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Talanta Aug 2024Enzyme handling and utilization bears many challenges such as their limited stability, intolerance of organic solvents, high cost, or inability to reuse. Most of these...
Enzyme handling and utilization bears many challenges such as their limited stability, intolerance of organic solvents, high cost, or inability to reuse. Most of these limitations can be overcome by enzyme immobilization on the surface of solid support. In this work, the recombinant form of human cholinesterases and monoamine oxidases as important drug targets for neurological diseases were immobilized on the surface of magnetic non-porous microparticles by a non-covalent bond utilizing the interaction between a His-tag terminus on the recombinant enzymes and cobalt (Co) ions immobilized on the magnetic microparticles. This type of binding led to targeted enzyme orientation, which completely preserved the catalytic activity and allowed high reproducibility of immobilization. In comparison with free enzymes, the immobilized enzymes showed exceptional stability in time and the possibility of repeated use. Relevant K, V, and IC values using known inhibitors were obtained using particular immobilized enzymes. Such immobilized enzymes on magnetic particles could serve as an excellent tool for a sustainable approach in the early stage of drug discovery.
Topics: Enzymes, Immobilized; Humans; Drug Discovery; Cobalt; Monoamine Oxidase; Nervous System Diseases; Acetylcholinesterase; Cost-Benefit Analysis; Recombinant Proteins; Enzyme Stability
PubMed: 38788378
DOI: 10.1016/j.talanta.2024.126263 -
Journal of the Neurological Sciences Jun 2024Safinamide is an effective adjunctive therapy for wearing-off in Parkinson's disease (PD); however, evidence is lacking in older patients and those in the early stages... (Observational Study)
Observational Study
BACKGROUND
Safinamide is an effective adjunctive therapy for wearing-off in Parkinson's disease (PD); however, evidence is lacking in older patients and those in the early stages of wearing-off. This study evaluated the efficacy and safety of safinamide as adjunctive therapy in patients with PD treated with levodopa monotherapy in clinical practice.
METHODS
This multicentre, open-label observational study was conducted at five sites in Japan. Patients diagnosed with PD and wearing-off initiated safinamide as adjunctive therapy with levodopa monotherapy. Efficacy endpoints were mean changes in Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part I, III, and IV scores; daily ON-time without dyskinesia using 24-h patient symptom diaries; and 39-item Parkinson's Disease Questionnaire (PDQ-39) scores at 18 weeks of treatment.
RESULTS
In total, 24 patients initiated safinamide (66.7% were aged ≥75 years); the mean duration of wearing-off was 1.2 years. MDS-UPDRS Part III total score, Part IV total score, and PDQ-39 summary index decreased significantly from baseline (mean change -7.0 [p = 0.012], -2.4 [p = 0.007] and - 5.3 [p = 0.012], respectively). There was a non-statistically significant increase of 1.55 h in mean daily ON-time without dyskinesia. Numerical Rating Scale total score for pain (p = 0.015), and scores for OFF-period pain (p = 0.012) and nocturnal pain (p = 0.021) subdomains were significantly improved in the subgroup with pain. Most reported adverse events were classified as mild.
CONCLUSION
Safinamide improved motor and non-motor symptoms and quality of life-related measures in older patients with PD in the early stages of wearing-off without new safety concerns.
STUDY REGISTRATION
University Hospital Medical Information Network in Japan; study ID: UMIN000044341.
Topics: Humans; Parkinson Disease; Male; Benzylamines; Female; Aged; Levodopa; Alanine; Japan; Antiparkinson Agents; Middle Aged; Treatment Outcome; Drug Therapy, Combination; Aged, 80 and over; Severity of Illness Index; East Asian People
PubMed: 38788287
DOI: 10.1016/j.jns.2024.123051 -
Molecular Biology Reports May 2024Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS) with inflammation and immune dysfunction. (Comparative Study)
Comparative Study
BACKGROUND
Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS) with inflammation and immune dysfunction.
OBJECTIVES
We compared the remyelination and immunomodulation properties of mesenchymal stem cells (MSCs) with their conditioned medium (CM) in the cuprizone model.
METHODS
Twenty-four C57BL/ 6 mice were divided into four groups. After cuprizone demyelination, MSCs and their CM were injected into the right lateral ventricle of mice. The expression level of IL-1β, TNF-α, and BDNF genes was evaluated using the qRT-PCR. APC antibody was used to assess the oligodendrocyte population using the immunofluorescent method. The remyelination and axonal repair were studied by specific staining of the LFB and electron microscopy techniques.
RESULTS
Transplantation of MSCs and CM increased the expression of the BDNF gene and decreased the expression of IL-1β and TNF-α genes compared to the cuprizone group, and these effects in the cell group were more than CM. Furthermore, cell transplantation resulted in a significant improvement in myelination and axonal repair, which was measured by luxol fast blue and transmission electron microscope images. The cell group had a higher number of oligodendrocytes than other groups.
CONCLUSIONS
According to the findings, injecting MSCs intraventricularly versus cell-conditioned medium can be a more effective approach to improving chronic demyelination in degenerative diseases like MS.
Topics: Animals; Cuprizone; Mesenchymal Stem Cell Transplantation; Mice; Mesenchymal Stem Cells; Demyelinating Diseases; Disease Models, Animal; Mice, Inbred C57BL; Culture Media, Conditioned; Inflammation; Brain-Derived Neurotrophic Factor; Interleukin-1beta; Oligodendroglia; Remyelination; Multiple Sclerosis; Tumor Necrosis Factor-alpha; Male; Myelin Sheath
PubMed: 38787497
DOI: 10.1007/s11033-024-09628-w -
Toxics May 2024In this study, a semi-static water exposure method was employed to investigate the early developmental and neurotoxic effects of four benzothiazole substances (BTHs),...
In this study, a semi-static water exposure method was employed to investigate the early developmental and neurotoxic effects of four benzothiazole substances (BTHs), namely benzothiazole (BTH), 2-mercaptobenzothiazole (MBT), 2-hydroxybenzothiazole (BTON), and 2-aminobenzothiazole (2-ABTH), on zebrafish at an equimolar concentration of 10 μM. The findings revealed that all four BTHs exerted certain impacts on early development in zebrafish. MBT stimulated spontaneous movement in juvenile zebrafish, whereas BTON inhibited such movements. Moreover, all four BTHs hindered the hatching process of zebrafish larvae, with MBT exhibiting the strongest inhibition at 24 h post-fertilization (hpf). Notably, MBT acted as a melanin inhibitor by suppressing melanin production in juvenile zebrafish eyes and weakening phototaxis. Additionally, both BTH and BTON exhibited significantly lower speeds than the control group and other test groups under conditions without bright field stimulation; however, their speeds increased to average levels after percussion stimulation, indicating no significant alteration in motor ability among experimental zebrafish groups. Short-term exposure to these four types of BTHs induced oxidative damage in zebrafish larvae; specifically, BTH-, MBT-, and BTON-exposed groups displayed abnormal expression patterns of genes related to oxidative damage. Exposure to both BTH and MBT led to reduced fluorescence intensity in transgenic zebrafish labeled with central nervous system markers, suggesting inhibition of central nervous system development. Furthermore, real-time quantitative PCR results demonstrated abnormal gene expression associated with neural development. However, no significant changes were observed in 2-ABTH gene expression at this concentration. Overall findings indicate that short-term exposure to BTHs stimulates neurodevelopmental gene expression accompanied by oxidative damage.
PubMed: 38787120
DOI: 10.3390/toxics12050341 -
BMC Pulmonary Medicine May 2024The incidence of checkpoint inhibitor-associated pneumonitis (CIP) in advanced non-small cell lung cancer (NSCLC) has been substantiated through large-scale clinical...
BACKGROUND
The incidence of checkpoint inhibitor-associated pneumonitis (CIP) in advanced non-small cell lung cancer (NSCLC) has been substantiated through large-scale clinical trials or real-world studies. However, reports on CIP incidence within the context of neoadjuvant immunotherapy for resectable NSCLC remain scarce. This study endeavors to investigate the incidence, risk factors, and outcomes of CIP in patients with resectable NSCLC receiving neoadjuvant immunochemotherapy.
METHODS
A retrospective, case-control study was conducted on patients diagnosed with NSCLC stages IIA-IIIB who received neoadjuvant immunochemotherapy between January 2018 and September 2022. Patients were stratified into two groups based on the presence or absence of CIP, facilitating a comparative analysis of clinical characteristics, treatment modalities, physiological indicators, and prognostic outcomes .
RESULTS
The study cohort comprised 245 patients, with 11.4% (28/245) experiencing CIP. The median period of CIP onset was 70 (range, 40-221) days. The incidence of severe CIP (grade 3-4) was 3.7% (9/245). Patients with CIP showed a higher all-cause mortality rate of 21.4% (6/28) compared to that of patients without CIP. Those who developed CIP exhibited elevated body mass index (BMI) values (p = 0.028) and increased fibrinogen (FIB) levels (p < 0.001), alongside a significant decrease in both diffusing capacity for carbon monoxide (DLCO)% pred (p = 0.001) and DLCO/VA% pred (p = 0.021) after neoadjuvant therapy compared to pre-indicators. Receiver operating characteristic curve (ROC) analysis showed that the area under the ROC curve of three assessed variables (FIB levels, BMI, DLCO) reached 0.806 in predicting CIP occurrence at an early stage.
CONCLUSIONS
This cohort demonstrated that elevated BMI, increased FIB levels, and decreased pulmonary diffusion function after neoadjuvant therapy are risk factors of CIP occurrence. Early assessment and continuous monitoring of these indicators are imperative for the predictive identification of CIP, enhancing patient management and outcomes.
Topics: Carcinoma, Non-Small-Cell Lung; Immune Checkpoint Inhibitors; Pneumonia; Neoadjuvant Therapy; Retrospective Studies; Case-Control Studies; Risk Factors; Humans; Male; Female; Middle Aged; Kaplan-Meier Estimate; Incidence; Comorbidity
PubMed: 38783253
DOI: 10.1186/s12890-024-03041-6 -
American Journal of Physiology. Renal... Jul 2024Diabetes is closely associated with K disturbances during disease progression and treatment. However, it remains unclear whether K imbalance occurs in diabetes with...
Diabetes is closely associated with K disturbances during disease progression and treatment. However, it remains unclear whether K imbalance occurs in diabetes with normal kidney function. In this study, we examined the effects of dietary K intake on systemic K balance and renal K handling in streptozotocin (STZ)-induced diabetic mice. The control and STZ mice were fed low or high K diet for 7 days to investigate the role of dietary K intake in renal K excretion and K homeostasis and to explore the underlying mechanism by evaluating K secretion-related transport proteins in distal nephrons. K-deficient diet caused excessive urinary K loss, decreased daily K balance, and led to severe hypokalemia in STZ mice compared with control mice. In contrast, STZ mice showed an increased daily K balance and elevated plasma K level under K-loading conditions. Dysregulation of the NaCl cotransporter (NCC), epithelial Na channel (ENaC), and renal outer medullary K channel (ROMK) was observed in diabetic mice fed either low or high K diet. Moreover, amiloride treatment reduced urinary K excretion and corrected hypokalemia in K-restricted STZ mice. On the other hand, inhibition of SGLT2 by dapagliflozin promoted urinary K excretion and normalized plasma K levels in K-supplemented STZ mice, at least partly by increasing ENaC activity. We conclude that STZ mice exhibited abnormal K balance and impaired renal K handling under either low or high K diet, which could be primarily attributed to the dysfunction of ENaC-dependent renal K excretion pathway, despite the possible role of NCC. Neither low dietary K intake nor high dietary K intake effectively modulates renal K excretion and K homeostasis in STZ mice, which is closely related to the abnormality of ENaC expression and activity. SGLT2 inhibitor increases urinary K excretion and reduces plasma K level in STZ mice under high dietary K intake, an effect that may be partly due to the upregulation of ENaC activity.
Topics: Animals; Diabetes Mellitus, Experimental; Potassium; Male; Potassium, Dietary; Epithelial Sodium Channels; Mice, Inbred C57BL; Sodium-Glucose Transporter 2 Inhibitors; Potassium Channels, Inwardly Rectifying; Mice; Diabetic Nephropathies; Kidney; Hypokalemia; Amiloride; Renal Elimination; Homeostasis; Solute Carrier Family 12, Member 3; Glucosides; Streptozocin; Benzhydryl Compounds; Sodium-Glucose Transporter 2
PubMed: 38779755
DOI: 10.1152/ajprenal.00240.2023 -
Mini Reviews in Medicinal Chemistry May 2024The oxidative deamination of a wide range of endogenous and exogenous amines is catalyzed by a family of enzymes known as monoamine oxidases (MAOs), which are reliant on...
BACKGROUND
The oxidative deamination of a wide range of endogenous and exogenous amines is catalyzed by a family of enzymes known as monoamine oxidases (MAOs), which are reliant on flavin-adenine dinucleotides. Numerous neurological conditions, such as Parkinson's disease (PD) and Alzheimer's disease (AD), are significantly correlated with changes in the amounts of biogenic amines in the brain caused by MAO. Hydrogen peroxide, reactive oxygen species, and ammonia, among other toxic consequences of this oxidative breakdown, can harm brain cells' mitochondria and cause oxidative damage.
OBJECTIVE
The prime objective of this review article was to highlight and conclude the recent advancements in structure-activity relationships of synthetic derivatives of coumarins for MAO-B inhibition, published in the last five years' research articles.
METHODS
The literature (between 2019 and 2023) was searched from platforms like Science Direct, Google Scholar, PubMed, etc. After going through the literature, we have found a number of coumarin derivatives being synthesized by researchers for the inhibition of MAO-B for the management of diseases associated with the enzyme such as Alzheimer's Disease and Parkinson's Disease. The effect of these coumarin derivatives on the enzyme depends on the substitutions associated with the structure. The structure-activity relationships of the synthetic coumarin derivatives that are popular nowadays have been described and summarized in the current study.
RESULTS
The results revealed the updated review on SAR studies of synthetic coumarins as MAO-B inhibitors, specifically for Alzheimer's Disease and Parkinson's Disease. The patents reported on coumarin derivatives as MAO-B inhibitors were also highlighted.
CONCLUSION
Recently, coumarins, a large class of chemicals with both natural and synthetic sources, have drawn a lot of attention because of the vast range of biological actions they have that are linked to neurological problems. Numerous studies have demonstrated that chemically produced and naturally occurring coumarin analogs both exhibited strong MAO-B inhibitory action. Coumarins bind to MAO-B reversibly thereby preventing the breakdown of neurotransmitters like dopamine leading to the inhibition of the enzyme A number of MAO-B blockers have been proven to be efficient therapies for treating neurological diseases like Alzheimer's Disease and Parkinson's Disease. To combat these illnesses, there is still an urgent need to find effective treatment compounds.
PubMed: 38778598
DOI: 10.2174/0113895575290599240503080025 -
Journal of Agricultural and Food... Jun 2024Excessive intake of fat and fructose in Western diets has been confirmed to induce renal lipotoxicity, thereby driving the progression of chronic kidney disease (CKD)....
Magnoflorine Ameliorates Chronic Kidney Disease in High-Fat and High-Fructose-Fed Mice by Promoting Parkin/PINK1-Dependent Mitophagy to Inhibit NLRP3/Caspase-1-Mediated Pyroptosis.
Excessive intake of fat and fructose in Western diets has been confirmed to induce renal lipotoxicity, thereby driving the progression of chronic kidney disease (CKD). This study was conducted to evaluate the efficacy of magnoflorine in a CKD mouse model subjected to high-fat and high-fructose diets. Our results demonstrated that magnoflorine treatment ameliorated abnormal renal function indices (serum creatinine, urea nitrogen, uric acid, and urine protein) in high-fat- and high-fructose-fed mice. Histologically, renal tubular cell steatosis, lipid deposition, tubular dilatation, and glomerular fibrosis were significantly reduced by the magnoflorine treatment in these mice. Mechanistically, magnoflorine promotes Parkin/PINK1-mediated mitophagy, thereby inhibiting NLRP3/Caspase-1-mediated pyroptosis. Consistent findings were observed in the palmitic acid-incubated HK-2 cell model. Notably, both silencing of Parkin and the use of a mitophagy inhibitor reversed the inhibitory effect of magnoflorine on NLRP3 inflammasome activation in vitro. Therefore, the present study provides compelling evidence that magnoflorine improves renal injury in high-fat- and high-fructose-fed mice by promoting Parkin/PINK1-dependent mitophagy to inhibit NLRP3 inflammasome activation and pyroptosis. Our findings suggest that dietary supplementation with magnoflorine and magnoflorine-rich foods (such as magnolia) might be an effective strategy for the prevention of CKD.
Topics: Animals; NLR Family, Pyrin Domain-Containing 3 Protein; Mice; Pyroptosis; Fructose; Ubiquitin-Protein Ligases; Male; Mitophagy; Renal Insufficiency, Chronic; Mice, Inbred C57BL; Diet, High-Fat; Humans; Protein Kinases; Caspase 1; Aporphines; Inflammasomes
PubMed: 38776285
DOI: 10.1021/acs.jafc.3c09634 -
Journal of Immunology Research 2024Immunotherapy has proven effective in treating advanced gastric cancer (AGC), yet its benefits are limited to a subset of patients. Our aim is to swiftly identify...
An On-Treatment Decreased Trend of Serum IL-6 and IL-8 as Predictive Markers Quickly Reflects Short-Term Efficacy of PD-1 Blockade Immunochemotherapy in Patients with Advanced Gastric Cancer.
OBJECTIVE
Immunotherapy has proven effective in treating advanced gastric cancer (AGC), yet its benefits are limited to a subset of patients. Our aim is to swiftly identify prognostic biomarkers using cytokines to improve the precision of clinical guidance and decision-making for PD-1 inhibitor-based cancer immunotherapy in AGC.
MATERIALS AND METHODS
The retrospective study compared 36 patients with AGC who received combined anti-PD-1 immunotherapy and chemotherapy (immunochemotherapy) with a control group of 20 patients who received chemotherapy alone. The concentrations of TNF-, IL-1, IL-2R, IL-6, IL-8, IL-10, and IL-17 in the serum were assessed using chemiluminescence immunoassay at three distinct time intervals following the commencement of immunochemotherapy.
RESULTS
When compared to controls, patients undergoing immunochemotherapy demonstrated a generalized rise in cytokine levels after the start of treatment. However, patients who benefited from immunochemotherapy showed a decrease in IL-6 or IL-8 concentrations throughout treatment (with varied trends observed for IL-1, IL-2R, IL-10, IL-17, and TNF-) was evident in patients benefiting from immunochemotherapy but not in those who did not benefit. Among these markers, the combination of IL-6, IL-8, and CEA showed optimal predictive performance for short-term efficacy of immunochemotherapy in AGC patients.
CONCLUSION
Reductions in IL-6/IL-8 levels observed during immunochemotherapy correlated with increased responsiveness to treatment effectiveness. These easily accessible blood-based biomarkers are predictive and rapid and may play a crucial role in identifying individuals likely to derive benefits from PD-1 blockade immunotherapy.
Topics: Humans; Stomach Neoplasms; Female; Male; Middle Aged; Aged; Biomarkers, Tumor; Immune Checkpoint Inhibitors; Interleukin-6; Programmed Cell Death 1 Receptor; Interleukin-8; Retrospective Studies; Treatment Outcome; Adult; Prognosis; Immunotherapy; Neoplasm Staging; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38774604
DOI: 10.1155/2024/3604935 -
European Journal of Medical Research May 2024Artesunate (ART), an effective antimalarial semisynthetic derivative of artemisinin, exhibits antitumour properties, but the mechanism(s) involved remain elusive. In...
Artesunate (ART), an effective antimalarial semisynthetic derivative of artemisinin, exhibits antitumour properties, but the mechanism(s) involved remain elusive. In this study, we investigated the antitumour effects of ART on human oesophageal squamous cell carcinoma (ESCC) cell lines. Treatment of ESCC cell lines with ART resulted in the production of excessive reactive oxygen species (ROS) that induced DNA damage, reduced cell proliferation and inhibited clonogenicity via G1-S cell cycle arrest and/or apoptosis in vitro. The administration of ART to nude mice with ESCC cell xenografts inhibited tumour formation in vivo. However, the cytotoxicity of ART strongly differed among the ESCC cell lines tested. Transcriptomic profiling revealed that although the expression of large numbers of genes in ESCC cell lines was affected by ART treatment, these genes could be functionally clustered into pathways involved in regulating cell cycle progression, DNA metabolism and apoptosis. We revealed that p53 and Cdk4/6-p16-Rb cell cycle checkpoint controls were critical determinants required for mediating ART cytotoxicity in ESCC cell lines. Specifically, KYSE30 cells with p53/p16 were the most sensitive to ART, KYSE150 and KYSE180 cells with p53/p16 exhibited intermediate responses to ART, and Eca109 cells with p53/p16 exhibited the most resistance to ATR. Consistently, perturbation of p53 expression using RNA interference (RNAi) and/or Cdk4/6 activity using the inhibitor palbociclib altered ART cytotoxicity in KYSE30 cells. Given that the p53 and Cdk4/6-cyclin D1-p16-Rb genes are commonly mutated in ESCC, our results potentially shed new light on neoadjuvant chemotherapy strategies for ESCC.
Topics: Humans; Artesunate; Esophageal Neoplasms; Animals; Esophageal Squamous Cell Carcinoma; Mice; Cell Line, Tumor; Cell Cycle Checkpoints; Cell Proliferation; Apoptosis; Mice, Nude; Carcinoma, Squamous Cell; DNA Damage; Xenograft Model Antitumor Assays; Artemisinins; Reactive Oxygen Species; Antineoplastic Agents
PubMed: 38773551
DOI: 10.1186/s40001-024-01882-9