Dysbiosis of the gut microbiota and its effect on α-synuclein and prion protein misfolding: consequences for neurodegeneration.

Abnormal behavior of α-synuclein and prion proteins is the hallmark of Parkinson's disease (PD) and prion illnesses, respectively, being complex neurological disorders. A primary cause of protein aggregation, brain injury, and cognitive loss in prion illnesses is the misfolding of normal cellular prion proteins (PrPC) into an infectious form (PrPSc). Aggregation of α-synuclein causes disruptions in cellular processes in Parkinson's disease (PD), leading to loss of dopamine-producing neurons and motor symptoms. Alteration in the composition or activity of gut microbes may weaken the intestinal barrier and make it possible for prions to go from the gut to the brain. The gut-brain axis is linked to neuroinflammation; the metabolites produced by the gut microbiota affect the aggregation of α-synuclein, regulate inflammation and immunological responses, and may influence the course of the disease and neurotoxicity of proteins, even if their primary targets are distinct proteins. This thorough analysis explores the complex interactions that exist between the gut microbiota and neurodegenerative illnesses, particularly Parkinson's disease (PD) and prion disorders. The involvement of the gut microbiota, a complex collection of bacteria, archaea, fungi, viruses etc., in various neurological illnesses is becoming increasingly recognized. The gut microbiome influences neuroinflammation, neurotransmitter synthesis, mitochondrial function, and intestinal barrier integrity through the gut-brain axis, which contributes to the development and progression of disease. The review delves into the molecular mechanisms that underlie these relationships, emphasizing the effects of microbial metabolites such as bacterial lipopolysaccharides (LPS), and short-chain fatty acids (SCFAs) in regulating brain functioning. Additionally, it looks at how environmental influences and dietary decisions affect the gut microbiome and whether they could be risk factors for neurodegenerative illnesses. This study concludes by highlighting the critical role that the gut microbiota plays in the development of Parkinson's disease (PD) and prion disease. It also provides a promising direction for future research and possible treatment approaches. People afflicted by these difficult ailments may find hope in new preventive and therapeutic approaches if the role of the gut microbiota in these diseases is better understood.

Identification of Muscle Strength-Related Gut Microbes through Human Fecal Microbiome Transplantation.

The gut microbiome is well known for its influence on human physiology and aging. Therefore, we speculate that the gut microbiome may affect muscle strength in the same way as the host's own genes. To demonstrate candidates for gut microbes affecting muscle strength, we remodeled the original gut microbiome of mice into human intestinal microbiome through fecal microbiome transplantation (FMT), using human feces and compared the changes in muscle strength in the same mice before and three months after FMT. After comparing before and after FMT, the mice were divided into three groups based on the observed changes in muscle strength: positive, none, and negative changes in muscle strength. As a result of analyzing the α-diversity, ß-diversity, and co-occurrence network of the intestinal microbial community before and after FMT, it was observed that a more diverse intestinal microbial community was established after FMT in all groups. In particular, the group with increased muscle strength had more gut microbiome species and communities than the other groups. Fold-change comparison showed that Eisenbergiella massiliensis and Anaeroplasma abactoclasticum from the gut microbiome had positive contributions to muscle strength, while Ileibacterium valens and Ethanoligenens harbinense had negative effects. This study identifies candidates for the gut microbiome that contribute positively and those that contribute negatively to muscle strength.

Nectandrin B significantly increases the lifespan of Drosophila - Nectandrin B for longevity.

Phytochemicals are increasingly recognized in the field of healthy aging as potential therapeutics against various aging-related diseases. Nutmeg, derived from the Myristica fragrans tree, is an example. Nutmeg has been extensively studied and proven to possess antioxidant properties that protect against aging and alleviate serious diseases such as cancer, heart disease, and liver disease. However, the specific active ingredient in nutmeg responsible for these health benefits has not been identified thus far. In this study, we present evidence that Nectandrin B (NecB), a bioactive lignan compound isolated from nutmeg, significantly extended the lifespan of the fruit fly Drosophila melanogaster by as much as 42.6% compared to the control group. NecB also improved age-related symptoms including locomotive deterioration, body weight gain, eye degeneration, and neurodegeneration in aging D. melanogaster. This result represents the most substantial improvement in lifespan observed in animal experiments to date, suggesting that NecB may hold promise as a potential therapeutic agent for promoting longevity and addressing age-related degeneration.

Oral delivery of a host-directed antiviral, niclosamide, as a cholate-coated nanoformulation.

Potentially significant drug candidates often face elimination from consideration due to the lack of an effective method for systemic delivery. The poor solubility of these candidates has posed a major obstacle for their development as oral pills or injectables. Niclosamide, a host-directed antiviral, is a good example. In this study, a nanoformulation technology that allows for the non-covalent formulation of niclosamide with cholic acids was developed. This formulation enables efficient systemic delivery through endocytosis and enterohepatic circulation of bile-acid-coated nanoparticles. The oral bioavailability of niclosamide-delivery nanoparticles (NDNs) was significantly enhanced to 38.3%, representing an eight-fold increase compared with pure niclosamide. Consequently, the plasma concentration of niclosamide for the NDN formulation reached 1179.6 ng/mL, which is 11 times higher than the therapeutic plasma level. This substantial increase in plasma level contributed to the complete resolution of clinical symptoms in animals infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). This nanoformulation not only provides an orally deliverable antiviral drug for SARS-CoV-2 with improved pharmaceutical bioavailability, but also offers a solution to the systemic delivery challenges faced by potentially significant drug candidates.

In Vivo, In Vitro and In Silico Study of Cucurbita moschata Flower Extract: A Promising Source of Natural Analgesic, Anti-Inflammatory, and Antibacterial Agents.

For thousands of years, medicinal plants have played a pivotal role in maintaining human health and improving the quality of human life. This study was designed to analyze the analgesic, anti-inflammatory, and antibacterial potentials of a hydro-methanolic extract of Cucurbita moschata flowers, along with qualitative and quantitative phytochemical screening. The anti-inflammatory effect was tested using the in vitro membrane stabilizing method for human red blood cells (HRBC), the analgesic effect was tested using the in vivo acetic acid-induced writing method, and the antibacterial effect was tested using the disc diffusion method. In silico ADME/T and molecular docking studies were performed to assess the potential of the stated phytochemicals against Cyclooxygenase-II enzyme. Phytochemical screening confirmed the presence of flavonoids, alkaloids, glycosides, tannins, and carbohydrates. The flower extract demonstrated the maximum protection of human red blood cells at 1000 µg/mL, with a 65.73% reduction in hemolysis in a hypotonic solution. The extract also showed significant (p < 0.05) and dose-dependent analgesic effects at oral doses of 200 and 400 mg/kg on the tested animals. Furthermore, the flower extract exhibited potent antibacterial activity due to the disc diffusion method, which was compared with standard ciprofloxacin. In silico testing revealed that 42 phytochemicals exhibited notable pharmacokinetic properties and passed drug likeness screening tests. Among the six best-selected compounds, 3,4-dihydro-2H-pyran-2-yl)methanamine showed the highest binding affinity (-10.1) with significant non-bonding interactions with the target enzyme. In conclusion, the hydro-methanolic extract of Cucurbita moschata was found to be rich in various phytochemicals that may be associated with therapeutic potential, and this study supports the traditional use of Cucurbita moschata flowers in the management of inflammation and painful conditions.

Identification of the Intestinal Microbes Associated with Locomotion.

Given the impact of the gut microbiome on human physiology and aging, it is possible that the gut microbiome may affect locomotion in the same way as the host's own genes. There is not yet any direct evidence linking the gut microbiome to locomotion, though there are some potential connections, such as regular physical activity and the immune system. In this study, we demonstrate that the gut microbiome can contribute differently to locomotion. We remodeled the original gut microbiome of mice through fecal microbiota transplantation (FMT) using human feces and compared the changes in locomotion of the same mice before and three months after FMT. We found that FMT affected locomotion in three different ways: positive, none (the same), and negative. Analysis of the phylogenesis, α-diversities, and ß-diversities of the gut microbiome in the three groups showed that a more diverse group of intestinal microbes was established after FMT in each of the three groups, indicating that the human gut microbiome is more diverse than that of mice. The FMT-remodeled gut microbiome in each group was also different from each other. Fold change and linear correlation analyses identified Lacrimispora indolis, Pseudoflavonifractor phocaeensis, and Alistipes senegalensis in the gut microbiome as positive contributors to locomotion, while Sphingobacterium cibi, Prevotellamassilia timonensis, Parasutterella excrementihominis, Faecalibaculum rodentium, and Muribaculum intestinale were found to have negative effects. This study not only confirms the presence of gut microbiomes that contribute differently to locomotion, but also explains the mixed results in research on the association between the gut microbiome and locomotion.

Machilin D Promotes Apoptosis and Autophagy, and Inhibits Necroptosis in Human Oral Squamous Cell Carcinoma Cells.

Oral squamous cell carcinoma (OSCC) accounts for about 90% of all head and neck cancers, the prognosis is very poor, and there are no effective targeted therapies. Herein, we isolated Machilin D (Mach), a lignin, from the roots of Saururus chinensis (S. chinensis) and assessed its inhibitory effects on OSCC. Herein, Mach had significant cytotoxicity against human OSCC cells and showed inhibitory effects against cell adhesion, migration, and invasion by inhibiting adhesion molecules, including the FAK/Src pathway. Mach suppressed the PI3K/AKT/mTOR/p70S6K pathway and MAPKs, leading to apoptotic cell death. We investigated other modes of programmed cell death in these cells and found that Mach increased LC3I/II and Beclin1 and decreased p62, leading to autophagosomes, and suppressed the necroptosis-regulatory proteins RIP1 and MLKL. Our findings provide evidence that the inhibitory effects of Mach against human YD-10B OSCC cells are related to the promotion of apoptosis and autophagy and inhibition of necroptosis and are mediated via focal adhesion molecules.

Role of Gut Microbiome in Autism Spectrum Disorder and Its Therapeutic Regulation.

Autism spectrum disorder (ASD) is a neurological disorder that affects normal brain development. The recent finding of the microbiota-gut-brain axis indicates the bidirectional connection between our gut and brain, demonstrating that gut microbiota can influence many neurological disorders such as autism. Most autistic patients suffer from gastrointestinal (GI) symptoms. Many studies have shown that early colonization, mode of delivery, and antibiotic usage significantly affect the gut microbiome and the onset of autism. Microbial fermentation of plant-based fiber can produce different types of short-chain fatty acid (SCFA) that may have a beneficial or detrimental effect on the gut and neurological development of autistic patients. Several comprehensive studies of the gut microbiome and microbiota-gut-brain axis help to understand the mechanism that leads to the onset of neurological disorders and find possible treatments for autism. This review integrates the findings of recent years on the gut microbiota and ASD association, mainly focusing on the characterization of specific microbiota that leads to ASD and addressing potential therapeutic interventions to restore a healthy balance of gut microbiome composition that can treat autism-associated symptoms.

Biological Functions of Dillenia pentagyna Roxb. Against Pain, Inflammation, Fever, Diarrhea, and Thrombosis: Evidenced From in vitro, in vivo, and Molecular Docking Study.

Dillenia pentagyna Roxb. is traditionally used to treat cancer, wound healing, diabetes, and diarrhea in local tribes. This study was designed to evaluate the pharmacological potentiality of this plant. In vivo analgesic, anti-inflammatory, and antipyretic studies of the methanol extracts of D. pentagyna (MEDP) leaves were performed by using acetic acid-induced nociception, formalin-induced paw licking, and yeast-induced pyrexia assay methods, respectively. In vivo antidiarrheal activity was carried out in mice by following castor oil-induced diarrhea and gastrointestinal transit manner. In vitro thrombolytic experiment was performed employing the clot lysis activity. Besides, a molecular docking study was performed by executing the software (PyRx, Discovery Studio, and UCSF Chimera). In the acetic acid-induced writhing study, MEDP possesses significant writhing inhibition in a dose-dependent manner. It showed 50.86% of maximum inhibition of pain in the case of MEDP at a dose of 400 mg/kg body weight. In the anti-inflammatory study, maximum inhibition rate was observed at a value of 59.98 and 41.29% in early and late phases, respectively, at the dose of 400 mg/kg body weight. In the case of yeast-induced hyperpyrexia, MEDP reduced hyperpyrexia in a dose-dependent manner. In the antidiarrheal assay, MEDP moderately inhibited the occurrence of diarrhea in all the experiments. In the thrombolytic study, a moderate (17.76%) clot lysis potency has been yielded by MEDP. Again, the molecular docking simulation revealed strong binding affinities with almost all the targeted proteins. The present study suggests that the MEDP possesses remarkable pharmacological activity and this finding validated the ethnobotanical significance of D. pentagyna as the source of pain, fever, and diarrhea management agent.

Chemico-Pharmacological Screening of the Methanol Extract of Gynura nepalensis D.C. Deciphered Promising Antioxidant and Hepatoprotective Potentials: Evidenced from in vitro, in vivo, and Computer-Aided Studies.

Gynura nepalensis D.C. (family: Asteraceae) has abundant uses in the alternative medicinal practice, and this species is commonly used in the treatment of diabetes, rheumatism, cuts or wounds, asthma, kidney stones, cough, urinary tract bleeding, gall bladder stones, hepatitis, diarrhea, hemorrhoids, constipation, vomiting, fertility problems, blood poisoning, septicemia, skin allergy, indigestion, high cholesterol levels, and so on. This study aims to investigate the hepatoprotective and antioxidant potential of the methanol extract of the Gynura nepalensis D.C. (GNME) along with chemical profiling with phytochemical screening. Moreover, prospective phytocompounds have been screened virtually to present the binding affinity of the bioactive components to the hepatic and oxidative receptors. In the hepatoprotective study, alanine transaminase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total protein (TP), and lipid peroxidation (LP) and total bilirubin (TB) have been assessed, and in the antioxidant study, the DPPH free radical scavenging, total antioxidant flavonoid, and phenolic contents were determined. Moreover, the molecular binding affinity of the bioactive component of the plant has been analyzed using PyRx AutoDock Vina, Chimera, and Discovery Studio software. The plant extract showed dose-dependent hepatoprotective potential (p < 0.05, 0.01, 0.001) as well as strong antioxidant properties. Moreover, hepatoprotective and antioxidant molecular docking studies revealed a result varying from −2.90 kcal/mol to −10.1 kcal/mol. 4,5-dicaffeoylquinic acid and chlorogenic acid revealed the highest binding affinity among the selected molecules. However, the plant showed portent antioxidant and hepatoprotective properties in the in vitro, in vivo, and in silico models, and it is presumed that the hepatoprotective properties of the plant extract have occurred due to the presence of the vast bioactive chemical compounds as well as their antioxidant properties. Therefore, advanced studies are recommended to elucidate the pharmacological properties of the plant extracts.

Comparative Analysis of Original and Replaced Gut Microbiomes within Same Individuals Identified the Intestinal Microbes Associated with Weight Gaining.

The precise mechanisms of action of the host's gut microbiome at the level of its constituting bacteria are obscure in most cases despite its definitive role. To study the precise role of the gut microbiome on the phenotypes of a host by excluding host factors, we analyzed two different gut microbiomes within the same individual mouse after replacing the gut microbiome with a new one to exclude the host factors. The gut microbiome of conventional C57BL/6 mice was randomly reestablished by feeding fecal samples from obese humans to the mice, and depleting their original gut microbiome with an antibiotic and antifungal treatment. Comparison of body weight changes before and 3 months after the replacement of the gut microbiome showed that the gut microbiome replacement affected the body weight gain in three different ways: positive, medium, and negative. The differences in body weight gain were associated with establishment of a different kind of gut microbiome in each of the mice. In addition, body weight gaining was negatively associated with the Firmicutes/Bacteroidetes ratio, which is consistent with previous recent findings. Thorough statistical analysis at low taxonomic levels showed that uncultured bacteria NR_074436.1, NR_144750.1, and NR_0421101.1 were positively associated with body weight gain, while Trichinella pseudospiralis and uncultured bacteria NR_024815.1 and NR_144616.1 were negatively associated. This work shows that replacement of the gut microbiome within the same individual provides an excellent opportunity for the purpose of gut microbiome analysis by excluding the host factors.

Chemical, Pharmacological and Computerized Molecular Analysis of Stem's Extracts of Bauhinia scandens L. Provide Insights into the Management of Diarrheal and Microbial Infections.

Bauhinia scandens L. (Family: Fabaceae) is commonly used to treat cholera, diarrhea, asthma, and diabetes disorder in integrative medicine. This study aimed to screen the presence of phytochemicals (preliminary and UPLC-QTOF-M.S. analysis) and to examine the pharmacological activities of Bauhinia scandens L. stems (MEBS) stem extracts. Besides, in silico study was also implemented to elucidate the binding affinity and drug capability of the selected phytochemicals. In vivo anti diarrheal activity was investigated in mice models. In vitro, antibacterial and antifungal properties of MEBS against several pathogenic strains were evaluated using the disc diffusion method. In addition, in silico study has been employed using Discovery studio 2020, UCFS Chimera, PyRx autodock vina, and online tools. In the anti-diarrheal investigation, MEBS showed a significant dose-dependent inhibition rate in all three methods. The antibacterial and antifungal screening showed a remarkable zone of inhibition, of the diameter 14-26 mm and 12-28 mm, by MEBS. The present study revealed that MEBS has remarkable anti-diarrheal potential and is highly effective in wide-spectrum bacterial and fungal strains. Moreover, the in silico study validated the results of biological screenings. To conclude, MEBS is presumed to be a good source in treating diarrhea, bacterial and fungal infections.

Host Factors Affect the Gut Microbiome More Significantly than Diet Shift.

The determining factors of the composition of the gut microbiome are one of the main interests in current science. In this work, we compared the effect of diet shift (DS) from heavily relying on meatatarian diets to vegetarian diets and physical exercise (EX) on the composition of the gut microbiome after 3 months. Although both DS and EX affected the composition of the gut microbiome, the patterns of alteration were different. The α-diversity analyzed by InvSimpson, Shannon, Simpson, and Evenness showed that both EX and DS affected the microbiome, causing it to become more diverse, but EX affected the gut microbiome more significantly than DS. The ß-diversity analyses indicated that EX and DS modified the gut microbiome in two different directions. Co-occurrence network analysis confirmed that both EX and DS modified the gut microbiome in different directions, although EX modified the gut microbiome more significantly. Most notably, the abundance of Dialister succinatiphilus was upregulated by EX, and the abundances of Bacteroides fragilis, Phascolarctobacterium faecium, and Megasphaera elsdenii were downregulated by both EX and DS. Overall, EX modulated the composition of the gut microbiome more significantly than DS, meaning that host factors are more important in determining the gut microbiome than diets. This work also provides a new theoretical basis for why physical exercise is more health-beneficial than vegetarian diets.

Roborovski hamster (Phodopus roborovskii) strain SH101 as a systemic infection model of SARS-CoV-2.

Severe acute respiratory syndrome CoV-2 (SARS-CoV-2) is currently causing a worldwide threat with its unusually high transmission rates and rapid evolution into diverse strains. Unlike typical respiratory viruses, SARS-CoV-2 frequently causes systemic infection by breaking the boundaries of the respiratory systems. The development of animal models recapitulating the clinical manifestations of COVID-19 is of utmost importance not only for the development of vaccines and antivirals but also for understanding the pathogenesis. However, there has not been developed an animal model for systemic infection of SARS-CoV-2 representing most aspects of the clinical manifestations of COVID-19 with systemic symptoms. Here we report that a Roborovski hamster strain SH101, a laboratory inbred hamster strain of P. roborovskii, displayed most symptoms of systemic infection upon SARS-CoV-2 infection as in the case of the human counterpart, unlike current COVID-19 animal models. Roborovski hamster strain SH101 post-infection of SARS-CoV-2 represented most clinical symptoms of COVID-19 such as snuffling, labored breathing, dyspnea, cough, hunched posture, progressive weight loss, ruffled fur, and high fever following shaking chills. Histological examinations also revealed initial right-predominated pneumonia as well as slight organ damages in the brain and liver, manifesting systemic COVID-19 cases. Considering the merit of a small animal as well as its clinical manifestations of SARS-CoV-2 infection in human, this hamster model seems to provide an ideal tool to investigate COVID-19.

Mitochondrial Targeting Domain Homologs Induce Necrotic Cell Death Via Mitochondrial and Endoplasmic Reticulum Disruption.

The mitochondrial targeting domain (MTD) of Noxa contributes to its mitochondrial localization and to apoptosis induction. As a peptide, MTD fused with octa-arginine (R8), a CPP, induces necrosis related to intracellular calcium influx and destruction of mitochondria and endoplasmic reticulum. We searched for homologs of MTD, and compared their cell killing capability when fused with R8. Three of the seven peptides triggered cell death with similar mechanisms. The comparative analysis of peptide sequences showed that four amino acid sites of MTD are critical in regulating necrosis, suggesting the potential to generate artificial, adjustable cytotoxic peptides, which could be effective medicines for many diseases. Thus, homologs functionality could hint to the functions of their belonging proteins.

The regional diversity of gut microbiome along the GI tract of male C57BL/6 mice.

BACKGROUND: The proliferation and survival of microbial organisms including intestinal microbes are determined by their surrounding environments. Contrary to popular myth, the nutritional and chemical compositions, water contents, O2 contents, temperatures, and pH in the gastrointestinal (GI) tract of a human are very different in a location-specific manner, implying heterogeneity of the microbial composition in a location-specific manner. RESULTS: We first investigated the environmental conditions at 6 different locations along the GI tract and feces of ten weeks' old male SPF C57BL/6 mice. As previously known, the pH and water contents of the GI contents at the different locations of the GI tract were very different from each other in a location-specific manner, and none of which were not even similar to those of feces. After confirming the heterogeneous nature of the GI contents in specific locations and feces, we thoroughly analyzed the composition of the microbiome of the GI contents and feces. 16S rDNA-based metagenome sequencing on the GI contents and feces showed the presence of 13 different phyla. The abundance of Firmicutes gradually decreased from the stomach to feces while the abundance of Bacteroidetes gradually increased. The taxonomic α-diversities measured by ACE (Abundance-based Coverage Estimator) richness, Shannon diversity, and Fisher's alpha all indicated that the diversities of gut microbiome at colon and cecum were much higher than that of feces. The diversities of microbiome compositions were lowest in jejunum and ileum while highest in cecum and colon. Interestingly, the diversities of the fecal microbiome were lower than those of the cecum and colon. Beta diversity analyses by NMDS plots, PCA, and unsupervised hierarchical clustering all showed that the microbiome compositions were very diverse in a location-specific manner. Direct comparison of the fecal microbiome with the microbiome of the whole GI tracts by α-and ß-diversities showed that the fecal microbiome did not represent the microbiome of the whole GI tract. CONCLUSION: The fecal microbiome is different from the whole microbiome of the GI tract, contrary to a baseline assumption of contemporary microbiome research work.

Enhanced Antibacterial Property of Sulfate-Doped Ag3PO4 Nanoparticles Supported on PAN Electrospun Nanofibers.

Heterojunction nanofibers of PAN decorated with sulfate doped Ag3PO4 nanoparticles (SO42--Ag3PO4/PAN electrospun nanofibers) were successfully fabricated by combining simple and versatile electrospinning technique with ion exchange reaction. The novel material possessing good flexibility could exhibit superior antibacterial property over sulfate undoped species (Ag3PO4/PAN electrospun nanofibers). FESEM, XRD, FTIR, XPS and DRS were applied to characterize the morphology, phase structure, bonding configuration, elemental composition, and optical properties of the as fabricated samples. FESEM characterization confirmed the successful incorporation of SO42--Ag3PO4 nanoparticles on PAN electrospun nanofibers. The doping of SO42- ions into Ag3PO4 crystal lattice by replacing PO43- ions can provide sufficient electron-hole separation capability to the SO42--Ag3PO4/PAN heterojunction to generate reactive oxygen species (ROS) under visible light irradiation and enhances its antibacterial performance. Finally, we hope this work may offer a new paradigm to design and fabricate other types of flexible self-supporting negative-ions-doped heterojunction nanofibers using electrospinning technique for bactericidal applications.

The function of bacterial HtrA is evolutionally conserved in mammalian HtrA2/Omi.

Although the malfunction of HtrA2/Omi leads to Parkinson's disease (PD), the underlying mechanism has remained unknown. Here, we showed that HtrA2/Omi specifically removed oligomeric α-Syn but not monomeric α-Syn to protect oligomeric α-Syn-induced neurodegeneration. Experiments using mnd2 mice indicated that HtrA2/Omi degraded oligomeric α-Syn specifically without affecting monomers. Transgenic Drosophila melanogaster experiments of the co-expression α-Syn and HtrA2/Omi and expression of genes individually also confirmed that pan-neuronal expression of HtrA2/Omi completely rescued Parkinsonism in the α-Syn-induced PD Drosophila model by specifically removing oligomeric α-Syn. HtrA2/Omi maintained the health and integrity of the brain and extended the life span of transgenic flies. Because HtrA2/Omi specifically degraded oligomeric α-Syn, co-expression of HtrA2/Omi and α-Syn in Drosophila eye maintained a healthy retina, while the expression of α-Syn induced retinal degeneration. This work showed that the bacterial function of HtrA to degrade toxic misfolded proteins is evolutionarily conserved in mammalian brains as HtrA2/Omi.

Tumor-specific delivery of a paclitaxel-loading HSA-haemin nanoparticle for cancer treatment.

A cancer-targeted chemotherapy could potentially eradicate cancers if anticancer drugs are delivered precisely to the cancers. Although various types of nanoparticles have been developed for cancer-specific delivery of anticancer drugs, the drug delivery capabilities of these nanoparticles were not specific enough to eradicate cancer. Here, we developed a targeting-enhancing nanoparticle of paclitaxel, in which paclitaxel was encapsulated with a human serum albumin-haemin complex through non-covalent bonding. The average diameter of TENPA was approximately 140 nm with a zeta potential of +29 mV. TENPA maintained its structural integrity and stability without forming protein coronas in the blood for optimal passive targeting. These characteristics of TENPA resulted in paclitaxel accumulation that was 4.1 times greater than that of Abraxane, an albumin-bound paclitaxel, in cancer tissue. The dramatic improvement in cancer targeting of TENPA led to reduced systemic toxicity of paclitaxel and eradication of end-stage cancer in a xenografted mouse experiment.

Neuroprotective function of Omi to α-synuclein-induced neurotoxicity.

The main pathological hallmark of Parkinson's disease (PD) is the presence of Lewy bodies, which mainly consist of aggregated α-synuclein. Based on the neurotoxicity of oligomeric α-synuclein and its significance in the aetiology of PD, there has been decades of effort to elucidate an enzyme specifically degrading oligomeric α-synuclein. Here we report an enzyme, Omi, which specifically recognizes and precisely degrades oligomeric α-synuclein but not monomeric α-synuclein. After enzymatic and functional analyses of Omi in in vitro, we developed an in vivo assay system of dual gene interaction in Drosophila to investigate further the etiological role of Omi in PD. Pan-neuronal expression of Omi rescued Parkinsonism in a Drosophila model of PD, while Knockout of Omi exacerbated Parkinsonism. Expression of Omi counteracted the α-synuclein-induced retinal degeneration, providing additional evidence for Omi's protective role oligomeric α-synuclein. This work reports identification of the catabolic pathway of oligomeric α-synuclein as well as showing how Omi functions as the key molecule in the recognition and degradation of toxic oligomeric α-synuclein, a possible cause of neurodegeneration in PD, without affecting monomeric α-synuclein which is a native essential molecule for the normal function of neurons.