Search Results (8)

Amyotrophic lateral sclerosis (ALS) is still a heterogeneous neurodegenerative disorder that can be identified clinically and biologically, without a strong set of biomarkers that can adequately measure its fast rate of progression and molecular heterogeneity. In this review, we intend to consolidate the most relevant and timely advances in ALS biomarker discovery, in order to begin to bring molecular, imaging, genetic, and digital areas together for potential integration into a precision medicine approach to ALS. Our goal is to begin to display how several biomarkers in development (e.g., neurofilament light chain (NfL), phosphorylated neurofilament heavy chain (pNfH), TDP-43 aggregates, mitochondrial stress markers, inflammatory markers, etc.) are changing our understanding of ALS and ALS dynamics. We will attempt to provide a framework for thinking about biomarkers in a systematic way where our candidates are not signals alone but part of a tethered pathophysiological cascade. We are particularly interested in the fast progressor phenotype, a devastating and under-characterized subset of ALS due to a rapid axonal degeneration, early respiratory failure, and very short life span. We will try to highlight the salient molecular features of this ALS subtype, including SOD1 A5V toxicity, C9orf72 repeats, FUS variants, mitochondrial collapse, and impaired autophagy mechanisms, and relate these features to measurable blood and CSF (biomarkers) and imaging platforms. We will elaborate on several interesting tools, for example, single-cell transcriptomics, CSF exosomal cargo analysis, MRI techniques, and wearable sensor outputs that are developing into high-resolution windows of disease progression and onset. Instead of providing a static catalog, we plan on providing a conceptual roadmap to integrate biomarker panels that will allow for earlier diagnosis, real-time disease monitoring, and adaptive therapeutic trial design. We hope this synthesis will make a meaningful contribution to the shift from observational neurology to proactive biologically informed clinical care in ALS. Although there are still considerable obstacles to overcome, the intersection of a precise molecular or genetic association approach, digital phenotyping, and systems-level understandings may ultimately redefine how we monitor, care for, and treat this challenging neurodegenerative disease. Full article

Background/Objectives: Muscle atrophy, defined by diminished muscle mass and function, is a notable concern associated with aging, disease, and glucocorticoid treatment. Pueraria montana var. lobata extract (PMLE) demonstrates multiple bioactive properties, such as antioxidant, anti-inflammatory, and metabolic regulatory activities; however, its role in muscle atrophy has not been extensively investigated to date. This study examined how PMLE influences both muscle cell differentiation and dexamethasone (DEX)-induced muscle degeneration by focusing on the underlying molecular mechanisms. Methods: This study examined the effects of PMLE on myogenic differentiation and DEX-induced muscle atrophy. C2C12 myoblasts were treated with PMLE (10–100 ng/mL) and assessed for changes in the expression of myogenesis-related genes and activation of Akt/mTOR and AMPK/SIRT1/PGC-1α signaling cascades. In vivo, a DEX-induced muscle atrophy model was used to assess muscle mass, fiber morphology, and molecular changes. Results: PMLE PMLE promoted muscle cell development by increasing the expression of MyHC, MyoD, and myogenin while activating protein synthesis and mitochondrial biogenesis pathways. PMLE counteracted DEX-induced myotube atrophy, restoring myotube diameter and promoting cellular fusion in vitro. In vivo, PMLE mitigated muscle degradation in fast-twitch muscle groups and reversed DEX-induced suppression of key anabolic and mitochondrial pathways. Conclusions: These findings suggest that PMLE promotes myogenic differentiation and protects against muscle atrophy by regulating critical molecular pathways, indicating its promise as a treatment candidate for conditions involving muscle wasting. Further studies are required to assess its clinical application and long-term safety efficacy. Full article

Retinal degenerative diseases lead to irreversible vision loss due to photoreceptor cell death, driven by complex genetic and environmental factors. Ceramide, a sphingolipid metabolite, emerges as a critical mediator in the apoptotic cascade associated with retinal degeneration. Our previous work demonstrated L-Cycloserine’s ability to protect photoreceptor-derived cells from oxidative stress by inhibiting the de novo ceramide pathway and thus prompting further investigation on its effect in the in vivo retina. This study investigates the potential of L-Cycloserine to protect albino BALB/c mice against light-induced retinal degeneration (LIRD). L-Cycloserine, in an optimal dose, administered systemically 30 min before LIRD, was found to prevent photoreceptor cell death significantly from light-induced degeneration. We further determined the retinal bioavailability and pharmacokinetic behavior of L-Cycloserine, its effect on sphingolipid profile, expression of sphingolipid biosynthetic, and cell death-promoting genes and proteins from the retina to understand the underlying mechanisms. This study lays the groundwork for further preclinical and clinical investigations into L-Cycloserine’s potential as a novel therapeutic in treating retinal degenerative diseases. Full article

Age-related macular degeneration (AMD), an oxidative stress-linked neurodegenerative disease, leads to irreversible damage of the central retina and severe visual impairment. Advanced age and the long-standing influence of oxidative stress and oxidative cellular damage play crucial roles in AMD etiopathogenesis. Many authors emphasize the role of heterophagy, autophagy, and mitophagy in maintaining homeostasis in the retina. Relevantly modifying the activity of both macroautophagy and mitophagy pathways represents one of the new therapeutic strategies in AMD. Our review provides an overview of the antioxidative roles of heterophagy, autophagy, and mitophagy and presents associations between dysregulations of these molecular mechanisms and AMD etiopathogenesis. The authors performed an extensive analysis of the literature, employing PubMed and Google Scholar, complying with the 2013–2023 period, and using the following keywords: age-related macular degeneration, RPE cells, reactive oxygen species, oxidative stress, heterophagy, autophagy, and mitophagy. Heterophagy, autophagy, and mitophagy play antioxidative roles in the retina; however, they become sluggish and dysregulated with age and contribute to AMD development and progression. In the retina, antioxidative roles also play in RPE cells, NFE2L2 and PGC-1α proteins, NFE2L2/PGC-1α/ARE signaling cascade, Nrf2 factor, p62/SQSTM1/Keap1-Nrf2/ARE pathway, circulating miRNAs, and Yttrium oxide nanoparticles performed experimentally in animal studies. Full article

Spinal cord injury (SCI) is characterized by a cascade of events that lead to sensory and motor disabilities. To date, this condition is irreversible, and no cure exists. To improve myelin repair and limit secondary degeneration, we developed a multitherapy based on nanomedicines (NMeds) loaded with the promyelinating agent triiodothyronine (T3), used in combination with systemic ibuprofen and mouse nerve growth factor (mNGF). Poly-L-lactic-co-glycolic acid (PLGA) NMeds were optimized and loaded with T3 to promote sustained release. In vitro experiments confirmed the efficacy of T3-NMeds to differentiate oligodendrocyte precursor cells. In vivo rat experiments were performed in contusion SCI to explore the NMed biodistribution and efficacy of combo drugs at short- and long-term post-lesion. A strong anti-inflammatory effect was observed in the short term with a reduction of type M1 microglia and glutamate levels, but with a subsequent increase of TREM2. In the long term, an improvement of myelination in NG2-IR, an increase in MBP content, and a reduction of the demyelination area were observed. These data demonstrated that NMeds can successfully be used to obtain more controlled local drug delivery and that this multiple treatment could be effective in improving the outcome of SCIs. Full article

This paper presents and discusses a Low-Band (LB) Low Noise Amplifier (LNA) design for a diversity receive module where the application is for multi-mode cellular handsets. The LB LNA covers the frequency range between 617 MHz to 960 MHz in 5 different frequency bands and a 5 Pole Single Throw (5PST) switch selects the different frequency bands where two of them are for the main and three for the auxiliary bands. The presented structure covers the gain modes from −12 to 18 dB with 6 dB gain steps where each gain mode has a different current consumption. In order to achieve the Noise Figure (NF) specifications in high gain modes, we have adopted a cascode Common-Source (CS) with inductive source degeneration structure for this design. To achieve the S₁₁ parameters and current consumption specifications, the core and cascode transistors for high gain modes (18 dB, 12 dB, and 6 dB) and low gain modes (0 dB, −6 dB, and −12 dB) have been separated. Nevertheless, to keep the area low and keep the phase discontinuity within ±10${}^{\circ }$, we have shared the degeneration and load inductors between two cores. To compensate the performance for Process, Voltage, and Temperature (PVT) variations, the structure applies a Low Drop-Out (LDO) regulator and a corner case voltage compensator. The design has been proceeded in a 65-nm RSB process design kit and the supply voltage is 1 V. For 18 dB and −12 dB gain modes as two examples, the NF, current consumption, and Input Third Order Intercept Point (IIP3) values are 1.2 dB and 16 dB, 10.8 mA and 1.2 mA, and −6 dBm and 8 dBm, respectively. Full article

Neurodegenerative diseases are characterized by the progressive degeneration of the function of the central nervous system or peripheral nervous system and the decline of cognition and memory abilities. The dysfunctions of the cognitive and memory battery are closely related to inhibitions of neurotrophic factor (BDNF) and brain-derived cAMP response element-binding protein (CREB) to associate with the cholinergic system and long-term potentiation. Vitis vinifera, the common grapevine, is viewed as the important dietary source of stilbenoids, particularly the widely-studied monomeric resveratrol to be used as a natural compound with wide-ranging therapeutic benefits on neurodegenerative diseases. Here we found that ampelopsin A is a major compound in V. vinifera and it has neuroprotective effects on experimental animals. Bath application of ampelopsin A (10 ng/µL) restores the long-term potentiation (LTP) impairment induced by scopolamine (100 μM) in hippocampal CA3-CA1 synapses. Based on these results, we administered the ampelopsin A (10 ng/µL, three times a week) into the third ventricle of the brain in C57BL/6 mice for a month. Chronic administration of ampelopsin A into the brain ameliorated cognitive memory-behaviors in mice given scopolamine (0.8 mg/kg, i.p.). Studies of mice’s hippocampi showed that the response of ampelopsin A was responsible for the restoration of the cholinergic deficits and molecular signal cascades via BDNF/CREB pathways. In conclusion, the central administration of ampelopsin A contributes to increasing neurocognitive and neuroprotective effects on intrinsic neuronal excitability and behaviors, partly through elevated BDNF/CREB-related signaling. Full article

Hyperleptinemia is implicated in obesity-associated lumbar disc degeneration. Nevertheless, the effect of leptin on the intracellular signaling of nucleus pulposus cells is not clear. The current study sought to delineate the possible involvement of the RhoA/ROCK pathway in leptin-mediated cytoskeleton reorganization in nucleus pulposus cells. Nucleus pulposus cells isolated from scoliosis patients were treated with 10 ng/mL of leptin. Fluorescent resonance energy transfer analysis was used to determine the activation of RhoA signaling in nucleus pulposus cells. The protein expression of LIMK1 and cofilin-2 were analyzed by western blot analysis. F-actin cytoskeletal reorganization was assessed by rhodamine-conjugated phalloidin immunoprecipitation. Leptin induced F-actin reorganization and stress fiber formation in nucleus pulposus cells, accompanied by localized RhoA activation and phosphorylation of LIMK1 and cofilin. The RhoA inhibitor C3 exoenzyme or the ROCK inhibitor Y-27632 potently attenuated the effects of leptin on F-actin reorganization and stress fiber formation. Both inhibitors also prevented leptin-induced phosphorylation of LIMK1 and cofilin-2. Our study demonstrated that leptin activated the RhoA/ROCK/LIMK/cofilin-2 cascade to induce cytoskeleton reorganization in nucleus pulposus cells. These findings may provide novel insights into the pathogenic mechanism of obesity-associated lumbar disc degeneration. Full article