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Presenilin-1 (PSEN1) has been verified as an important causative factor for early onset Alzheimer’s disease (EOAD). PSEN1 is a part of γ-secretase, and in addition to amyloid precursor protein (APP) cleavage, it can also affect other processes, such as Notch signaling, β-cadherin processing, and calcium metabolism. Several motifs and residues have been identified in PSEN1, which may play a significant role in γ-secretase mechanisms, such as the WNF, GxGD, and PALP motifs. More than 300 mutations have been described in PSEN1; however, the clinical phenotypes related to these mutations may be diverse. In addition to classical EOAD, patients with PSEN1 mutations regularly present with atypical phenotypic symptoms, such as spasticity, seizures, and visual impairment. In vivo and in vitro studies were performed to verify the effect of PSEN1 mutations on EOAD. The pathogenic nature of PSEN1 mutations can be categorized according to the ACMG-AMP guidelines; however, some mutations could not be categorized because they were detected only in a single case, and their presence could not be confirmed in family members. Genetic modifiers, therefore, may play a critical role in the age of disease onset and clinical phenotypes of PSEN1 mutations. This review introduces the role of PSEN1 in γ-secretase, the clinical phenotypes related to its mutations, and possible significant residues of the protein.

Phytosterols constitute a class of natural products that are an important component of diet and have vast applications in foods, cosmetics, and herbal medicines. With many and diverse isolated structures in nature, they exhibit a broad range of biological and pharmacological activities. Among over 200 types of phytosterols, stigmasterol and β-sitosterol were ubiquitous in many plant species, exhibiting important aspects of activities related to neurodegenerative diseases. Hence, this mini-review presented an overview of the reported studies on selected phytosterols related to neurodegenerative diseases. It covered the major phytosterols based on biosynthetic considerations, including other phytosterols with significant in vitro and in vivo biological activities.

Presenilin 1 (PSEN1) is a part of the gamma secretase complex with several interacting substrates, including amyloid precursor protein (APP), Notch, adhesion proteins and beta catenin. PSEN1 has been extensively studied in neurodegeneration, and more than 300 PSEN1 mutations have been discovered to date. In addition to the classical early onset Alzheimer’s disease (EOAD) phenotypes, PSEN1 mutations were discovered in several atypical AD or non-AD phenotypes, such as frontotemporal dementia (FTD), Parkinson’s disease (PD), dementia with Lewy bodies (DLB) or spastic paraparesis (SP). For example, Leu113Pro, Leu226Phe, Met233Leu and an Arg352 duplication were discovered in patients with FTD, while Pro436Gln, Arg278Gln and Pro284Leu mutations were also reported in patients with motor dysfunctions. Interestingly, PSEN1 mutations may also impact non-neurodegenerative phenotypes, including PSEN1 Pro242fs, which could cause acne inversa, while Asp333Gly was reported in a family with dilated cardiomyopathy. The phenotypic diversity suggests that PSEN1 may be responsible for atypical disease phenotypes or types of disease other than AD. Taken together, neurodegenerative diseases such as AD, PD, DLB and FTD may share several common hallmarks (cognitive and motor impairment, associated with abnormal protein aggregates). These findings suggested that PSEN1 may interact with risk modifiers, which may result in alternative disease phenotypes such as DLB or FTD phenotypes, or through less-dominant amyloid pathways. Next-generation sequencing and/or biomarker analysis may be essential in clearly differentiating the possible disease phenotypes and pathways associated with non-AD phenotypes.

Alzheimer’s disease (AD) is the most common type of neurodegenerative dementia, but the cause of AD remained poorly understood. Many mutations in the amyloid precursor protein ( APP ) and presenilin 1 and 2 ( PSEN1 and PSEN2 ) have been reported as the pathogenic causes of early-onset AD (EOAD), which accounts for up to 5% of all AD cases. In this study, we screened familiar/ de novo EOAD (n = 67) samples by next-generation sequencing (NGS) of a 50-gene panel, which included causative and possible pathogenic variants linked to neurodegenerative disorders. Remarkably, three missense mutations in PSEN1 (T119I, G209A, and G417A) and one known variant in PSEN2 (H169N) were discovered in 6% of the cases. Additionally, 67 missense mutations in susceptibility genes for late-onset AD were identified, which may be involved in cholesterol transport, inflammatory response, and β-amyloid modulation. We identified 70 additional novel and missense variants in other genes, such as MAPT , GRN , CSF1R , and PRNP , related to neurodegenerative diseases, which may represent overlapping clinical and neuropathological features with AD. Extensive genetic screening of Korean patients with EOAD identified multiple rare variants with potential roles in AD pathogenesis. This study suggests that individuals diagnosed with AD should be screened for other neurodegenerative disease-associated genes. Our findings expand the classic set of genes involved in neurodegenerative pathogenesis, which should be screened for in clinical trials. Main limitation of this study was the absence of functional assessment for possibly and probably pathogenic variants. Additional issues were that we could not perform studies on copy number variants, and we could not verify the segregation of mutations.

Metformin is a biguanide widely prescribed as an antidiabetic drug for type 2 diabetes mellitus patients. The purpose of the present study was to observe the effects of the new metformin derivative, HL156A, on human oral cancer cell and to investigate its possible mechanisms. It was observed that HL156A significantly decreased FaDu and YD‐10B cell viability and colony formation in a dose‐dependent way. HL156A also markedly reduced wound closure and migration of FaDu and YD‐10B cells. We observed that HL156A decreased mitochondrial membrane potential and induced reactive oxygen species (ROS) levels and apoptotic cells with caspase‐3 and ‐9 activation. HL156A inhibited the expression and activation of insulin‐like growth factor (IGF)‐1 and its downstream proteins, AKT, mammalian target of rapamycin (mTOR), and ERK1/2. In addition, HL156A activated AMP‐activated protein kinase/nuclear factor kappa B (AMPK‐NF‐κB) signaling of FaDu and YD‐10B cells. A xenograft mouse model further showed that HL156A suppressed AT84 mouse oral tumor growth, accompanied by down‐regulated p‐IGF‐1, p‐mTOR, proliferating cell nuclear antigen (PCNA) and promoted p‐AMPK and TUNEL expression. These results suggest the potential value of the new metformin derivative HL156A as a candidate for a therapeutic modality for the treatment of oral cancer. We observed that HL156A decreased mitochondrial membrane potential and cell migration and increased the rate of apoptosis. The mechanism of HL156A activity appears to be dependent on regulation of cellular signaling, including IGF/AKT/mTOR and/or AMPK/NF‐κB pathways.

Skin aging occurs inevitably as a natural result of physiological changes over time. In particular, solar exposure of the skin accounts for up to 90% of skin damage. Numerous studies have examined the ability of dietary constituents to prevent skin aging, and recent research has emphasized the role of functional probiotics in intestinal function and skin aging. However, the mechanism of the interactions between aging and probiotics has not been elucidated yet. The aim of this study was to determine the role of exopolysaccharides (EPS) produced by lactic acid bacteria (LAB) identified as Lactobacillus plantarum HY7714 in regulating tight junctions in intestinal epithelial cells and increasing moisture retention in human dermal fibroblasts cells. We observed that HY7714 EPS controlled intestinal tight junctions in Caco-2 cells by upregulating the genes encoding occludin-1 (OCL-1) and zonula occluden-1 (ZO-1). In addition, HY7714 EPS effectively improved UVB-induced cytotoxicity and hydration capacity in HS68 cells by downregulating production of metalloproteinases (MMPs) and reactive oxygen species (ROS). In summary, HY7714 EPS is an effective anti-aging molecule in skin and may have therapeutic potential against skin diseases and UVB-induced damage. Therefore, HY7714 EPS serves as a functional substance in skin–gut axis communication.

TNF-α-induced protein 3 (TNFAIP3), commonly referred to as A20, is an integral part of the ubiquitin-editing complex that significantly influences immune regulation, apoptosis, and the initiation of diverse immune responses. The A20 protein is characterized by an N-terminal ovarian tumor (OTU) domain and a series of seven zinc finger (ZNF) domains. Mutations in the TNFAIP3 gene are implicated in various immune-related diseases, such as Behçet’s disease, polyarticular juvenile idiopathic arthritis, autoimmune thyroiditis, autoimmune hepatitis, and rheumatoid arthritis. These mutations can lead to a spectrum of symptoms, including, but not limited to, recurrent fever, ulcers, rashes, musculoskeletal and gastrointestinal dysfunctions, cardiovascular issues, and respiratory infections. The majority of these mutations are either nonsense (STOP codon) or frameshift mutations, which are typically associated with immune dysfunctions. Nonetheless, missense mutations have also been identified as contributors to these conditions. These genetic alterations may interfere with several biological pathways, notably abnormal NF-κB signaling and dysregulated ubiquitination. Currently, there is no definitive treatment for A20 haploinsufficiency; however, therapeutic strategies can alleviate the symptoms in patients. This review delves into the mutations reported in the TNFAIP3 gene, the clinical progression in affected individuals, potential disease mechanisms, and a brief overview of the available pharmacological interventions for A20 haploinsufficiency. Mandatory genetic testing of the TNFAIP3 gene should be performed in patients diagnosed with autoinflammatory disorders to better understand the genetic underpinnings and guide treatment decisions.

The present study investigated the neuroprotective potential of the Murraya carbazole derivatives murrayanol, mahanimbine, murrayafoline A, and 9-methyl-9H-carbazole-2-carbaldehyde using in silico and in vitro assays. The pharmacokinetic properties and potential toxicity (ADME/T) of the carbazole derivatives were assessed to evaluate their prospects as up-and-coming drug candidates. Molecular docking was used to investigate the interactions of the compounds with Aβ (PDB: 1IYT, 2BEG, and 8EZE) and AChE receptors (PDB: 4EY7 and 1C2B). The results from the in vitro assays were used to validate and support the findings from the in silico assays. The compounds demonstrated significant inhibition of acetylcholinesterase (AChE), a key target in neurodegenerative disorders. Murrayanol and mahanimbine presented superior inhibitory activity (IC50 ~0.2 μg/mL), outperforming the reference drug, galantamine. The inhibition mechanisms were competitive (murrayanol, murrayafoline A, and 9-methyl-9H-carbazole-2-carbaldehyde) and non-competitive (mahanimbine), supported by low Ki values and strong docking affinities. The compounds also proved effective in reducing Aβ fibrillization (murrayanol: 40.83 ± 0.30%; murrayafoline A: 33.60 ± 0.55%, mahanimbine: 27.68 ± 2.71%). These findings highlight Murraya carbazoles as promising scaffolds for multifunctional agents in AD therapy. Further optimization and mechanistic studies are warranted to advance their development into clinically relevant neuroprotective agents.

The common gardening herbicides and fertilizers are crucial for weed control and plant growth, yet they may have potentially harmful impacts on neurological health. This review explored the possible effects of these chemicals on neurodegenerative disorders, especially Alzheimer’s disease (AD) and Parkinson’s disease (PD). The mode of action of several frequently used gardening chemicals (paraquat, glyphosate, 2,4-dichlorophenoxyacetic acid: 2,4-D, and ammonium chloride) in AD and PD has been highlighted. The mechanisms involved are glutamate excitotoxicity, dopaminergic pathway disruption, oxidative stress, mitochondrial dysfunction, neuroinflammation, synaptic dysfunction, and gut–brain-axis dysregulation, crucial in the pathophysiology of AD and PD. Although the links between these substances and neurodegenerative conditions remained to be seen, growing evidence indicated their detrimental effects on brain health. This highlights the need for further research to understand their long-term consequences and develop effective interventions to mitigate the adverse effects of commonly used chemicals on human health and the environment.

Lorlatinib is a potent, brain-penetrant, third-generation tyrosine kinase inhibitor (TKI) that targets ALK and ROS1 with preclinical activity against most known resistance mutations in ALK and ROS1. We investigated the antitumour activity and safety of lorlatinib in advanced, ROS1-positive non-small-cell lung cancer (NSCLC). In this open-label, single-arm, phase 1–2 trial, we enrolled patients (aged ≥18 years) with histologically or cytologically confirmed advanced ROS1-positive NSCLC, with or without CNS metastases, with an Eastern Cooperative Oncology Group performance status of 2 or less (≤1 for phase 1 only) from 28 hospitals in 12 countries worldwide. Lorlatinib 100 mg once daily (escalating doses of 10 mg once daily to 100 mg twice daily in phase 1 only) was given orally in continuous 21-day cycles until investigator-determined disease progression, unacceptable toxicity, withdrawal of consent, or death. The primary endpoint was overall and intracranial tumour response, assessed by independent central review. Activity endpoints were assessed in patients who received at least one dose of lorlatinib. This study is ongoing and is registered with ClinicalTrials.gov, NCT01970865. Between Jan 22, 2014, and Oct 2, 2016, we assessed 364 patients, of whom 69 with ROS1-positive NSCLC were enrolled. 21 (30%) of 69 patients were TKI-naive, 40 (58%) had previously received crizotinib as their only TKI, and eight (12%) had previously received one non-crizotinib ROS1 TKI or two or more ROS1 TKIs. The estimated median duration of follow-up for response was 21·1 months (IQR 15·2–30·3). 13 (62%; 95% CI 38–82) of 21 TKI-naive patients and 14 (35%; 21–52) of 40 patients previously treated with crizotinib as their only TKI had an objective response. Intracranial responses were achieved in seven (64%; 95% CI 31–89) of 11 TKI-naive patients and 12 (50%; 29–71) of 24 previous crizotinib-only patients. The most common grade 3–4 treatment-related adverse events were hypertriglyceridaemia (13 [19%] of 69 patients) and hypercholesterolaemia (ten [14%]). Serious treatment-related adverse events occurred in five (7%) of 69 patients. No treatment-related deaths were reported. Lorlatinib showed clinical activity in patients with advanced ROS1-positive NSCLC, including those with CNS metastases and those previously treated with crizotinib. Because crizotinib-refractory patients have few treatment options, lorlatinib could represent an important next-line targeted agent. Pfizer.