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Investigative Ophthalmology & Visual... Jul 2024Light detection destroys the visual pigment. Its regeneration, necessary for the recovery of light sensitivity, is accomplished through the visual cycle. Release of...
PURPOSE
Light detection destroys the visual pigment. Its regeneration, necessary for the recovery of light sensitivity, is accomplished through the visual cycle. Release of all-trans retinal by the light-activated visual pigment and its reduction to all-trans retinol comprise the first steps of the visual cycle. In this study, we determined the kinetics of all-trans retinol formation in human rod and cone photoreceptors.
METHODS
Single living rod and cone photoreceptors were isolated from the retinas of human cadaver eyes (ages 21 to 90 years). Formation of all-trans retinol was measured by imaging its outer segment fluorescence (excitation, 360 nm; emission, >420 nm). The extent of conversion of released all-trans retinal to all-trans retinol was determined by measuring the fluorescence excited by 340 and 380 nm. Measurements were repeated with photoreceptors isolated from Macaca fascicularis retinas. Experiments were carried out at 37°C.
RESULTS
We found that ∼80% to 90% of all-trans retinal released by the light-activated pigment is converted to all-trans retinol, with a rate constant of 0.24 to 0.55 min-1 in human rods and ∼1.8 min-1 in human cones. In M. fascicularis rods and cones, the rate constants were 0.38 ± 0.08 min-1 and 4.0 ± 1.1 min-1, respectively. These kinetics are several times faster than those measured in other vertebrates. Interphotoreceptor retinoid-binding protein facilitated the removal of all-trans retinol from human rods.
CONCLUSIONS
The first steps of the visual cycle in human photoreceptors are several times faster than in other vertebrates and in line with the rapid recovery of light sensitivity exhibited by the human visual system.
Topics: Humans; Retinal Cone Photoreceptor Cells; Aged; Retinal Rod Photoreceptor Cells; Aged, 80 and over; Middle Aged; Adult; Vitamin A; Animals; Macaca fascicularis; Young Adult; Male; Retinaldehyde; Cadaver; Female; Vision, Ocular; Retinal Pigments
PubMed: 38958967
DOI: 10.1167/iovs.65.8.9 -
Applied Microbiology and Biotechnology Jul 2024This study investigated the potential of endophytic fungi to produce paclitaxel (Taxol®), a potent anticancer compound widely employed in chemotherapy. This research...
This study investigated the potential of endophytic fungi to produce paclitaxel (Taxol®), a potent anticancer compound widely employed in chemotherapy. This research aimed to identify, confirm, and characterize endophytic fungi capable of paclitaxel (PTX) production and assess their paclitaxel yield. Additionally, it aimed to investigate factors influencing paclitaxel production. A total of 100 endophytic fungal isolates were collected and identified from the roots of Artemisia judaica. Aspergillus fumigatiaffinis exhibited the highest PTX production (26.373 μg L) among the isolated endophytic fungi. The strain was identified as A. fumigatiaffinis (Accession No. PP235788.1). Molecular identification confirmed its novelty, representing the first report of PTX production by A. fumigatiaffinis, an endophyte of Artemisia judaica. Optimization through full factorial design of experiments (DOE) and response surface methodology (RSM) significantly enhanced PTX production to 110.23 μg L from 1 g of dry weight of the fungal culture under optimal conditions of pH 8.0, 150 μg L becozyme supplementation, and 18 days of fermentation in potato dextrose broth. The presence of paclitaxel was confirmed using thin layer chromatography, high performance liquid chromatography, and gas chromatography-mass spectrometry. These findings maximize the role of endophytic fungus to produce a secondary metabolite that might be able to replace the chemically produced PTX and gives an opportunity to provide a sustainable source of PTX eco-friendly at high concentrations. KEY POINTS: • Endophytic fungi, like A. fumigatiaffinis, show promise for eco-friendly paclitaxel production • Optimization strategies boost paclitaxel yield significantly, reaching 110.23 μg L • Molecular identification confirms novelty, offering a sustainable PTX source.
Topics: Paclitaxel; Aspergillus; Endophytes; Fermentation; Plant Roots; Culture Media; Gas Chromatography-Mass Spectrometry; Chromatography, High Pressure Liquid
PubMed: 38958755
DOI: 10.1007/s00253-024-13230-2 -
CNS Neuroscience & Therapeutics Jul 2024A recent study by Brian Mac Grory and colleagues investigated the safety of endovascular thrombectomy (EVT) among patients under vitamin K antagonists (VKAs) use within...
A recent study by Brian Mac Grory and colleagues investigated the safety of endovascular thrombectomy (EVT) among patients under vitamin K antagonists (VKAs) use within 7 days prior to hospital admission. Through this retrospective, observational cohort study, they found prior VKA use did not increase the risk of symptomatic intracranial hemorrhage (sICH) overall. However, recent VKA use with a presenting international normalized ratio (INR) > 1.7 was associated with a significantly increased risk of sICH. Future large-scale randomized controlled trials should be conducted to further clarify the effects and feasibility of EVT therapy in ischemic stroke patients under anticoagulation.
Topics: Humans; Vitamin K; Thrombectomy; Anticoagulants; Endovascular Procedures; Ischemic Stroke; Retrospective Studies
PubMed: 38958388
DOI: 10.1111/cns.14777 -
Critical Care (London, England) Jul 2024Vitamin K is essential for numerous physiological processes, including coagulation, bone metabolism, tissue calcification, and antioxidant activity. Deficiency,... (Review)
Review
BACKGROUND
Vitamin K is essential for numerous physiological processes, including coagulation, bone metabolism, tissue calcification, and antioxidant activity. Deficiency, prevalent in critically ill ICU patients, impacts coagulation and increases the risk of bleeding and other complications. This review aims to elucidate the metabolism of vitamin K in the context of critical illness and identify a potential therapeutic approach.
METHODS
In December 2023, a scoping review was conducted using the PRISMA Extension for Scoping Reviews. Literature was searched in PubMed, Embase, and Cochrane databases without restrictions. Inclusion criteria were studies on adult ICU patients discussing vitamin K deficiency and/or supplementation.
RESULTS
A total of 1712 articles were screened, and 13 met the inclusion criteria. Vitamin K deficiency in ICU patients is linked to malnutrition, impaired absorption, antibiotic use, increased turnover, and genetic factors. Observational studies show higher PIVKA-II levels in ICU patients, indicating reduced vitamin K status. Risk factors include inadequate intake, disrupted absorption, and increased physiological demands. Supplementation studies suggest vitamin K can improve status but not normalize it completely. Vitamin K deficiency may correlate with prolonged ICU stays, mechanical ventilation, and increased mortality. Factors such as genetic polymorphisms and disrupted microbiomes also contribute to deficiency, underscoring the need for individualized nutritional strategies and further research on optimal supplementation dosages and administration routes.
CONCLUSIONS
Addressing vitamin K deficiency in ICU patients is crucial for mitigating risks associated with critical illness, yet optimal management strategies require further investigation.
IMPACT RESEARCH
To the best of our knowledge, this review is the first to address the prevalence and progression of vitamin K deficiency in critically ill patients. It guides clinicians in diagnosing and managing vitamin K deficiency in intensive care and suggests practical strategies for supplementing vitamin K in critically ill patients. This review provides a comprehensive overview of the existing literature, and serves as a valuable resource for clinicians, researchers, and policymakers in critical care medicine.
Topics: Humans; Critical Illness; Vitamin K; Vitamin K Deficiency; Intensive Care Units
PubMed: 38956732
DOI: 10.1186/s13054-024-05001-2 -
Scientific Reports Jul 2024Adjuvant oxaliplatin plus S-1 (SOX) chemotherapy for gastric cancer (GC) after D2 gastrectomy has been proven effective. There has yet to be a study that evaluates...
Adjuvant oxaliplatin plus S-1 (SOX) chemotherapy for gastric cancer (GC) after D2 gastrectomy has been proven effective. There has yet to be a study that evaluates adjuvant nanoparticle albumin-bound paclitaxel (nab-paclitaxel) plus S-1. In this single-center, retrospective study, GC patients after D2 gastrectomy received either nab-paclitaxel plus S-1 (AS group) or SOX group were recruited between January 2018 and December 2020 in The First Affiliated Hospital of Zhejiang University. Intravenous nab-paclitaxel 120 mg/m or 260 mg/m and oxaliplatin 130 mg/m were administered as eight 3 week cycle, especially in the AS and SOX group. Patients received S-1 twice daily with a dose of 40 mg/m in the two groups on days 1-14 of each cycle. The end points were disease-free survival (DFS) rate at 3 years and adverse events (AEs). There were 56 eligible patients, 28 in the AS group and 35 in the SOX group. The 3 year DFS rate was 78.0% in AS group versus 70.7% in SOX group (p = 0.46). Subgroup analysis showed that the patients with signet-ring positive in the AS group had a prolonged DFS compared with the SOX group (40.0 vs. 13.8 m, p = 0.02). The diffuse-type GC or low differentiation in the AS group was associated with numerically prolonged DFS compared with the SOX group, but the association was not statistically significant (p = 0.27 and p = 0.15 especially). Leukopenia (14.3%) were the most prevalent AEs in the AS group, while thrombocytopenia (28.5%) in the SOX group. Neutropenia (7.1% in AS group) and thrombocytopenia (22.8% in SOX group) were the most common grade 3 or 4 AEs. In this study analyzing past data, a tendency towards a greater 3 year DFS was observed when using AS regimen in signet-ring positive patients. AS group had fewer thrombocytopenia compared to SOX group. More studies should be conducted with larger sample sizes.
Topics: Humans; Stomach Neoplasms; Male; Female; Tegafur; Middle Aged; Oxaliplatin; Retrospective Studies; Gastrectomy; Drug Combinations; Oxonic Acid; Antineoplastic Combined Chemotherapy Protocols; Aged; Chemotherapy, Adjuvant; Albumin-Bound Paclitaxel; Adult; Disease-Free Survival; Paclitaxel; Albumins
PubMed: 38956232
DOI: 10.1038/s41598-024-65724-8 -
Journal of Natural Medicines Jul 2024A phytochemical investigation of Kaempferia champasakensis rhizomes led to the isolation of five new pimarane diterpenes, kaempferiols E-I (1-5). The structures of 1-5...
A phytochemical investigation of Kaempferia champasakensis rhizomes led to the isolation of five new pimarane diterpenes, kaempferiols E-I (1-5). The structures of 1-5 were elucidated by extensive spectroscopic techniques, including HR-ESI-MS, UV, IR, and 1D and 2D NMR. The absolute configurations of 1-3 were determined by the modified Mosher method, and those of 4 and 5 were established by ECD calculations. Further cytotoxic assay for all isolated compounds against three human cancer cell lines, lung cancer (A549), cervical cancer (HeLa), and breast cancer (MCF-7) indicated that 5 showed moderate cytotoxic activities against the three tested cell lines, with IC values of 44.78, 25.97, and 41.39 Mμ for A549, HeLa, and MCF-7 cell lines, respectively.
PubMed: 38955955
DOI: 10.1007/s11418-024-01829-8 -
Open Heart Jul 2024The extent to which differences in results from Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) and Rivaroxaban Once...
BACKGROUND
The extent to which differences in results from Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) and Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial (ROCKET) atrial fibrillation (AF)-the landmark trials for the approval of apixaban and rivaroxaban, respectively, for non-valvular AF-were influenced by differences in their protocols is debated. The potential influence of selection criteria on trial results was assessed by emulating these trials in data from the Global Anticoagulant Registry in the Field (GARFIELD)-AF registry.
METHODS
Vitamin K antagonist (VKA) and non-vitamin K oral antagonist (NOAC) users from GARFIELD-AF were selected according to eligibility for the original ARISTOTLE or ROCKET AF trials. A propensity score overlap weighted Cox model was used to emulate trial randomisation between treatment groups. Adjusted HRs for stroke or systemic embolism (SE) within 2 years of enrolment were calculated for each NOAC versus VKA.
RESULTS
Among patients on apixaban, rivaroxaban and VKA, 2570, 3560 and 8005 were eligible for ARISTOTLE, respectively, and 1612, 2005 and 4368, respectively, for ROCKET AF. When selecting for ARISTOTLE criteria, apixaban users had significantly lower stroke/SE risk versus VKA (HR 0.57; 95% CI 0.34 to 0.94) while no reduction was observed with rivaroxaban (HR 0.98; 95% CI 0.68 to 1.40). When selecting for ROCKET AF criteria, safety and efficacy versus VKA were similar across the NOACs.
CONCLUSION
Apixaban and rivaroxaban showed similar results versus VKA in high-risk patients selected according to ROCKET AF criteria, whereas differences emerged when selecting for the more inclusive ARISTOTLE criteria. Our results highlight the importance of trial selection criteria in interpreting trial results and underline the problems faced in comparing treatments across rather than within clinical trials.
Topics: Humans; Atrial Fibrillation; Factor Xa Inhibitors; Patient Selection; Stroke; Pyrazoles; Pyridones; Rivaroxaban; Male; Female; Aged; Treatment Outcome; Registries; Administration, Oral; Risk Factors; Randomized Controlled Trials as Topic; Risk Assessment; Anticoagulants; Vitamin K
PubMed: 38955399
DOI: 10.1136/openhrt-2024-002708 -
GSDME-mediated pyroptosis promotes anti-tumor immunity of neoadjuvant chemotherapy in breast cancer.Cancer Immunology, Immunotherapy : CII Jul 2024Paclitaxel and anthracycline-based chemotherapy is one of the standard treatment options for breast cancer. However, only about 6-30% of breast cancer patients achieved...
Paclitaxel and anthracycline-based chemotherapy is one of the standard treatment options for breast cancer. However, only about 6-30% of breast cancer patients achieved a pathological complete response (pCR), and the mechanism responsible for the difference is still unclear. In this study, random forest algorithm was used to screen feature genes, and artificial neural network (ANN) algorithm was used to construct an ANN model for predicting the efficacy of neoadjuvant chemotherapy for breast cancer. Furthermore, digital pathology, cytology, and molecular biology experiments were used to verify the relationship between the efficacy of neoadjuvant chemotherapy and immune ecology. It was found that paclitaxel and doxorubicin, an anthracycline, could induce typical pyroptosis and bubbling in breast cancer cells, accompanied by gasdermin E (GSDME) cleavage. Paclitaxel with LDH release and Annexin V/PI doubule positive cell populations, and accompanied by the increased release of damage-associated molecular patterns, HMGB1 and ATP. Cell coculture experiments also demonstrated enhanced phagocytosis of macrophages and increased the levels of IFN-γ and IL-2 secretion after paclitaxel treatment. Mechanistically, GSDME may mediate paclitaxel and doxorubicin-induced pyroptosis in breast cancer cells through the caspase-9/caspase-3 pathway, activate anti-tumor immunity, and promote the efficacy of paclitaxel and anthracycline-based neoadjuvant chemotherapy. This study has practical guiding significance for the precision treatment of breast cancer, and can also provide ideas for understanding molecular mechanisms related to the chemotherapy sensitivity.
Topics: Breast Neoplasms; Humans; Pyroptosis; Female; Neoadjuvant Therapy; Mice; Animals; Paclitaxel; Doxorubicin; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Xenograft Model Antitumor Assays; Gasdermins
PubMed: 38954046
DOI: 10.1007/s00262-024-03752-z -
Indian Journal of Public Health Apr 2024Cancer patients suffer from complicated chemotoxicity. Pharmacogenomics can help stratify patients by predicting their response to treatment and susceptibility toward...
Cancer patients suffer from complicated chemotoxicity. Pharmacogenomics can help stratify patients by predicting their response to treatment and susceptibility toward severe side effects. The spindle-assembly checkpoint (SAC) is an important pathway that is activated by platinum and taxane compounds and plays a crucial role in their cytotoxic activity. This study investigated a SAC component, Budding Uninhibited by Benzimidazoles 3 (BUB3), its expression, and genetic variants in advanced ovarian cancer patients treated with paclitaxel-carboplatin chemotherapy. Among 80 patients, BUB3 expression correlated with chemosensitivity, suggesting its potential as a predictive marker for chemotherapy response. However, high BUB3 expression was associated with a higher risk of poor survival. In addition, genetic polymorphisms in BUB3 (rs11248416 and rs11248419) were significantly linked to chemotherapy-related toxicities, with rs11248416 showing a negative impact on the patient's physical quality of life.
Topics: Humans; Female; Paclitaxel; Ovarian Neoplasms; Carboplatin; Middle Aged; M Phase Cell Cycle Checkpoints; Antineoplastic Combined Chemotherapy Protocols; Polymorphism, Single Nucleotide; Cell Cycle Proteins; Adult; Antineoplastic Agents; Quality of Life
PubMed: 38953826
DOI: 10.4103/ijph.ijph_809_23 -
PeerJ 2024Andrographolide (Andro), an extract of (Burm.f.) Wall. ex Nees (Acanthaceae), possesses diverse biologically active properties. However, the precise mechanisms and...
BACKGROUND
Andrographolide (Andro), an extract of (Burm.f.) Wall. ex Nees (Acanthaceae), possesses diverse biologically active properties. However, the precise mechanisms and effects of Andro on pancreatic cancer (PC) remain unclear.
METHODS
The cytotoxic potential of Andro and underlying mechanism towards PC cells was investigated through experiments and a xenograft mouse model. PC cells were first subjected to varying concentrations of Andro. The reactive oxygen species (ROS) was assessed using flow cytometry and DCFH-DA staining. The apoptosis rate was detected by flow cytometry. Additionally, western blot was applied to evaluate the expression levels of cleaved-caspase-3, DJ-1, LC3-I, LC3-II, and p62. To further elucidate the involvement of ROS accumulation and autophagy, we employed N-acetylcysteine as a scavenger of ROS and 3-Methyladenine as an inhibitor of autophagy.
RESULTS
Andro demonstrated potent anti-proliferative effects on PC cells and induced apoptosis, both and . The cytotoxicity of Andro on PC cells was counteracted by DJ-1 overexpression. The reduction in DJ-1 expression caused by Andro led to ROS accumulation, subsequently inhibiting the growth of PC cells. Furthermore, Andro stimulated cytoprotective autophagy, thus weakening the antitumor effect. Pharmacological blockade of autophagy further enhanced the antitumor efficacy of Andro.
CONCLUSION
Our study indicated that ROS accumulation induced by the DJ-1 reduction played a key role in Andro-mediated PC cell inhibition. Furthermore, the protective autophagy induced by the Andro in PC cells is a mechanism that needs to be addressed in future studies.
Topics: Reactive Oxygen Species; Diterpenes; Pancreatic Neoplasms; Autophagy; Protein Deglycase DJ-1; Animals; Humans; Mice; Cell Line, Tumor; Apoptosis; Xenograft Model Antitumor Assays; Mice, Nude
PubMed: 38952980
DOI: 10.7717/peerj.17619