The accumulation and deposition of amyloid can cause a variety of neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease. The degradation or clearance of this accumulation is currently the most widely accepted therapeutic strategy for intervention in these pathologies. Our study on amyloid-β (Aβ) oligomers in vitro revealed that high-frequency terahertz (THz) waves at a specific frequency of 34.88 THz could serve as a physical, efficient, non-thermal denaturation technique to delay the fibrotic process by 80%, as monitored by a thioflavine T (ThT) binding assay and Fourier transform infrared (FTIR) spectroscopy. Additionally, THz waves of this frequency have been shown to have no side effects on normal cells, as confirmed by cell viability and mitochondrial membrane potential assays. Furthermore, molecular dynamic (MD) simulations revealed that the THz waves could resonate with Aβ fibrils, disrupting the dense conformation by breaking the β-sheet structure and promoting the formation of abundant coil and bend structures. This study uses the amyloid of Aβ as an example, and the results will further guide interventions for the accumulation of other amyloids, which may provide new ideas for the remission of related diseases.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a common heritable heart disease. Although HCM has been reported to be associated with many variants of genes involved in sarcomeric protein biomechanics, pathogenic genes have not been identified in patients with partial HCM. FARS2 (the mitochondrial phenylalanyl-tRNA synthetase), a type of mitochondrial aminoacyl-tRNA synthetase, plays a role in the mitochondrial translation machinery. Several variants of FARS2 have been suggested to cause neurological disorders; however, FARS2-associated diseases involving other organs have not been reported. We identified FARS2 as a potential novel pathogenic gene in cardiomyopathy and investigated its effects on mitochondrial homeostasis and the cardiomyopathy phenotype. METHODS: FARS2 variants in patients with HCM were identified using whole-exome sequencing, Sanger sequencing, molecular docking analyses, and cell model investigation. Fars2 conditional mutant (p.R415L) or knockout mice, fars2 -knockdown zebrafish, and Fars2 -knockdown neonatal rat ventricular myocytes were engineered to construct FARS2 deficiency models both in vivo and in vitro. The effects of FARS2 and its role in mitochondrial homeostasis were subsequently evaluated using RNA sequencing and mitochondrial functional analyses. Myocardial tissues from patients were used for further verification. RESULTS: We identified 7 unreported FARS2 variants in patients with HCM. Heart-specific Fars2 -deficient mice presented cardiac hypertrophy, left ventricular dilation, progressive heart failure accompanied by myocardial and mitochondrial dysfunction, and a short life span. Heterozygous cardiac-specific Fars2 ^R415L mice displayed a tendency to cardiac hypertrophy at age 4 weeks, accompanied by myocardial dysfunction. In addition, fars2 -knockdown zebrafish presented pericardial edema and heart failure. FARS2 deficiency impaired mitochondrial homeostasis by directly blocking the aminoacylation of mt-tRNA ^Phe and inhibiting the synthesis of mitochondrial proteins, ultimately contributing to an imbalanced mitochondrial quality control system by accelerating mitochondrial hyperfragmentation and disrupting mitochondrion-related autophagy. Interfering with the mitochondrial quality control system using adeno-associated virus 9 or specific inhibitors mitigated the cardiac and mitochondrial dysfunction triggered by FARS2 deficiency by restoring mitochondrial homeostasis. CONCLUSIONS: Our findings unveil the previously unrecognized role of FARS2 in heart and mitochondrial homeostasis. This study may provide new insights into the molecular diagnosis and prevention of heritable cardiomyopathy as well as therapeutic options for FARS2-associated cardiomyopathy.

Background: Neurodegenerative diseases encompass an extensive and heterogeneous group of nervous system disorders which are characterized by progressive degeneration and death of neurons. Many lines of evidence suggest the participation of mitochondria dysfunction in these diseases. Mitochondrial phenylalanyl-tRNA synthetase, encoded by FARS2, catalyzes the transfer of phenylalanine to its cognate tRNA for protein synthesis. As a member of mt-aaRSs genes, FARS2 missense homozygous mutation c.424G > T (p.D142Y) found in a Chinese consanguineous family first built the relationship between pure hereditary spastic paraplegia (HSP) and FARS2 gene. More FARS2 variations were subsequently found to cause heterogeneous group of neurologic disorders presenting three main phenotypic manifestations: infantile-onset epileptic mitochondrial encephalopathy, later-onset spastic paraplegia and juvenile onset refractory epilepsy. Studies showed that aminoacylation activity is frequently disrupt in cases with FARS2 mutations, indicating a loss-of-function mechanism. However, the underlying pathogenesis of neuropathy-associated Fars2 deficiency is still largely unknown. Results: Early gestation lethality of global Fars2 knockout mice was observed prior to neurogenesis. The conditional Fars2 knockout-mouse model delayed lethality to late-gestation, resulting in a thinner cortex and an enlarged ventricle which is consist with the MRI results revealing cortical atrophy and reduced cerebral white matter volume in FARS2-deficient patients. Delayed development of neurite outgrowth followed by neuronal apoptosis was confirmed in Fars2-knockdown mouse primary cultured neurons. Zebrafish, in which fars2 was knocked down, exhibited aberrant motor neuron function including reduced locomotor capacity which well restored the spastic paraplegia phenotype of FARS2-deficient patients. Altered mitochondrial protein synthesis and reduced levels of oxidative phosphorylation complexes were detected in Fars2-deficient samples. And thus, reduced ATP, total NAD levels and mitochondrial membrane potential, together with increased ROS production, revealed mitochondrial dysfunction both in vitro and in vivo. Dctn3 is a potential downstream molecule in responds to Fars2 deficient in neurons, which may provide some evidence for the development of pathogenesis study and therapeutic schedule. Conclusions: The Fars2 deficiency genetic models developed in this study cover the typical clinical manifestations in FARS2 patients, and help clarify how neuropathy-associated Fars2 deficiency, by damaging the mitochondrial respiratory chain and impairing mitochondrial function, affects neuronal development and potentiates neuronal cell apoptosis.

ObjectiveInflammatory pain, is caused by lesions or diseases of the somatosensory tissue, is a prevalent chronic condition that profoundly impacts the quality of life. However, clinical treatment for this type of pain remains limited. Traditionally, the stimulation of microglia and subsequent inflammatory reactions are considered crucial elements to promote the worsening of inflammatory pain. Recent research has shown the crucial importance of the cGAS-STING pathway in promoting inflammation. It is still uncertain if the cGAS-STING pathway plays the role in the fundamental cause of inflammatory pain. We aim to explore the treatment of inflammatory pain by interfering with cGAS-STING signaling pathway.MethodsIn this study, we established an inflammatory pain model by CFA into the plantar of mice. Activation of microglia, various inflammatory factors and cGAS-STING protein in the spinal dorsal horn were evaluated. Immunofluorescence staining was used to observe the cellular localization of cGAS and STING. The cGAS-STING pathway proteins expression and mRNA expression of indicated microglial M1/M2 phenotypic markers in the BV2 microglia were detected. STING inhibitor C-176 was intrathecal injected into mice with inflammatory pain, and the pain behavior and microglia were observed.ResultsThis research showed that injecting CFA into the left hind paw of mice caused mechanical allodynia and increased inflammation in the spine. Our research results suggested that the cGAS-STING pathway had a function in the inflammation mediated by microglia in the spinal cord dorsal horn. Blocking the cGAS-STING pathway using STING antagonists (C-176) led to reduced release of inflammatory factors and prevented M1 polarization of BV2 microglia in a laboratory setting. Additionally, intrathecal administration of C-176 reduced the allodynia in CFA treated mice.ConclusionOur results suggest that inhibiting microglial polarization through the cGAS-STING pathway represents a potential novel therapeutic strategy for inflammatory pain.

Cardiac fibrosis plays a critical role in the progression of various forms of heart disease, significantly increasing the risk of sudden cardiac death. However, currently, there are no therapeutic strategies available to prevent the onset of cardiac fibrosis. Here, biomimetic ATP-responsive nanozymes based on genetically engineered cell membranes are adapted to specifically recognize activated cardiac fibroblasts (CFs) for the treatment of cardiac fibrosis. By fusing the anti-FAP CAR genetically engineered cell membrane to zeolitic imidazole frameworks-90 (zif-90) cores loaded with antioxidant nanozymes CeO2 and siCTGF (siRNA targeting CTGF), these nanoparticles, called FM@zif-90/Ce/siR NPs, are demonstrated to effectively reduce the accumulation of myofibroblasts and the formation of fibrotic tissue, while restoring cardiac function. These findings demonstrate that the combination of CeO2 and siCTGF has a beneficial curative effect on cardiac fibrosis, with significant translational potential.