Late-onset major depressive disorder: exploring the therapeutic potential of enhancing cerebral brain-derived neurotrophic factor expression through targeted microRNA delivery

Major depressive disorder (MDD) is a severe psychiatric condition that significantly impacts the overall quality of life. Although MDD can occur across all age groups, it is notably prevalent among older individuals, with the aggravating circumstance that the clinical condition is frequently overlooked and undertreated. Furthermore, older adults often encounter resistance to standard treatments, experience adverse events, and face challenges associated with polypharmacy. Given that late-life MDD is associated with heightened rates of disability and mortality, as well as imposing a significant economic and logistical burden on healthcare systems, it becomes imperative to explore novel therapeutic approaches. These could serve as either supplements to standard guidelines or alternatives for non-responsive patients, potentially enhancing the management of geriatric MDD patients. This review aims to delve into the potential of microRNAs targeting Brain-Derived Neurotrophic Factor (BDNF). In MDD, a significant decrease in both central and peripheral BDNF has been well-documented, raising implications for therapy response. Notably, BDNF appears to be a key player in the intricate interplay between microRNA-induced neuroplasticity deficits and neuroinflammation, both processes deeply implicated in the onset and progression of the disease. Special emphasis is placed on delivery methods, with a comprehensive comparison of the strengths and weaknesses of each proposed approach. Our hypothesis proposes that employing multiple microRNAs concurrently, with the ability to directly influence BDNF and activate closely associated pathways, may represent the most promising strategy. Regarding vehicles, although the perfect nanoparticle remains elusive, considering the trade-offs, liposomes emerge as the most suitable option

Analysis of Secreted Proteins from Prepubertal Ovarian Tissues Exposed In Vitro to Cisplatin and LH

It is well known that secreted and exosomal proteins are associated with a broad range of physiological processes involving tissue homeostasis and differentiation. In the present paper, our purpose was to characterize the proteome of the culture medium in which the oocytes within the primordial/primary follicles underwent apoptosis induced by cisplatin (CIS) or were, for the most part, protected by LH against the drug. To this aim, prepubertal ovarian tissues were cultured under control and in the presence of CIS, LH, and CIS + LH. The culture media were harvested after 2, 12, and 24 h from chemotherapeutic drug treatment and analyzed by liquid chromatography–mass spectrometry (LC-MS). We found that apoptotic conditions generated by CIS in the cultured ovarian tissues and/or oocytes are reflected in distinct changes in the extracellular microenvironment in which they were cultured. These changes became evident mainly from 12 h onwards and were characterized by the inhibition or decreased release of a variety of compounds, such as the proteases Htra1 and Prss23, the antioxidants Prdx2 and Hbat1, the metabolic regulators Ldha and Pkm, and regulators of apoptotic pathways such as Tmsb4x. Altogether, these results confirm the biological relevance of the LH action on prepuberal ovaries and provide novel information about the proteins released by the ovarian tissues exposed to CIS and LH in the surrounding microenvironment. These data might represent a valuable resource for future studies aimed to clarify the effects and identify biomarkers of these compounds’ action on the developing ovary

VST: the telescope progress toward stars

The VST telescope is in an advanced stage of integration in Chile, after a period of work spent mainly on the active optics system, started in mid-2007. We present the results of the recent work on the primary and secondary mirror support systems and on the mirror cell auxiliary units

Comprehensive longitudinal non-invasive quantification of healthspan and frailty in a large cohort (n = 546) of geriatric C57BL/6 J mice

Frailty is an age-related condition characterized by a multisystem functional decline, increased vulnerability to stressors, and adverse health outcomes. Quantifying the degree of frailty in humans and animals is a health measure useful for translational geroscience research. Two frailty measurements, namely the frailty phenotype (FP) and the clinical frailty index (CFI), have been validated in mice and are frequently applied in preclinical research. However, these two tools are based on different concepts and do not necessarily identify the same mice as frail. In particular, the FP is based on a dichotomous classification that suffers from high sample size requirements and misclassification problems. Based on the monthly longitudinal non-invasive assessment of frailty in a large cohort of mice, here we develop an alternative scoring method, which we called physical function score (PFS), proposed as a continuous variable that resumes into a unique function, the five criteria included in the FP. This score would not only reduce misclassification of frailty but it also makes the two tools, PFS and CFI, integrable to provide an overall measurement of health, named vitality score (VS) in aging mice. VS displays a higher association with mortality than PFS or CFI and correlates with biomarkers related to the accumulation of senescent cells and the epigenetic clock. This longitudinal non-invasive assessment strategy and the VS may help to overcome the different sensitivity in frailty identification, reduce the sample size in longitudinal experiments, and establish the effectiveness of therapeutic/preventive interventions for frailty or other age-related diseases in geriatric animals

Electrically Detected Magnetic Resonance on a Chip EDMRoC for Analysis of Thin Film Silicon Photovoltaics

Electrically detected magnetic resonance EDMR is a spectroscopic technique that provides information about the physical properties of materials through the detection of variations in conductivity induced by spin dependent processes. EDMR has been widely applied to investigate thin film semiconductor materials in which the presence of defects can induce the current limiting processes. Conventional EDMR measurements are performed on samples with a special geometry that allows the use of a typical electron paramagnetic resonance EPR resonator. For such measurements, it is of utmost importance that the geometry of the sample under assessment does not influence the results of the experiment. Here, we present a single board EPR spectrometer using a chip integrated, voltage controlled oscillator VCO array as a planar microwave source, whose geometry optimally matches that of a standard EDMR sample, and which greatly facilitates electrical interfacing to the device under assessment. The probehead combined an ultrasensitive transimpedance amplifier TIA with a twelve coil array, VCO based, single board EPR spectrometer to permit EDMR on a Chip EDMRoC investigations. EDMRoC measurements were performed at room temperature on a thin film hydrogenated amorphous silicon a Si H pin solar cell under dark and forward bias conditions, and the recombination current driven by the a Si H dangling bonds db was detected. These experiments serve as a proof of concept for a new generation of small and versatile spectrometers that allow in situ and operando EDMR experiment

Desmoglein 2 is a substrate of kallikrein 7 in pancreatic cancer

<p>Abstract</p> <p>Background</p> <p>In a previous report we have demonstrated that the chymotryptic-like serine protease kallikrein 7 (<it>KLK7</it>/hK7) is overexpressed in pancreatic cancer. In normal skin, hK7 is thought to participate in skin desquamation by contributing in the degradation of desmosomal components, such as desmogleins. Thus, the ability of hK7 to degrade desmogleins was assessed and the effect of hK7 expression on desmoglein 2 was examined in cultured pancreatic cancer cells.</p> <p>Methods</p> <p>The expression of Dsg1, Dsg2, and Dsg3 in pancreatic tissues was examined by immunohistochemistry and their expression in two pancreatic cancer cell lines, BxPC-3 and Panc-1, was determined by western blot analysis. The ability of hK7 to degrade Dsg1 and Dsg2 was investigated using <it>in vitro </it>degradation assays. BxPC-3 cells stably transfected to overexpress hK7 were used to examine the effect of hK7 on cell-surface resident Dsg2.</p> <p>Results</p> <p>The levels of immunoreactive Dsg1 and Dsg2 were reduced in pancreatic adenocarcinomas compared with both normal pancreatic and chronic pancreatitis tissues. Among the desmosomal proteins examined, Dsg2 exhibited robust expression on the surface of BxPC-3 cells. When hK7 was overexpressed in this cell line, there was a significant increase in the amount of soluble Dsg2 released into the culture medium compared with vector-transfected control cells.</p> <p>Conclusion</p> <p>A reduction in the amount of the cell adhesion components Dsg1 and Dsg2 in pancreatic tumors suggests that loss of these desmosomal proteins may play a role in pancreatic cancer invasion. Using <it>in vitro </it>degradation assays, both Dsg1 and Dsg2 could be readily proteolyzed by hK7, which is overexpressed in pancreatic adenocarcinomas. The enforced expression of hK7 in BxPC-3 cells that express significant amounts of Dsg2 resulted in a marked increase in the shedding of soluble Dsg2, which is consistent with the notion that aberrant expression of hK7 in pancreatic tumors may result in diminished cell-cell adhesion and facilitate tumor cell invasion.</p

Restoration of plakoglobin expression in bladder carcinoma cell lines suppresses cell migration and tumorigenic potential

The reduction or loss of plakoglobin expression in late-stage bladder cancer has been correlated with poor survival where upregulation of this catenin member by histone deacetylase inhibitors has been shown to accompany tumour suppression in an in vivo model. In this study, we directly addressed the question of the role of plakoglobin in bladder tumorigenesis following restoration, or knockdown of expression in bladder carcinoma cell lines. Restoration of plakoglobin expression resulted in a reduction in migration and suppression of tumorigenic potential in vivo. Immunocytochemistry revealed cytoplasmic and membranous localisation of plakoglobin in transfectants with <1% of cells displaying detectable nuclear localisation of plakoglobin. siRNA knockdown experiments targeting plakoglobin, revealed enhanced migration in all cell lines in the presence and absence of E-cadherin expression. In bladder cell lines expressing low levels of plakoglobin and desmoglein-2, elevated levels of desmoglein-2 were detected following restoration of plakoglobin expression in transfected cell lines. Analysis of wnt signalling revealed no activation event associated with plakoglobin expression in the bladder model. These results show that plakoglobin acts as a tumour suppressor gene in bladder carcinoma cells and the silencing of plakoglobin gene expression in late-stage bladder cancer is a primary event in tumour progression