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Cell Biochemistry and Biophysics Jun 2024Chronic arsenic-exposure causes neuromuscular disorders and other health anomalies. Damage to DNA and cytoskeletal/extracellular matrix is brought on by...
Arsenic Induced Oxidative Neural-Damages in Rat are Mitigated by Tea-Leave Extract via MMPs and AChE Inactivation, Shown by Molecular Docking and in Vitro Studies with Pure Theaflavin and AChE.
BACKGROUND
Chronic arsenic-exposure causes neuromuscular disorders and other health anomalies. Damage to DNA and cytoskeletal/extracellular matrix is brought on by reactive-oxygen-species (ROS)-induced intrinsic antioxidant depletion (thiols/urate). Therapeutic chelating-agents have multiple side-effects.
OBJECTIVES
The protection of (Camellia sinensis) tea-extract and role of uric-acid (UA) or allopurinol (urate-depletor) on arsenic-toxicity were verified in rat model.
METHODS
Camellia sinensis (CS dry-leaves), UA or allopurinol was supplemented to arsenic-intoxicated rats for 4-weeks. Purified theaflavins and their galloyl-ester were tested in-vitro on pure AChE (acetylcholinesterase) and their PDB/PubChem 3-D structures were utilized for in-silico binding studies. The primary chemical components were evaluated from CS-extracts. Biochemical analysis, PAGE-zymogram, DNA-stability comet analysis, HE-staining was performed in arsenic-exposed rat brain tissues.
RESULTS
Animals exposed to arsenic showed symptoms of erratic locomotion, decreased intrinsic antioxidants (catalase/SOD1/uric acid), increased AChE, and malondialdehyde. Cerebellar and cerebrum tissue damages were shown with increased levels of matrix-metalloprotease (MMP2/9) and DNA damage (comets). Allopurinol- supplemented group demonstrated somewhat similar biochemical responses. In the CS-group brain tissues especially cerebellum is considerably protected which is evident from endogenous antioxidant and DNA and cytoskeleton protection with concomitant inactivation of MMPs and AChE. Present study indicates theaflavin-digallate (TFDG) demonstrated the highest inhibition of purified AChE (IC = 2.19 µg/ml with the lowest binding free-energy; -369.87 kcal/mol) followed by TFMG (IC = 3.86 µg/ml, -347.06 kcal/mol) suggesting their possible restoring effects of cholinergic response.
CONCLUSIONS
Favorable responses in UA-group and adverse outcome in allo-group justify the neuro-protective effects of UA as an endogenous antioxidant. Role of flavon-gallate in neuro protection mechanism may be further studied.
PubMed: 38943009
DOI: 10.1007/s12013-024-01369-8 -
British Journal of Cancer Jun 2024Certain paediatric nervous system malignancies have dismal prognoses. Retinoic acid (RA) is used in neuroblastoma treatment, and preclinical data indicate potential...
BACKGROUND
Certain paediatric nervous system malignancies have dismal prognoses. Retinoic acid (RA) is used in neuroblastoma treatment, and preclinical data indicate potential benefit in selected paediatric brain tumour entities. However, limited single-agent efficacy necessitates combination treatment approaches.
METHODS
We performed drug sensitivity profiling of 76 clinically relevant drugs in combination with RA in 16 models (including patient-derived tumouroids) of the most common paediatric nervous system tumours. Drug responses were assessed by viability assays, high-content imaging, and apoptosis assays and RA relevant pathways by RNAseq from treated models and patient samples obtained through the precision oncology programme INFORM (n = 2288). Immunoprecipitation detected BCL-2 family interactions, and zebrafish embryo xenografts were used for in vivo efficacy testing.
RESULTS
Group 3 medulloblastoma (MB) and neuroblastoma models were highly sensitive to RA treatment. RA induced differentiation and regulated apoptotic genes. RNAseq analysis revealed high expression of BCL2L1 in MB and BCL2 in neuroblastomas. Co-treatments with RA and BCL-2/X inhibitor navitoclax synergistically decreased viability at clinically achievable concentrations. The combination of RA with navitoclax disrupted the binding of BIM to BCL-X in MB and to BCL-2 in neuroblastoma, inducing apoptosis in vitro and in vivo.
CONCLUSIONS
RA treatment primes MB and NB cells for apoptosis, triggered by navitoclax cotreatment.
PubMed: 38942989
DOI: 10.1038/s41416-024-02740-5 -
Scientific Reports Jun 2024To evaluate the protective effect of gallic acid on the optic nerve by studying the inhibitory effect of gallic acid on oxidative stress in retinal ganglion cells. 100...
To evaluate the protective effect of gallic acid on the optic nerve by studying the inhibitory effect of gallic acid on oxidative stress in retinal ganglion cells. 100 male SD rats were randomly divided into four groups: normal control group, simple high IOP group, 0.5% gallic acid experimental group, and 1% gallic acid experimental group. HE staining, immunofluorescence, DHE staining, Western blot, and q-PCR were used to observe the antioxidant effect of gallic acid on the retina of acute ocular hypertension rats. HE staining of the retina of SD rats confirmed that the nucleus of RGCs was clear, the thickness of the RNFL was regular in the normal control group, and the nucleus of RGCs was ruptured and lysed in the simple high intraocular pressure (IOP) group and the gallic acid group, and the thickness of the RNFL was significantly thickened, but the thickness of the RNFL in the gallic acid group was significantly reduced compared with that in the simple high IOP group (p < 0.05). DHE staining showed that ROS content in the simple high IOP group was significantly increased compared with the normal control group, and ROS content was significantly decreased after the application of gallic acid (p < 0.05). Immunofluorescence staining with Brn-3a antibody confirmed that the number of RGCs was significantly reduced in the simple high IOP group compared with the normal control group, whereas after application of gallic acid, the number of RGCs was significantly more in the gallic acid group than in the simple high IOP group (p < 0.05). Western Blot and q-PCR confirmed that hypoxia-inducing factor 1α (HIF-1α) protein content and transcription level were significantly increased in the retinal tissue of the simple high IOP group, and gallic acid could inhibit HIF-1α protein content (p < 0.05) and reduce transcription factor level (p < 0.05). Gallic acid exerts a protective effect on RGC by inhibiting oxidative stress in rats with acute IOP elevation.
Topics: Gallic Acid; Animals; Retinal Ganglion Cells; Antioxidants; Male; Rats; Rats, Sprague-Dawley; Disease Models, Animal; Glaucoma; Oxidative Stress; Reactive Oxygen Species; Hypoxia-Inducible Factor 1, alpha Subunit; Intraocular Pressure; Ocular Hypertension
PubMed: 38942959
DOI: 10.1038/s41598-024-65965-7 -
Analytical and Bioanalytical Chemistry Jun 2024Accurate diagnostic and serology assays are required for the continued management of the COVID-19 pandemic yet spike protein mutations and intellectual property concerns...
Accurate diagnostic and serology assays are required for the continued management of the COVID-19 pandemic yet spike protein mutations and intellectual property concerns with antigens and antibodies used in various test kits render comparability assessments difficult. As the use of common, well-characterized reagents can help address this lack of standardization, the National Research Council Canada has produced two protein reference materials (RMs) for use in SARS-CoV-2 serology assays: biotinylated human angiotensin-converting enzyme 2 RM, ACE2-1, and SARS-CoV-2 Omicron BA.4/5 spike protein RM, OMIC-1. Reference values were assigned through a combination of amino acid analysis via isotope dilution liquid chromatography tandem mass spectrometry following acid hydrolysis, and ultraviolet-visible (UV-Vis) spectrophotometry at 280 nm. Vial-to-vial homogeneity was established using UV-Vis measurements, and protein oligomeric status, monitored by size exclusion liquid chromatography (LC-SEC), was used to evaluate transportation, storage, and freeze-thaw stabilities. The molar protein concentration in ACE2-1 was 25.3 ± 1.7 µmol L (k = 2, 95% CI) and consisted almost exclusively (98%) of monomeric ACE2, while OMIC-1 contained 5.4 ± 0.5 µmol L (k = 2) spike protein in a mostly (82%) trimeric form. Glycoprotein molar mass determination by LC-SEC with multi-angle light scattering detection facilitated calculation of corresponding mass concentrations. To confirm protein functionality, the binding of OMIC-1 to immobilized ACE2-1 was investigated with surface plasmon resonance and the resulting dissociation constant, K ~ 4.4 nM, was consistent with literature values.
PubMed: 38942955
DOI: 10.1007/s00216-024-05413-7 -
Aesthetic Plastic Surgery Jun 2024Projection and upper rotation to the tip is fundamental in the nasal rejuvenation, as a matter of fact the tip is the most important and has strongly effects on the...
INTRODUCTION
Projection and upper rotation to the tip is fundamental in the nasal rejuvenation, as a matter of fact the tip is the most important and has strongly effects on the improve appearance and quality of life. The aim of the present study was to evaluate reshaping the tip of the nose by cross-linked hyaluronic acid using Italian technique.
METHODS
In a period between November 2019 and 2023, a total of one hundred and forty healthy, 95 females and 45 man patients, were performed with a mean age 44±5 (age range: 31-52 years old) affected by tip of congenital (22) or ageing nose hypotonia (118), and reduced volume that need of an elevation of the nose tip. The anatomic markers have been considered for the anthropometric measurements after the filler rhinoplasty. Two infiltrations were performed, one in the infiltration into the antero-caudal access over the columella produce upward rotation of the tip of the nose and second infiltration into the antero-superior access produce the projection of the tip of the nose. Medical device used in the study was Neofound STRUCT LIDO (LOVE COSMEDICAL srls-Via Toniolo 9, 57022 Castagneto Carducci, ITALY) containing sodium hyaluronate/hyaluronic acid high molecular weight (1.500
acid low molecular weight (155 RESULTS
The effect on the upward rotation of the tip nose was evaluated using Global Aesthetic Improvement Scale and morphometric evaluation. All the subjects showed at least 2-3 grade improvement in GAIS score after HA filler injection. The analysis of patient satisfaction after the last follow-up visits clearly demonstrated good results. A significant morphometric difference was detected comparing the T and T (p<0,0001), while no difference was present comparing T and T means (p=0.11). The outcome of the present clinical study gives greater projection and upper rotation to the tip with great gratification of the patients and the surgeon. An augmentation of the tip nose with hyaluronic acid filler produces a rejuvenation of the nose area resulted in a more youthful appearance. No adverse event was observed. In 35 patients, additional HA infiltration had to be performed after 2 weeks.
CONCLUSION
In conclusion, the Italian technique descripted in the present paper is safe, simply, and efficacious for rejuvenation of the nose, with elevated levels of patient satisfaction.
LEVEL OF EVIDENCE II
This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
PubMed: 38942953
DOI: 10.1007/s00266-024-04197-6 -
Scientific Reports Jun 2024Cancer remains a formidable global health challenge, with metastasis being a key contributor to its lethality. Abundant high molecular mass hyaluronic acid, a major...
Cancer remains a formidable global health challenge, with metastasis being a key contributor to its lethality. Abundant high molecular mass hyaluronic acid, a major non-protein component of extracellular matrix, protects naked mole rats from cancer and reduces cancer incidence in mice. Hyaluronidase plays a critical role in degrading hyaluronic acid and is frequently overexpressed in metastatic cancer. Here we investigated the potential of targeting hyaluronidases to reduce metastasis. A high throughput screen identified delphinidin, a natural plant compound found in fruits and vegetables, as a potent hyaluronidase inhibitor. Delphinidin-mediated inhibition of hyaluronidase activity led to an increase in high molecular weight hyaluronic acid in cell culture and in mouse tissues, and reduced migration and invasion behavior of breast, prostate, and melanoma cancer cells. Moreover, delphinidin treatment suppressed melanoma metastasis in mice. Our study provides a proof of principle that inhibition of hyaluronidase activity suppresses cancer cell migration, invasion and metastasis. Furthermore, we identified a natural compound delphinidin as a potential anticancer therapeutic. Thus, we have identified a path for clinical translation of the cancer resistance mechanism identified in the naked mole rat.
Topics: Hyaluronoglucosaminidase; Animals; Mice; Humans; Anthocyanins; Cell Movement; Cell Line, Tumor; Neoplasm Metastasis; Female; Hyaluronic Acid; Male; Enzyme Inhibitors
PubMed: 38942920
DOI: 10.1038/s41598-024-64924-6 -
Nature Communications Jun 2024Transition metal-catalyzed asymmetric hydrogenation is one of the most efficient methods for the preparation of chiral α-substituted propionic acids. However, research...
Transition metal-catalyzed asymmetric hydrogenation is one of the most efficient methods for the preparation of chiral α-substituted propionic acids. However, research on this method, employing cleaner earth-abundant metal catalysts, is still insufficient in both academic and industrial contexts. Herein, we report an efficient nickel-catalyzed asymmetric hydrogenation of α-substituted acrylic acids affording the corresponding chiral α-substituted propionic acids with up to 99.4% ee (enantiomeric excess) and 10,000 S/C (substrate/catalyst). In particular, this method can be used to obtain (R)-dihydroartemisinic acid with 99.8:0.2 dr (diastereomeric ratio) and 5000 S/C, which is an essential intermediate for the preparation of the antimalarial drug Artemisinin. The reaction mechanism has been investigated via experiments and DFT (Density Functional Theory) calculations, which indicate that the protonolysis of the C-Ni bond of the key intermediate via an intramolecular proton transfer from the carboxylic acid group of the substrate, is the rate-determining step.
PubMed: 38942809
DOI: 10.1038/s41467-024-49801-0 -
Scientific Reports Jun 2024HIV/AIDS is one of the most devastating infectious diseases affecting humankind all over the world and its impact goes beyond public health problems. This study was...
Determinants of hemoglobin level and time to default from Highly Active Antiretroviral Therapy (HAART) for adult clients living with HIV under treatment; a retrospective cohort study design.
HIV/AIDS is one of the most devastating infectious diseases affecting humankind all over the world and its impact goes beyond public health problems. This study was conducted to investigate the joint predictors of hemoglobin level and time to default from treatment for adult clients living with HIV/AIDS under HAART at the University of Gondar Comprehensive and Specialized Hospital, North-west Ethiopia. The study was conducted using a retrospective cohort design from the medical records of 403 randomly selected adult clients living with HIV whose follow-ups were from September 2015 to March 2022. Hemoglobin level was projected using Sahli's acid-hematin method. Hence, the hemoglobin tube was filled with N/10 hydrochloric acid up to 2 g % marking and the graduated tube was placed in Sahli's hemoglobin meter. The blood samples were collected using the finger-pick method, considering 22 G disposable needles. The health staff did this. From a total of 403 adult patients living with HIV/AIDS included in the current study, about 44.2% defaulted from therapy. The overall mean and median estimated survival time of adult clients under study were 44.3 and 42 months respectively. The patient's lymphocyte count (AHR = 0.7498, 95% CI: (0.7411: 0.7587), p-value < 0.01), The weight of adult patients living with HIV/AIDS (AHR = 0.9741, 95% CI: (0.9736: 0.9747), p-value = 0.012), sex of adult clients (AHR = 0.6019, 95% CI: (0.5979, 0.6059), p-value < 0.01), WHO stages III compared to Stage I (AHR = 1.4073, 95% CI: (1.3262, 1.5078), p-value < 0.01), poor adherence level (AHR = 0.2796, 95% CI: (0.2082, 0.3705) and p-value < 0.01), bedridden patients (AHR = 1.5346, 95% CI: (1.4199, 1.6495), p-value = 0.008), and opportunistic infections (AHR = 0.2237, 95% CI: (0.0248, 0.4740), p-value = 0.004) had significant effect on both hemoglobin level and time to default from treatment. Similarly, other co-morbidity conditions, disclosure status of the HIV disease, and tobacco and alcohol addiction had a significant effect on the variables of interest. The estimate of the association parameter in the slope value of Hgb level and time default was negative, indicating that the Hgb level increased as the hazard of defaulting from treatment decreased. A patient with abnormal BMI like underweight, overweight, or obese was negatively associated with the risk of anemia (lower hemoglobin level). As a recommendation, more attention should be given to those patients with abnormal BMI, patients with other co-morbidity conditions, patients with opportunistic infections, and low lymphocytes, and bedridden and ambulatory patients. Health-related education should be given to adult clients living with HIV/AIDS to be good adherents for medical treatment.
Topics: Humans; Male; Adult; Female; Retrospective Studies; HIV Infections; Antiretroviral Therapy, Highly Active; Hemoglobins; Middle Aged; Ethiopia; Young Adult; Anti-HIV Agents; Undertreatment
PubMed: 38942753
DOI: 10.1038/s41598-024-62952-w -
Dental Materials : Official Publication... Jun 2024Streptococcus mutans (S. mutans) is a major contributor to dental caries, with its ability to synthesize extracellular polysaccharides (EPS) and biofilms. The gcrR gene...
OBJECTIVE
Streptococcus mutans (S. mutans) is a major contributor to dental caries, with its ability to synthesize extracellular polysaccharides (EPS) and biofilms. The gcrR gene is a regulator of EPS synthesis and biofilm formation. The objectives of this study were to investigate a novel strategy of combining gcrR gene over-expression with dimethylaminohexadecyl methacrylate (DMAHDM), and to determine their in vivo efficacy in reducing caries in rats for the first time.
METHODS
Two types of S. mutans were tested: Parent S. mutans; and gcrR gene over-expressed S. mutans (gcrR OE S. mutans). Bacterial minimum inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) were measured with DMAHDM and chlorhexidine (CHX). Biofilm biomass, polysaccharide, lactic acid production, live/dead staining, colony-forming units (CFUs), and metabolic activity (MTT) were evaluated. A Sprague-Dawley rat model was used with parent S. mutans and gcrR OE S. mutans colonization to determine caries-inhibition in vivo.
RESULTS
Drug-susceptibility of gcrR OE S. mutans to DMAHDM or CHX was 2-fold higher than that of parent S. mutans. DMAHDM reduced biofilm CFU by 3-4 logs. Importantly, the combined gcrR OE S. mutans+ DMAHDM dual strategy reduced biofilm CFU by 5 logs. In the rat model, the parent S. mutans group had a higher cariogenicity in dentinal (D) and extensive dentinal (D) regions. The DMAHDM + gcrR OE group reduced the D and D caries to only 20 % and 0 %, those of parent S. mutans + PBS control group (p < 0.05). The total caries severity of gcrR OE + DMAHDM group was decreased to 51 % that of parent S. mutans control (p < 0.05).
SIGNIFICANCE
The strategy of combining S. mutans gcrR over-expression with antibacterial monomer reducing biofilm acids by 97 %, and reduced in vivo total caries in rats by 48 %. The gcrR over-expression + DMAHDM strategy is promising for a wide range of dental applications to inhibit caries and protect tooth structures.
PubMed: 38942710
DOI: 10.1016/j.dental.2024.06.018 -
Science Bulletin Jun 2024Electrocatalytic oxidation of 5-hydroxymethylfurfural (HMF) to 2,5-furandicarboxylic acid (FDCA), a sustainable strategy to produce bio-based plastic monomer, is always...
Electrocatalytic oxidation of 5-hydroxymethylfurfural (HMF) to 2,5-furandicarboxylic acid (FDCA), a sustainable strategy to produce bio-based plastic monomer, is always conducted in a high-concentration alkaline solution (1.0 mol L KOH) for high activity. However, such high concentration of alkali poses challenges including HMF degradation and high operation costs associated with product separation. Herein, we report a single-atom-ruthenium supported on CoO (Ru-CoO) as a catalyst that works efficiently in a low-concentration alkaline electrolyte (0.1 mol L KOH), exhibiting a low potential of 1.191 V versus a reversible hydrogen electrode to achieve 10 mA cm in 0.1 mol L KOH, which outperforms previous catalysts. Electrochemical studies demonstrate that single-atom-Ru significantly enhances hydroxyl (OH) adsorption with insufficient OH supply, thus improving HMF oxidation. To showcase the potential of Ru-CoO catalyst, we demonstrate its high efficiency in a flow reactor under industrially relevant conditions. Eventually, techno-economic analysis shows that substitution of the conventional 1.0 mol L KOH with 0.1 mol L KOH electrolyte may significantly reduce the minimum selling price of FDCA by 21.0%. This work demonstrates an efficient catalyst design for electrooxidation of biomass working without using strong alkaline electrolyte that may contribute to more economic biomass electro-valorization.
PubMed: 38942696
DOI: 10.1016/j.scib.2024.06.015