ABSTRACT
Background: Postmenopausal osteoporosis (PMOP) increases fracture risk in women. Though traditional treatments are slow to act, combining romosozumab with conventional therapy shows promise. Despite its growing use, studies on effectiveness are limited. This study aims to systematically evaluate the combined therapy's impact on pain relief, disease progression, and adverse reactions in PMOP patients. Methods: Databases including PubMed, EMBASE, ScienceDirect, and the Cochrane Library were searched from their inception to September 2023 to identify randomized controlled trials (RCTs) evaluating the role of romosozumab in PMOP. Random or fixed effect models were employed for statistical analysis. Two reviewers independently assessed the quality of the included studies and extracted the data. The meta-analysis was conducted using RevMan 5.4 software. Results: Six RCTs with a total sample size of 17,985 cases were included. The incidence of vertebral fractures was compared and analyzed after 12 and 24 months of treatment. Romosozumab significantly reduced the incidence of vertebral fractures at 24 months (OR = 0.36; 95% CI: 0.35-0.52) but not at 12 months (OR = 0.39; 95% CI: 0.14-1.05). It was also associated with a decreased incidence of nonvertebral fractures (OR = 0.79; 95% CI: 0.66-0.94) and clinical fractures at 24 months (OR = 0.70; 95% CI: 0.59-0.82) compared to standard therapy. Romosozumab demonstrated a significant improvement in percentage change in bone mineral density (BMD) [mean difference (MD) = 10.38; 95% CI: 4.62-16.14] and in hip joint BMD (MD = 4.24; 95% CI: 2.92-5.56). There was no notable difference in adverse reactions compared to standard care (p > 0.05). Funnel plots displayed a predominantly symmetrical pattern, suggesting no evidence of publication bias in the selected literature. Conclusion: Combining romosozumab with conventional therapy effectively treats PMOP, significantly reducing vertebral, non-vertebral, and clinical fractures while increasing BMD in the hip, femoral neck, and lumbar spine. However, further high-quality studies are needed for validation.
ABSTRACT
The creation of synthetic materials that emulate the complexity of natural systems, such as enzymes, remains a challenge in biomimicry. Here, we present a simple yet effective strategy to introduce substrate selectivity and dynamic responsiveness into an enzyme-mimetic supramolecular material. We achieved this by anchoring γ-cyclodextrin to a fluorene-modified Lys/Cu2+ assembly, which mimics copper-dependent oxidase. The binding affinity among the components was examined using 1H NMR, isothermal titration calorimetry (ITC), and theoretical simulation. The γ-cyclodextrin acts as a host, forming a complex with the fluorenyl moiety and aromatic substrates of specific sizes. This ensures the proximity of the substrate reactive groups to the copper center, leading to size-selective enhancement of aromatic substrate oxidation, particularly favoring biphenyl substrates. Notably, α- and ß-cyclodextrins do not exhibit this effect, and the native oxidase lacks this selectivity. Additionally, the binding affinity of the aromatic substrate to the catalyst can be dynamically tuned by adding α-cyclodextrin or by irradiating with different wavelengths in the presence of competitive azo-guests, resulting in switched oxidative activities. This approach offers a new avenue for designing biomimetic materials with tailorable active site structures and catalytic properties.
ABSTRACT
The healing of severe chronic skin wounds in chronic diabetic patients is still a huge clinical challenge due to complex regeneration processes and control signals. Therefore, a single approach is difficult in obtaining satisfactory therapeutic efficacy for severe diabetic skin wounds. In this study, we adopted a composite strategy for diabetic skin wound healing. First, we fabricated a collagen-based biomimetic skin scaffold. The human basic fibroblast growth factor (bFGF) gene was electrically transduced into human umbilical cord mesenchymal stromal cells (UC-MSCs), and the stable bFGF-overexpressing UC-MSCs (bFGF-MSCs) clones were screened out. Then, an inspired collagen scaffold loaded with bFGF-MSCs was applied to treat full-thickness skin incision wounds in a streptozotocin-induced diabetic rat model. The mechanism of skin damage repair in diabetes mellitus was investigated using RNA-Seq and Western blot assays. The bioinspired collagen scaffold demonstrated good biocompatibility for skin-regeneration-associated cells such as human fibroblast (HFs) and endothelial cells (ECs). The bioinspired collagen scaffold loaded with bFGF-MSCs accelerated the diabetic full-thickness incision wound healing including cell proliferation enhancement, collagen deposition, and re-epithelialization, compared with other treatments. We also showed that the inspired skin scaffold could enhance the in vitro tube formation of ECs and the early angiogenesis process of the wound tissue in vivo. Further findings revealed enhanced angiogenic potential in ECs stimulated by bFGF-MSCs, evidenced by increased AKT phosphorylation and elevated HIF-1α and HIF-1ß levels, indicating the activation of HIF-1 pathways in diabetic wound healing. Based on the superior biocompatibility and bioactivity, the novel bioinspired skin healing materials composed of the collagen scaffold and bFGF-MSCs will be promising for healing diabetic skin wounds and even other refractory tissue regenerations. The bioinspired collagen scaffold loaded with bFGF-MSCs could accelerate diabetic wound healing via neovascularization by activating HIF-1 pathways.
Subject(s)
Collagen , Diabetes Mellitus, Experimental , Fibroblast Growth Factor 2 , Mesenchymal Stem Cells , Neovascularization, Physiologic , Signal Transduction , Skin , Tissue Scaffolds , Wound Healing , Humans , Wound Healing/drug effects , Animals , Mesenchymal Stem Cells/metabolism , Fibroblast Growth Factor 2/chemistry , Fibroblast Growth Factor 2/pharmacology , Collagen/chemistry , Rats , Tissue Scaffolds/chemistry , Skin/pathology , Neovascularization, Physiologic/drug effects , Rats, Sprague-Dawley , Male , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Hypoxia-Inducible Factor 1/metabolismABSTRACT
AIMS: To investigate the diagnostic and predictive role of 18F-FDG PET/CT in patients with autoimmune encephalitis (AE) as a whole group. METHODS: Thrty-five patients (20 females and 15 males) with AE were recruited. A voxel-to-voxel semi-quantitative analysis based on SPM12 was used to analyze 18F-FDG PET/CT imaging data compared to healthy controls. Further comparison was made in different prognostic groups categorized by modified Rankin Scale (mRS). RESULTS: In total, 24 patients (68.6%) were tested positive neuronal antibodies in serum and/or CSF. Psychiatric symptoms and seizure attacks were major clinical symptoms. In the acute stage, 13 patients (37.1%) demonstrated abnormal brain MRI results, while 33 (94.3%) presented abnormal metabolism patterns. 18F-FDG PET/CT was more sensitive than MRI (p < 0.05). Patients with AE mainly presented mixed metabolism patterns compared to the matched controls, demonstrating hypermetabolism mainly in the cerebellum, BG, MTL, brainstem, insula, middle frontal gyrus, and relatively hypometabolism in the frontal cortex, occipital cortex, temporal gyrus, right parietal gyrus, left cingulate gyrus (p < 0.05, FWE corrected). After a median follow-up of 26 months, the multivariable analysis identified a decreased level of consciousness as an independent risk factor associated with poor outcome of AE (HR = 3.591, p = 0.016). Meanwhile, decreased metabolism of right superior frontal gyrus along with increased metabolism of the middle and upper brainstem was more evident in patients with poor outcome (p < 0.001, uncorrected). CONCLUSION: 18F-FDG PET/CT was more sensitive than MRI to detect neuroimaging abnormalities of AE. A mixed metabolic pattern, characterized by large areas of cortical hypometabolism with focal hypermetabolism was a general metabolic pattern. Decreased metabolism of right superior frontal gyrus with increased metabolism of the middle and upper brainstem may predict poor long-term prognosis of AE.
Subject(s)
Encephalitis , Fluorodeoxyglucose F18 , Positron Emission Tomography Computed Tomography , Humans , Female , Male , Positron Emission Tomography Computed Tomography/methods , Adult , Middle Aged , Encephalitis/diagnostic imaging , Encephalitis/metabolism , Young Adult , Cohort Studies , Predictive Value of Tests , Hashimoto Disease/diagnostic imaging , Hashimoto Disease/metabolism , Brain/diagnostic imaging , Brain/metabolism , Adolescent , China , Radiopharmaceuticals , Aged , Magnetic Resonance Imaging , East Asian PeopleABSTRACT
Highly sensitive and rapid detection of ethylene, the smallest alkene of great significance in human physiological metabolism remains a great challenge. In this study, we developed a new photoionization-induced substitution reaction chemical ionization time-of-flight mass spectrometry (PSCI-TOFMS) for trace exhaled ethylene detection. An intriguing ionization phenomenon involving a substitution reaction between the CH2Br2+ reactant ion and ethylene molecule was discovered and studied for the first time. The formation of readily identifiable [CH2Br·C2H4]+ product ion greatly enhanced the ionization efficiency of ethylene, which led to approximately 800-fold improvement of signal intensity over that in single photon ionization mode. The CH2Br2+ reactant ion intensity and ion-molecule reaction time were optimized, and a Nafion tube was employed to eliminate the influence of humidity on the ionization of ethylene. Consequently, a limit of detection (LOD) as low as 0.1 ppbv for ethylene was attained within 30 s at 100 % relative humidity. The application of PSCI-TOFMS on the rapid detection of trace amounts of exhaled ethylene from healthy smoker and non-smoker volunteers demonstrated the satisfactory performance and potential of this system for trace ethylene measurement in clinical diagnosis, atmospheric measurement, and process monitoring.
Subject(s)
Ethylenes , Ethylenes/chemistry , Ethylenes/analysis , Humans , Limit of Detection , Breath Tests/methods , Photochemical Processes , Exhalation , Mass Spectrometry/methodsABSTRACT
A series of chromone-deferiprone hybrids were designed, synthesized, and evaluated as inhibitors of human monoamine oxidase B (hMAO-B) with iron-chelating activity for the treatment of Alzheimer's disease (AD). The majority exhibited moderate inhibitory activity towards hMAO-B and potent iron-chelating properties. Particularly, compound 25c demonstrated remarkable selectivity against hMAO-B with an IC50 value of 1.58 µM and potent iron-chelating ability (pFe3+ = 18.79) comparable to that of deferiprone (pFe3+ = 17.90). Molecular modeling and kinetic studies showed that 25c functions as a non-competitive hMAO-B inhibitor. According to the predicted results, compound 25c can penetrate the blood-brain barrier (BBB). Additionally, it has been proved to display significant antioxidant activity and the ability to inhibit neuronal ferroptosis. More importantly, compound 25c reduced the cognitive impairment induced by scopolamine and showed significant non-toxicity in short-term toxicity assays. In summary, compound 25c was identified as a potential anti-AD agent with hMAO-B inhibitory, iron-chelating and anti-ferroptosis activities.
Subject(s)
Alzheimer Disease , Chromones , Deferiprone , Iron Chelating Agents , Monoamine Oxidase Inhibitors , Monoamine Oxidase , Monoamine Oxidase Inhibitors/pharmacology , Monoamine Oxidase Inhibitors/chemistry , Monoamine Oxidase Inhibitors/chemical synthesis , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Iron Chelating Agents/pharmacology , Iron Chelating Agents/chemistry , Iron Chelating Agents/chemical synthesis , Deferiprone/pharmacology , Deferiprone/chemistry , Monoamine Oxidase/metabolism , Humans , Chromones/chemistry , Chromones/pharmacology , Chromones/chemical synthesis , Structure-Activity Relationship , Animals , Antioxidants/pharmacology , Antioxidants/chemistry , Antioxidants/chemical synthesis , Ferroptosis/drug effects , Molecular Structure , Molecular Docking Simulation , Blood-Brain Barrier/metabolism , Blood-Brain Barrier/drug effects , Dose-Response Relationship, DrugABSTRACT
BACKGROUND AND AIM: The objective of our study was to examine the association between composite dietary antioxidant index (CDAI) and atherosclerotic cardiovascular disease (ASCVD) in adults. METHODS AND RESULTS: Data was gathered from the National Health and Nutrition Examination Survey (NHANES) between 2001 and 2018. To examine the connection between CDAI and ASCVD, multiple logistic regression analyses were performed. Restricted cubic splines were utilized to examine non-linear correlations, and the inflection point was identified using a two-piecewise linear regression approach. Subgroup analyses were performed to demonstrate stability of results. A total of 44,494 individuals were included in the study. The multivariate logistic regression model was fully adjusted and revealed an odds ratio of 0.968 (95% CI: 0.959-0.978; P < 0.001) for the correlation between CDAI and ASCVD. Furthermore, individuals in the highest quartile of CDAI exhibited a decreased risk of ASCVD compared to those in the lowest quartile [0.716 (0.652-0.787); P < 0.001]. Moreover, restricted cubic spline (RCS) analysis revealed non-linear relationship between CDAI and ASCVD, with inflection point at -0.387. The analysis of subgroups showed that the importance of CDAI remained consistent among various age, sex, race, body mass index (BMI), and physical activity. CONCLUSIONS: Our research revealed an inverse and non-linear relationship between CDAI and ASCVD in adults. The implications of these findings are significant for future studies and the formulation of dietary guidelines.
Subject(s)
Antioxidants , Atherosclerosis , Diet, Healthy , Nutrition Surveys , Protective Factors , Humans , Male , Cross-Sectional Studies , Female , Middle Aged , Adult , United States/epidemiology , Risk Assessment , Atherosclerosis/epidemiology , Atherosclerosis/prevention & control , Atherosclerosis/blood , Atherosclerosis/diagnosis , Aged , Nutritive Value , Risk Factors , Diet/adverse effects , Heart Disease Risk Factors , PrognosisABSTRACT
This study investigated the effects of dietary erucic acid (EA) on growth, lipid accumulation, antioxidant and immune abilities, and lipid metabolism in black carp fed six diets containing varying levels of EA (0.00%, 0.44%, 0.81%, 1.83%, 2.74%, and 3.49%), for 8 weeks. Results showed that fish fed the 3.49% EA diet exhibited lower weight gain, compared to those fed the 0.81% EA diet. In a dose-dependent manner, the serum triglycerides and total cholesterol were significantly elevated in the EA groups. The 1.83%, 2.74%, and 3.49% levels of EA increased alanine aminotransferase and aspartate aminotransferase activities, as well as decreased acid phosphatase and alkaline phosphatase values compared to the EA-deficient group. The hepatic catalase activity and transcriptional level were notably reduced, accompanied by increased hydrogen peroxide contents in the EA groups. Furthermore, dietary EA primarily increased the C22:1n-9 and C20:1n-9 levels, while decreasing the C18:0 and C18:1n-9 contents. In the EA groups, expressions of genes, including hsl, cpt1a, cpt1b, and ppara were downregulated, whereas the fas and gpat expressions were enhanced. Additionally, dietary EA elevated the mRNA level of il-1ß and reduced the expression of il-10. Collectively, high levels of EA (2.74% and 3.49%) induced lipid accumulation, reduced antioxidative and immune abilities in black carp by inhibiting lipid catabolism and increasing lipogenesis. These findings provide valuable insights for optimizing the use of rapeseed oil rich in EA for black carp and other carnivorous fish species.
ABSTRACT
Temozolomide (TMZ) is widely utilized as the primary chemotherapeutic intervention for glioblastoma. However, the clinical use of TMZ is limited by its various side effects and resistance to chemotherapy. The present study revealed the synergistic inhibition of glioblastoma through the combined administration of TMZ and perifosine. This combination therapy markedly diminished BRCA1 expression, resulting in the suppression of DNA repair mechanisms. Furthermore, the combination of TMZ and perifosine elicited caspase-dependent apoptosis, decreasing glioblastoma cell viability and proliferation. The observed synergistic effect of this combination therapy on glioblastoma was validated in vivo, as evidenced by the substantial reduction in glioblastoma xenograft growth following combined treatment with TMZ and perifosine. In recurrent glioma patients, higher BRCA1 expression is associated with worse prognosis, especially the ones that received TMZ-treated. These findings underscore the potent antitumor activity of the AKT inhibitor perifosine when combined with TMZ and suggest that this approach is a promising strategy for clinical glioblastoma treatment.
ABSTRACT
OBJECTIVE: α-HBDH serves as a biomarker of myocardial damage and is implicated in adverse outcomes across various critical illnesses. Our study aimed to assess the correlation between α-HBDH levels, and severity and recurrence of acute ischemic stroke (AIS). METHODS: We enrolled patients with mild-to-moderate AIS within 72 h of onset. Based on the baseline score of the National Institutes of Health Stroke Scale (bNIHSS) at registration, patients were categorized into mild (bNIHSS ≤ 4 points) and moderate AIS groups (4 < bNIHSS ≤ 10 points). Subsequently, based on the normal upper limit of α-HBDH, patients were divided into low-level α-HBDH (≤ 180 U/L) and high-level α-HBDH (> 180 U/L) groups. Multivariate logistic regression analysis and Cox proportional hazard regression analysis were employed to evaluate the relationship between α-HBDH levels and bNIHSS scores as well as the risk of recurrent AIS within 90 days. RESULTS: We observed a significant association between higher baseline levels of α-HBDH and increased bNIHSS scores, indicating a more severe AIS (odds ratio = 24.449; 95% confidence interval [CI], 8.749-68.324; p < 0.01). Additionally, the risk of recurrent AIS within 90 days was 4.666 times higher in the high-level α-HBDH group compared to the low-level group (hazard ratio = 4.666; 95% CI, 2.481-8.777; p < 0.01). CONCLUSIONS: The baseline level of α-HBDH is significantly correlated with the severity of AIS and the risk of recurrent AIS within 90 days.
Subject(s)
Ischemic Stroke , Recurrence , Severity of Illness Index , Humans , Male , Female , Ischemic Stroke/diagnosis , Ischemic Stroke/etiology , Middle Aged , Aged , Biomarkers/blood , Brain Ischemia/etiology , Brain Ischemia/pathologyABSTRACT
Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta. The development of novel scaffolds for human monoamine oxidase B (hMAO-B) inhibitors with reversible properties represents an important strategy to improve the efficacy and safety for PD treatment. In the current work, we have devised and assessed two innovative derivative series serving as hMAO-B inhibitors. These series have utilized benzimidazole as a scaffold and strategically incorporated a primary amide group, which is recognized as a pivotal pharmacophore in subsequent activity screening and reversible mode of action. Among these compounds, 16d has emerged as the most potent hMAO-B inhibitor with an IC50 value of 67.3 nM, comparable to safinamide (IC50 = 42.6 nM) in vitro. Besides, 16d demonstrated good selectivity towards hMAO-B isoenzyme with a selectivity index over 387. Importantly, in line with the design purpose, 16d inhibited hMAO-B in a competitive and reversible manner (Ki = 82.50 nM). Moreover, 16d exhibited a good safety profile in both cellular and acute toxicity assays in mice. It also displayed ideal pharmacokinetic properties and blood-brain barrier permeability in vivo, essential prerequisites for central nervous system medicines. In the MPTP-induced PD mouse model, 16d significantly alleviated the motor impairment, especially muscle relaxation and motor coordination. Therefore, 16d, serving as a lead compound, holds instructive significance for subsequent investigations regarding its application in the treatment of PD.
Subject(s)
Benzimidazoles , Drug Discovery , Monoamine Oxidase Inhibitors , Monoamine Oxidase , Parkinson Disease , Monoamine Oxidase Inhibitors/pharmacology , Monoamine Oxidase Inhibitors/chemistry , Monoamine Oxidase Inhibitors/chemical synthesis , Monoamine Oxidase/metabolism , Humans , Animals , Structure-Activity Relationship , Mice , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Benzimidazoles/chemical synthesis , Parkinson Disease/drug therapy , Molecular Structure , Dose-Response Relationship, Drug , Male , Mice, Inbred C57BL , Antiparkinson Agents/pharmacology , Antiparkinson Agents/chemical synthesis , Antiparkinson Agents/chemistry , Antiparkinson Agents/therapeutic useABSTRACT
The abnormal GGGGCC hexanucleotide repeat expansions (HREs) in C9orf72 cause the fatal neurodegenerative diseases including amyotrophic lateral sclerosis and frontotemporal dementia. The transcribed RNA HREs, short for r(G4C2)n, can form toxic RNA foci which sequestrate RNA binding proteins and impair RNA processing, ultimately leading to neurodegeneration. Here, we determined the crystal structure of r(G4C2)2, which folds into a parallel tetrameric G-quadruplex composed of two four-layer dimeric G-quadruplex via 5'-to-5' stacking in coordination with a K+ ion. Notably, the two C bases locate at 3'- end stack on the outer G-tetrad with the assistance of two additional K+ ions. The high-resolution structure reported here lays a foundation in understanding the mechanism of neurological toxicity of RNA HREs. Furthermore, the atomic details provide a structural basis for the development of potential therapeutic agents against the fatal neurodegenerative diseases ALS/FTD.
Subject(s)
Amyotrophic Lateral Sclerosis , C9orf72 Protein , DNA Repeat Expansion , Frontotemporal Dementia , G-Quadruplexes , RNA , C9orf72 Protein/genetics , C9orf72 Protein/chemistry , Amyotrophic Lateral Sclerosis/genetics , Frontotemporal Dementia/genetics , Humans , RNA/chemistry , RNA/genetics , DNA Repeat Expansion/genetics , Crystallography, X-Ray , Models, MolecularABSTRACT
Multitargeting has become a promising strategy for the development of anti-Alzheimer's disease (AD) drugs, considering the complexity of molecular mechanisms in AD pathology. In most pre-clinical studies, the effectiveness of these multi-targeted anti-AD drugs has been demonstrated but comprehensive safety assessments are lacking. Here, the safety evaluation of a novel multi-targeted candidate in AD (XYY-CP1106), characterized by its dual-property of iron chelation and monoamine oxidase B inhibition, was conducted by multifaceted analysis. Acute toxicity in mice was conducted to investigate the safety of oral administration and the maximum tolerated dose of the agent. In vitro Ames analysis, CHL chromosomal aberration analysis, and bone marrow micronucleus analysis were executed to evaluate the genotoxicity. A teratogenesis investigation in pregnant mice were meticulously performed to evaluate the teratogenesis of XYY-CP1106. Furthermore, a 90-day long-term toxicity analysis in rats was investigated to evaluate the cumulative toxicity after long-term administration. Strikingly, no toxic phenomena were found in all investigations, demonstrating relatively high safety profile of the candidate compound. The securing of safety heightened the translational significance of XYY-CP1106 as a novel multi-targeted anti-AD candidate, supporting the rationality of multitargeting strategy in the designs of smart anti-AD drugs.
Subject(s)
Alzheimer Disease , Animals , Alzheimer Disease/drug therapy , Female , Mice , Male , Pregnancy , Rats , Rats, Sprague-Dawley , Mice, Inbred ICR , Maximum Tolerated Dose , Monoamine Oxidase Inhibitors/pharmacology , Monoamine Oxidase Inhibitors/toxicity , Chromosome Aberrations/drug effects , Teratogenesis/drug effectsABSTRACT
Electron-rich and hindered aryl chlorides are the most challenging substrates in Suzuki-Miyaura cross-coupling (SMC) reactions. Herein, we report a highly efficient catalytic system for the SMC reaction using trace amounts of commercially available catalysts [Pd(PPh3)4/(t-Bu)PCy2; Pd loading as low as 9.5 × 10-5 mol%]. This catalytic system can efficiently couple deactivated and sterically hindered aryl chlorides with various substituted phenylboronic acids, even in one-pot multiple coupling reactions (yield of products up to 92%). The impact of solvents on SMC reactions and the mechanisms of by-product formation in aryl boronic acid couplings are analyzed using density functional theory (DFT). Utilizing trace amounts of commercially available catalysts avoids complex synthesis, reduces costs, and minimizes metal residues.
ABSTRACT
This study investigated the effects of glucose (GLU), tapioca starch (TS), gelatinized tapioca starch (GTS), potato starch (PS) and gelatinized potato starch (GPS) on growth and physiological responses in juvenile largemouth bass Micropterus salmoides. After 8 weeks, fish fed with starch diets had better weight gain and growth rates. Counts of red blood cells and monocytes were increased in the PS and GPS groups, compared to GLU group. Contents of serum triglyceride and total cholesterol were markedly elevated in the TS, PS and GPS groups. There were lower levels of serum glucose, insulin and cholecystokinin, and higher agouti-related peptide contents in the PS group compared to GLU group. PS and GPS could enhance glycolysis and TCA cycle by increasing their enzyme activities and transcriptional levels. Additionally, starch sources markedly heightened mRNA levels of key genes involved in the respiratory electron transport chain. Additionally, elevated mRNA levels of key antioxidant genes were shown in the TS and GTS groups. Moreover, TS and PS could promote immunity by upregulating transcriptional levels of the complement system, lysozyme and hepcidin. Taken together, starch exhibited better growth via increasing glycolysis and TCA cycle compared with GLU, and PS could improve antioxidant and immune capacities in largemouth bass.
ABSTRACT
Three-dimensional (3D) cell culture has been used in many fields of biology because of its unique advantages. As a representative of the 3D systems, 3D spheroids are used as building blocks for tissue construction. Larger tumor aggregates can be assembled by manipulating or stacking the tumor spheroids. The motivation of this study is to investigate the behavior of the cells distributed at different locations of the spheroids in the fusion process and the mechanism behind it. To this aim, spheroids with varying grades of maturity or age were generated for fusion to assemble micro-tumor tissues. The dynamics of the fusion process, the motility of the cells distributed in different heterogeneous architecture sites, and their reactive oxygen species profiles were studied. We found that the larger the spheroid necrotic core, the slower the fusion rate of the spheroid. The cells that move were mainly distributed on the spheroid's surface during fusion. In addition to dense microfilament distribution and low microtubule content, the reactive oxygen content was high in the fusion site, while the non-fusion site was the opposite. Last, multi-spheroids with different maturities were fused to complex micro-tissues to mimic solid tumors and evaluate Doxorubicin's anti-tumor efficacy.
Subject(s)
Doxorubicin , Reactive Oxygen Species , Spheroids, Cellular , Spheroids, Cellular/metabolism , Spheroids, Cellular/cytology , Spheroids, Cellular/pathology , Humans , Reactive Oxygen Species/metabolism , Doxorubicin/pharmacology , Cell Fusion , Neoplasms/pathology , Neoplasms/metabolism , Cell Line, Tumor , Cell Culture Techniques, Three Dimensional , Cell Movement , Tissue EngineeringABSTRACT
OBJECTIVE: To delineate the efficacy and safety profile of hemodiafiltration with endogenous reinfusion (HFR) for uremic toxin removal in patients undergoing maintenance hemodialysis (MHD). METHODS: Patients who have been on MHD for a period of at least 3 months were enrolled. Each subject underwent one HFR and one hemodiafiltration (HDF) treatment. Blood samples were collected before and after a single HFR or HDF treatment to test uremic toxin levels and to calculate clearance rate. The primary efficacy endpoint was to compare uremic toxin levels of indoxyl sulfate (IS), λ-free light chains (λFLC), and ß2-microglobulin (ß2-MG) before and after HFR treatment. Secondary efficacy endpoints was to compare the levels of urea, interleukin-6 (IL-6), P-cresol, chitinase-3-like protein 1 (YKL-40), leptin (LEP), hippuric acid (HPA), trimethylamine N-oxide (TMAO), asymmetric dimethylarginine (ADMA), tumor necrosis factor-α (TNF-α), fibroblast growth factor 23 (FGF23) before and after HFR treatment. The study also undertook a comparative analysis of uremic toxin clearance between a single HFR and HDF treatment. Meanwhile, the lever of serum albumin and branched-chain amino acids before and after a single HFR or HDF treatment were compared. In terms of safety, the study was meticulous in recording vital signs and the incidence of adverse events throughout its duration. RESULTS: The study enrolled 20 patients. After a single HFR treatment, levels of IS, λFLC, ß2-MG, IL-6, P-cresol, YKL-40, LEP, HPA, TMAO, ADMA, TNF-α, and FGF23 significantly decreased (p < 0.001 for all). The clearance rates of λFLC, ß2-MG, IL-6, LEP, and TNF-α were significantly higher in HFR compared to HDF (p values: 0.036, 0.042, 0.041, 0.019, and 0.036, respectively). Compared with pre-HFR and post-HFR treatment, levels of serum albumin, valine, and isoleucine showed no significant difference (p > 0.05), while post-HDF, levels of serum albumin significantly decreased (p = 0.000). CONCLUSION: HFR treatment effectively eliminates uremic toxins from the bloodstream of patients undergoing MHD, especially protein-bound toxins and large middle-molecule toxins. Additionally, it retains essential physiological compounds like albumin and branched-chain amino acids, underscoring its commendable safety profile.
Subject(s)
Cresols , Hemodiafiltration , Methylamines , Humans , Hemodiafiltration/adverse effects , Pilot Projects , Uremic Toxins , Chitinase-3-Like Protein 1 , Interleukin-6 , Tumor Necrosis Factor-alpha , Renal Dialysis , Amino Acids, Branched-Chain , Serum AlbuminABSTRACT
5-Aminolevulinic acid (ALA) and its derivatives, serving as the endogenous precursor of the photosensitizer (PS) protoporphyrin IX (PpIX), successfully applied in tumor imaging and photodynamic therapy (PDT). ALA and its derivatives have been used to treat actinic keratosis (AK), basal cell carcinoma (BCC), and improve the detection of superficial bladder cancer. However, the high hydrophilicity of ALA and the conversion of PpIX to heme have limited the accumulation of PpIX, hindering the efficiency and potential application of ALA-PDT. This study aims to evaluate the PDT activity of three rationally designed series of ALA-HPO prodrugs, which were based on enhancing the lipophilicity of the prodrugs and reducing the labile iron pool (LIP) through HPO iron chelators to promote PpIX accumulation. Twenty-four ALA-HPO conjugates, incorporating amide, amino acid, and ester linkages, were synthesized. Most of the conjugates, exhibited no dark-toxicity to cells, according to bioactivity evaluation. Ester conjugates 19a-g showed promoted phototoxicity when tested on tumor cell lines, and this increased phototoxicity was strongly correlated with elevated PpIX levels. Among them, conjugate 19c emerged as the most promising (HeLa, IC50 = 24.25 ± 1.43 µM; MCF-7, IC50 = 43.30 ± 1.76 µM; A375, IC50 = 28.03 ± 1.00 µM), displaying superior photodynamic anticancer activity to ALA (IC50 > 100 µM). At a concentration of 80 µM, the fluorescence intensity of PpIX induced by compound 19c in HeLa, MCF-7, and A375 cells was 18.9, 5.3, and 2.8 times higher, respectively, than that induced by ALA. In conclusion, cellular phototoxicity showed a strong correlation with intracellular PpIX fluorescence levels, indicating the potential application of ALA-HPO conjugates in ALA-PDT.
Subject(s)
Aminolevulinic Acid , Antineoplastic Agents , Drug Screening Assays, Antitumor , Photochemotherapy , Photosensitizing Agents , Humans , Aminolevulinic Acid/pharmacology , Aminolevulinic Acid/chemistry , Photosensitizing Agents/pharmacology , Photosensitizing Agents/chemistry , Photosensitizing Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Structure-Activity Relationship , Molecular Structure , Pyridones/pharmacology , Pyridones/chemistry , Pyridones/chemical synthesis , Cell Line, Tumor , Protoporphyrins/chemistry , Protoporphyrins/pharmacology , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Cell Survival/drug effects , Prodrugs/pharmacology , Prodrugs/chemistry , Prodrugs/chemical synthesisABSTRACT
Administering medication is a crucial strategy in improving the prognosis for advanced endometrial cancer. However, the rise of drug resistance often leads to the resurgence of cancer or less-than-ideal treatment outcomes. Prior studies have shown that autophagy plays a dual role in the development and progression of endometrial cancer, closely associated with drug resistance. As a result, concentrating on autophagy and its combination with medical treatments might be a novel approach to improve the prognosis for endometrial cancer. This study explores the impact of autophagy on drug resistance in endometrial cancer, investigates its core mechanisms, and scrutinizes relevant treatments aimed at autophagy, aiming to illuminate the issue of treatment resistance in advanced endometrial cancer.