Emerging physiological and pathological roles of MeCP2 in non-neurological systems.

Numerous neurological and non-neurological disorders are associated with dysfunction of epigenetic modulators, and methyl CpG binding protein 2 (MeCP2) is one of such proteins. Initially identified as a transcriptional repressor, MeCP2 specifically binds to methylated DNA, and mutations of MeCP2 have been shown to cause Rett syndrome (RTT), a severe neurological disorder. Recently, accumulating evidence suggests that ubiquitously expressed MeCP2 also plays a central role in non-neurological disorders including cardiac dysfunction, liver injury, respiratory disorders, urological dysfunction, adipose tissue metabolism disorders, movement abnormality and inflammatory responses in a DNA methylation dependent or independent manner. Despite significant progresses in our understanding of MeCP2 over the last few decades, there is still a considerable knowledge gap to translate the in vitro and in vivo experimental findings into therapeutic interventions. In this review, we provide a synopsis of the role of MeCP2 in the pathophysiology of non-neurological disorders, MeCP2-based research directions and therapeutic strategies for non-neurological disorders are also discussed.

ß-synuclein regulates the phase transitions and amyloid conversion of α-synuclein.

Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB) are neurodegenerative disorders characterized by the accumulation of α-synuclein aggregates. α-synuclein forms droplets via liquid-liquid phase separation (LLPS), followed by liquid-solid phase separation (LSPS) to form amyloids, how this process is physiologically-regulated remains unclear. ß-synuclein colocalizes with α-synuclein in presynaptic terminals. Here, we report that ß-synuclein partitions into α-synuclein condensates promotes the LLPS, and slows down LSPS of α-synuclein, while disease-associated ß-synuclein mutations lose these capacities. Exogenous ß-synuclein improves the movement defects and prolongs the lifespan of an α-synuclein-expressing NL5901 Caenorhabditis elegans strain, while disease-associated ß-synuclein mutants aggravate the symptoms. Decapeptides targeted at the α-/ß-synuclein interaction sites are rationally designed, which suppress the LSPS of α-synuclein, rescue the movement defects, and prolong the lifespan of C. elegans NL5901. Together, we unveil a Yin-Yang balance between α- and ß-synuclein underlying the normal and disease states of PD and DLB with therapeutical potentials.

A renal YY1-KIM1-DR5 axis regulates the progression of acute kidney injury.

Acute kidney injury (AKI) exhibits high morbidity and mortality. Kidney injury molecule-1 (KIM1) is dramatically upregulated in renal tubules upon injury, and acts as a biomarker for various renal diseases. However, the exact role and underlying mechanism of KIM1 in the progression of AKI remain elusive. Herein, we report that renal tubular specific knockout of Kim1 attenuates cisplatin- or ischemia/reperfusion-induced AKI in male mice. Mechanistically, transcription factor Yin Yang 1 (YY1), which is downregulated upon AKI, binds to the promoter of KIM1 and represses its expression. Injury-induced KIM1 binds to the ECD domain of death receptor 5 (DR5), which activates DR5 and the following caspase cascade by promoting its multimerization, thus induces renal cell apoptosis and exacerbates AKI. Blocking the KIM1-DR5 interaction with rationally designed peptides exhibit reno-protective effects against AKI. Here, we reveal a YY1-KIM1-DR5 axis in the progression of AKI, which warrants future exploration as therapeutic targets.

Nano-based approaches in the development of antiviral agents and vaccines.

Outbreaks and the rapid transmission of viruses, such as coronaviruses and influenza viruses, are serious threats to human health. A major challenge in combating infectious diseases caused by viruses is the lack of effective methods for prevention and treatment. Nanotechnology has provided a basis for the development of novel antiviral strategies. Owing to their large modifiable surfaces that can be functionalized with multiple molecules to realize sophisticated designs, nanomaterials have been developed as nanodrugs, nanocarriers, and nano-based vaccines to effectively induce sufficient immunologic memory. From this perspective, we introduce various nanomaterials with diverse antiviral mechanisms and summarize how nano-based antiviral agents protect against viral infection at the molecular, cellular, and organismal levels. We summarize the applications of nanomaterials for defense against emerging viruses by trapping and inactivating viruses and inhibiting viral entry and replication. We also discuss recent progress in nano-based vaccines with a focus on the mechanisms by which nanomaterials contribute to immunogenicity. We further describe how nanotechnology may improve vaccine efficacy by delivering large amounts of antigens to target immune cells and enhancing the immune response by mimicking viral structures and activating dendritic cells. Finally, we provide an overview of future prospects for nano-based antiviral agents and vaccines.

A Systematic Screening of Traditional Chinese Medicine Identifies Two Novel Inhibitors Against the Cytotoxic Aggregation of Amyloid Beta.

The toxic aggregates of amyloid beta (Aß) disrupt the cell membrane, induce oxidative stress and mitochondrial dysfunction, and eventually lead to Alzheimer's disease (AD). Intervening with this cytotoxic aggregation process has been suggested as a potential therapeutic approach for AD and other protein misfolding diseases. Traditional Chinese Medicine (TCM) has been used to treat AD and related cognitive impairment for centuries with obvious efficacy. Extracts or active ingredients of TCMs have been reported to inhibit the aggregation and cytotoxicity of Aß. However, there is a lack of systematic research on the anti-Aß aggregation effects of TCM components. In this study, we performed a systematic screening to identify the active ingredients of TCM against the cytotoxic aggregation of Aß42. Through a literature and database survey, we selected 19 TCM herbals frequently used in the treatment of AD, from which 76 major active chemicals without known anti-amyloid effects were further screened. This took place through two rounds of MTT-based screening detection of the cytotoxicity of these chemicals and their effects on Aß42-induced cytotoxicity, respectively. Tetrahydroxystilbene-2-O-ß-D-glucoside (TSG) and sinapic acid (SA) were found to be less toxic, and they inhibited the cytotoxicity of Aß42. Further studies demonstrated that TSG and SA concentration-dependently attenuated the amyloidosis and membrane disruption ability of Aß42. Thus, we identified two novel chemicals (TSG and SA) against the cytotoxic aggregation of Aß42. Nonetheless, further exploration of their therapeutic potential is warranted.

Non-polyphenolic natural inhibitors of amyloid aggregation.

Protein misfolding diseases (PMDs) are chronic and progressive, with no effective therapy so far. Aggregation and misfolding of amyloidogenic proteins are closely associated with the onset and progression of PMDs, such as amyloid-ß (Aß) in Alzheimer's disease, α-Synuclein (α-Syn) in Parkinson's disease and human islet amyloid polypeptide (hIAPP) in type 2 diabetes. Inhibiting toxic aggregation of amyloidogenic proteins is regarded as a promising therapeutic approach in PMDs. The past decade has witnessed the rapid progresses of this field, dozens of inhibitors have been screened and verified in vitro and in vivo, demonstrating inhibitory effects against the aggregation and misfolding of amyloidogenic proteins, together with beneficial effects. Natural products are major sources of small molecule amyloid inhibitors, a number of natural derived compounds have been identified with great bioactivities and translational prospects. Here, we review the non-polyphenolic natural inhibitors that potentially applicable for PMDs treatment, along with their working mechanisms. Future directions are proposed for the development and clinical applications of these inhibitors.