate released both therapeutic modules within targeted cells. This activation was accompanied by the recovery of its fluorescence and the generation of reactive oxygen species. Investigation of photodynamic and dark toxicity in vitro revealed that the novel conjugate had an excellent safety profile and was able to inhibit tumor cells proliferation at submicromolar concentrations. Additionally, combined therapy effects were also observed in 3D models of tumor growth, demonstrating synergistic suppression through the activation of both photodynamic and targeted therapy.

Anomia: Deciphering Functional Neuroanatomy in Primary Progressive Aphasia Variants.

Naming decline is one of the most common symptoms of primary progressive aphasia (PPA). Most studies on anomia in PPA are performed without taking into account PPA variants, especially for action naming. Only limited data are available for the neuroanatomical basis of anomia considering differences in the pathogenesis of PPAs. The aim of our study is to investigate the associations between anomia severity for both noun and verb naming and gray matter (GM) atrophy, as well as accompanying functional connectivity (FC) changes in three PPA variants. A total of 17 patients with non-fluent (nfvPPA), 11 with semantic (svPPA), and 9 with logopenic (lvPPA) PPA variants were included in the study and underwent cognitive/naming assessments and brain MRIs. Voxel-based morphometry was performed to evaluate GM volume. A resting-state functional MRI was applied to investigate FC changes in the identified GM areas. The study shows that different brain regions are involved in naming decline in each PPA variant with a predominantly temporal lobe involvement in svPPA, parietal lobe involvement in lvPPA, and frontal lobe involvement in nfvPPA. Separate data for object and action naming in PPA variants are provided. The obtained results mainly correspond to the current understanding of language processing and indicate that the evaluation of language impairments is preferable for each PPA variant separately. A further analysis of larger cohorts of patients is necessary to confirm these preliminary results.

Analysis of ADORA2A, MTA1, PTGDS, PTGS2, NSF, and HNMT Gene Expression Levels in Peripheral Blood of Patients with Early Stages of Parkinson's Disease.

Parkinson's disease (PD) is a common chronic, age-related neurodegenerative disease. This disease is characterized by a long prodromal period. In this context, it is important to search for the genes and mechanisms that are involved in the development of the pathological process in the earliest stages of the disease. Published data suggest that blood cells, particularly lymphocytes, may be a model for studying the processes that occur in the brain in PD. Thus, in the present work, we performed an analysis of changes in the expression of the genes ADORA2A, MTA1, PTGDS, PTGS2, NSF, and HNMT in the peripheral blood of patients with early stages of PD (stages 1 and 2 of the Hoehn-Yahr scale). We found significant and PD-specific expression changes of four genes, i.e., MTA1, PTGS2, NSF, and HNMT, in the peripheral blood of patients with early stages of PD. These genes may be associated with PD pathogenesis in the early clinical stages and can be considered as potential candidate genes for this disease. Altered expression of the ADORA2A gene in treated PD patients may indicate that this gene is involved in processes affected by antiparkinsonian therapy.

SNCA Gene Methylation in Parkinson's Disease and Multiple System Atrophy.

In recent years, epigenetic mechanisms have been implicated in the development of multifactorial diseases including neurodegenerative disorders. In Parkinson's disease (PD), as a synucleinopathy, most studies focused on DNA methylation of SNCA gene coding alpha-synuclein but obtained results were rather contradictory. In another neurodegenerative synucleinopathy, multiple system atrophy (MSA), very few studies investigated the epigenetic regulation. This study included patients with PD (n = 82), patients with MSA (n = 24), and a control group (n = 50). In three groups, methylation levels of CpG and non-CpG sites in regulatory regions of the SNCA gene were analyzed. We revealed hypomethylation of CpG sites in the SNCA intron 1 in PD and hypermethylation of predominantly non-CpG sites in the SNCA promoter region in MSA. In PD patients, hypomethylation in the intron 1 was associated with earlier age at the disease onset. In MSA patients, hypermethylation in the promotor was associated with shorter disease duration (before examination). These results showed different patterns of the epigenetic regulation in two synucleinopathies-PD and MSA.

Embracing Monogenic Parkinson's Disease: The MJFF Global Genetic PD Cohort.

BACKGROUND: As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited. OBJECTIVE: The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD. METHODS: We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype-phenotype relationships were analyzed. RESULTS: We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published. CONCLUSIONS: Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene-targeted clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Mutation analysis of the TATA box-binding protein (TBP) gene in Russian patients with spinocerebellar ataxia and Huntington disease-like phenotype.

OBJECTIVE: We aimed to analyze the occurrence and clinical and genetic characteristics of spinocerebellar ataxia type 17 (SCA17) among Russian patients with progressive cerebellar ataxia or Huntington disease-like phenotype. METHODS: Genetic analysis of CAG/CAA repeats in TBP gene was carried out in 217 patients, including 153 patients with progressive unspecified ataxia and 64 patients with Huntington disease-like phenotype. SCA types 1, 2, 3, 6 and 8, Friedreich's ataxia, CANVAS and Huntington disease were preliminarily excluded. RESULTS: Six unrelated patients with SCA17 (2.8 %) were identified (43-57 CAG/CAA repeats in TBP gene). Two patients had a positive family history. Age at the disease onset ranged from 15 to 47 years. The core clinical syndrome included progressive cerebellar ataxia, dysarthria, movement disorders, cognitive impairment, and psychiatric symptoms. One patient had epilepsy with rare generalized tonic-clonic seizures. Another patient with diffuse muscle atrophy and small expansion size (43 CAG/CAA repeats) had myopathic changes in skeletal muscles on EMG study. We also described a patient with a large expansion size of 57 CAA/CAG repeats with early onset and rapid disease progression. CONCLUSION: SCA17 is a relatively rare cause of progressive disorders with ataxia and chorea, but it should be considered in the spectrum of differential diagnosis in such patients. Most of our SCA17 cases were sporadic which should be kept in mind when planning genetic testing in patients with spinocerebellar ataxia and chorea.

Alterations in Proteostasis System Components in Peripheral Blood Mononuclear Cells in Parkinson Disease: Focusing on the HSP70 and p62 Levels.

Parkinson disease (PD) is attributed to a proteostasis disorder mediated by α-synuclein accumulating in a specific brain region. PD manifestation is often related to extraneuronal alterations, some of which could be used as diagnostic or prognostic PD biomarkers. In this work, we studied the shifts in the expression of proteostasis-associated chaperones of the HSP70 family and autophagy-dependent p62 protein values in the peripheral blood mononuclear cells (PBMC) of mild to moderate PD patients. Although we did not detect any changes in the intracellular HSP70 protein pool in PD patients compared to non-PD controls, an increase in the transcriptional activity of the stress-associated HSPA1A/B and HSPA6 genes was observed in these cells. Basal p62 content was found to be increased in PD patients' PBMC, similarly to the p62 level in substantia nigra neural cells in PD. Moreover, the spontaneous apoptosis level was increased among PBMC and positively correlated with the p62 intracellular level in the PD group. A combined HSPA6- and p62-based analysis among 26 PD patients and 36 age-matched non-PD controls pointed out the diagnostic significance of these markers, with intermediate sensitivity and high specificity of this combination when observing patients diagnosed with PD.

Reduced Immunosenescence of Peripheral Blood T Cells in Parkinson's Disease with CMV Infection Background.

Immunosenescence is a process of remodeling the immune system under the influence of chronic inflammation during aging. Parkinson's disease (PD) is a common age-associated neurodegenerative disorder and is frequently accompanied by neuroinflammation. On the other hand, cytomegalovirus (CMV), one of the most spread infections in humans, may induce chronic inflammation which contributes to immunosenescence, differentiation and the inflation of T cells and NK cells. Currently, there is no clear understanding of immunosenescence severity in PD patients infected with CMV. In this study, we analyzed differentiation stages and immunosenescence characteristics of T cells and NK cells in 31 patients with mild and moderate PD severity, 33 age-matched and 30 young healthy donors. The PD patients were 100% CMV-seropositive compared to 76% age-matched and 73% young CMV-infected healthy donors. The proportion of effector memory T cells re-expressing CD45RA, CD57+CD56- T cells and CD57+CD56+ T cells was significantly reduced in PD patients compared with CMV-seropositive age-matched healthy individuals. The CD57+CD56- T cell proportion in PD patients was similar to that of CMV-seropositive young healthy donors. Thus, PD is characterized by reduced peripheral blood T cell immunosenescence, even against the background of CMV infection.

Parkinson's Disease: Available Clinical and Promising Omics Tests for Diagnostics, Disease Risk Assessment, and Pharmacotherapy Personalization.

Parkinson's disease is the second most frequent neurodegenerative disease, representing a significant medical and socio-economic problem. Modern medicine still has no answer to the question of why Parkinson's disease develops and whether it is possible to develop an effective system of prevention. Therefore, active work is currently underway to find ways to assess the risks of the disease, as well as a means to extend the life of patients and improve its quality. Modern studies aim to create a method of assessing the risk of occurrence of Parkinson's disease (PD), to search for the specific ways of correction of biochemical disorders occurring in the prodromal stage of Parkinson's disease, and to personalize approaches to antiparkinsonian pharmacotherapy. In this review, we summarized all available clinically approved tests and techniques for PD diagnostics. Then, we reviewed major improvements and recent advancements in genomics, transcriptomics, and proteomics studies and application of metabolomics in PD research, and discussed the major metabolomics findings for diagnostics and therapy of the disease.

Whole-Exome Sequencing in Searching for New Variants Associated With the Development of Parkinson's Disease.

Background: Parkinson's disease (PD) is a complex disease with its monogenic forms accounting for less than 10% of all cases. Whole-exome sequencing (WES) technology has been used successfully to find mutations in large families. However, because of the late onset of the disease, only small families and unrelated patients are usually available. WES conducted in such cases yields in a large number of candidate variants. There are currently a number of imperfect software tools that allow the pathogenicity of variants to be evaluated. Objectives: We analyzed 48 unrelated patients with an alleged autosomal dominant familial form of PD using WES and developed a strategy for selecting potential pathogenetically significant variants using almost all available bioinformatics resources for the analysis of exonic areas. Methods: DNA sequencing of 48 patients with excluded frequent mutations was performed using an Illumina HiSeq 2500 platform. The possible pathogenetic significance of identified variants and their involvement in the pathogenesis of PD was assessed using SNP and Variation Suite (SVS), Combined Annotation Dependent Depletion (CADD) and Rare Exome Variant Ensemble Learner (REVEL) software. Functional evaluation was performed using the Pathway Studio database. Results: A significant reduction in the search range from 7082 to 25 variants in 23 genes associated with PD or neuronal function was achieved. Eight (FXN, MFN2, MYOC, NPC1, PSEN1, RET, SCN3A and SPG7) were the most significant. Conclusions: The multistep approach developed made it possible to conduct an effective search for potential pathogenetically significant variants, presumably involved in the pathogenesis of PD. The data obtained need to be further verified experimentally.

Second mutation in PARK2 is absent in patients with sporadic Parkinson's disease and heterozygous exonic deletions/duplications in parkin gene.

AIM OF THE STUDY: Mutations in PARK2 are one of the causes of Parkinson's disease (PD). Deletions and duplications/triplications of one exon or exon groups account for a large proportion of mutations in the gene. At the present time, it is still not fully clear whether heterozygous mutations cause the development of PD. Our study aimed at conducting screening for mutations in PARK2 in patients with a sporadic form of PD to clarify the role of PARK2 in the development of PD. MATERIALS AND METHODS: The cohort of 327 patients with PD was screened by quantitative real-time polimerase chain reaction (PCR) with subsequent Sanger sequencing. RESULTS: It was found that a sufficiently large proportion of these patients (21 patients, 6.4%) were carriers of heterozygous deletions or duplications in PARK2. Analysis of PARK2 exon rearrangement carriers for the presence of point mutations in PARK2 did not reveal any variants with pathogenic significance. CONCLUSIONS: Thus, our data indicate that heterozygous deletions and duplications can play an important role in the pathogenesis of PD and can be considered as dominant mutations with low penetrance.

A green synthesis in water of novel (1,5,3-dithiazepan-3-yl)alkanoic acids by the multicomponent reaction of amino acids, CH2O, and 1,2-ethanedithiol.

A library of new (1,5,3-dithiazepan-3-yl)alkanoic acids was prepared by the multicomponent cyclocondensation of amino acids, formaldehyde, and 1,2-ethanedithiol in water at room temperature for 1 to 5 h in high yields. This green procedure offers several advantages such as an operational simplicity, no catalyst, and no production of hazardous materials.

New mutations in the Notch3 gene in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL).

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a cerebrovascular small-vessel disease caused by stereotyped mutations in the Notch3 gene altering the number of cysteine residues. METHODS: We directly sequenced exons 2-23 of the Notch3 gene in 30 unrelated Russian patients with clinical/neuroimaging picture suggestive of CADASIL. To confirm the pathogenicity of new nucleotide variants, we used the standard bioinformatics tools and screened 200 ethnically matched individuals as controls. RESULTS: We identified 16 different point mutations in the Notch3 gene in 18 unrelated patients, including 4 new missense mutations (C194G, V252M, C338F, and C484G). All but two mutations affected the cysteine residue. The non-cysteine change V322M was shown to be associated with CADASIL-specific deposits of granular osmiophilic material in the vascular smooth-muscle cells, which confirmed the pathogenicity of this Notch3 variant. Two patients were shown to be compound-heterozygotes carrying two pathogenic Notch3 mutations. The disease was characterized by marked clinical variability, without evident phenotype-genotype correlations. CONCLUSIONS: In our sample, 60% of Russian patients with 'clinically suspected' CADASIL received the definitive molecularly proven diagnosis. Careful assessment of genealogical, clinical, and neuroimaging data in patients with lacunar stroke can help selecting patients with a high probability of finding mutations on genetic screening.