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Biomolecules & Therapeutics Jun 2024Colorectal cancer (CRC) continues to demonstrate high incidence and mortality rates, emphasizing that implementing strategic measures for prevention and treatment is...
Colorectal cancer (CRC) continues to demonstrate high incidence and mortality rates, emphasizing that implementing strategic measures for prevention and treatment is crucial. Recently, the dopamine receptor D2 (DRD2), a G protein-coupled receptor, has been reported to play multiple roles in growth of tumor cells. This study investigated the anticancer potential of domperidone, a dopamine receptor D2 antagonist, in HCT116 human CRC cells. Domperidone demonstrated concentration- and time-dependent reductions in cell viability, thereby inducing apoptosis. The molecular mechanism revealed that domperidone modulated the mitochondrial pathway, decreasing mitochondrial Bcl-2 levels, elevating cytosolic cytochrome C expression, and triggering caspase- 3, -7, and -9 cleavage. Domperidone decreased in formation of β-arrestin2/MEK complex, which contributing to inhibition of ERK activation. Additionally, treatment with domperidone diminished JAK2 and STAT3 activation. Treatment of U0126, the MEK inhibitor, resulted in reduced phosphorylation of MEK, ERK, and STAT3 without alteration of JAK2 activation, indicating that domperidone targeted both MEK-ERK-STAT3 and JAK2-STAT3 signaling pathways, respectively. Immunoblot analysis revealed that domperidone also downregulated DRD2 expression. Domperidone-induced reactive oxygen species (ROS) generation and -acetylcysteine treatment mitigated ROS levels and restored cell viability. An xenograft study verified the significant antitumor effects of domperidone. These results emphasize the multifaceted anticancer effects of domperidone, highlighting its potential as a promising therapeutic agent for human CRC.
PubMed: 38914471
DOI: 10.4062/biomolther.2024.048 -
The American Journal of Managed Care Jun 2024To assess whether hospitals participating in Medicare's Bundled Payments for Care Improvement (BPCI) program for joint replacement changed their referral patterns to... (Observational Study)
Observational Study
OBJECTIVES
To assess whether hospitals participating in Medicare's Bundled Payments for Care Improvement (BPCI) program for joint replacement changed their referral patterns to favor higher-quality skilled nursing facilities (SNFs).
STUDY DESIGN
Retrospective observational study using 2009-2015 inpatient and outpatient claims from a 20% sample of Medicare beneficiaries undergoing joint replacement in US hospitals (N = 146,074) linked with data from Medicare's BPCI program and Nursing Home Compare.
METHODS
We ran fixed effect regression models regressing BPCI participation on hospital-SNF referral patterns (number of SNF discharges, number of SNF partners, and SNF referral concentration) and SNF quality (facility inspection survey rating, patient outcome rating, staffing rating, and registered nurse staffing rating).
RESULTS
We found that BPCI participation was associated with a decrease in the number of SNF referrals and no significant change in the number of SNF partners or concentration of SNF partners. BPCI participation was associated with discharge to SNFs with a higher patient outcome rating by 0.04 stars (95% CI, 0.04-0.26). BPCI participation was not associated with improvements in discharge to SNFs with a higher facility survey rating (95% CI, -0.03 to 0.11), staffing rating (95% CI, -0.07 to 0.04), or registered nurse staffing rating (95% CI, -0.09 to 0.02).
CONCLUSIONS
BPCI participation was associated with lower volume of SNF referrals and small increases in the quality of SNFs to which patients were discharged, without narrowing hospital-SNF referral networks.
Topics: Skilled Nursing Facilities; Humans; United States; Retrospective Studies; Medicare; Referral and Consultation; Quality Improvement; Female; Patient Care Bundles; Male; Arthroplasty, Replacement; Aged
PubMed: 38912933
DOI: 10.37765/ajmc.2024.89566 -
Folia Histochemica Et Cytobiologica Jun 2024Diabetic cataract (DC) is a common ocular complication of diabetes. Mitofusin 2 (MFN2), a mitochondrial fusion protein, is involved in the pathogenesis of cataract and...
INTRODUCTION
Diabetic cataract (DC) is a common ocular complication of diabetes. Mitofusin 2 (MFN2), a mitochondrial fusion protein, is involved in the pathogenesis of cataract and diabetic complications. However, its role and molecular mechanisms in DC remain unclear.
MATERIALS AND METHODS
DC models in rats were induced by intraperitoneal injection of streptozocin (STZ) for 12 weeks. We measured the body weight of rats, blood glucose concentrations, sorbitol dehydrogenase (SDH) activity and advanced glycation end products (AGE) content in the lenses of rats. MFN2 mRNA and protein expression levels in the lenses were detected by RT-qPCR and western blot assays. In vitro, human lens epithelial (HLE) B3 cells were treated for 48 h with 25 mM glucose (high glucose, HG) to induce cell damage. To determine the role of MFN2 in HG-induced cell damage, HLE-B3 cells were transfected with lentivirus loaded with MFN2 overexpression plasmid or short hairpin RNA (shRNA) to overexpress or knock down MFN2 expression, followed by HG exposure. Cell viability was assessed by CCK-8 assay. Flow cytometry was used to detect cell apoptosis and reactive oxygen species (ROS) level. JC-1 staining showed the changes in mitochondrial membrane potential (Δψm). The mediators related to apoptosis, mitochondrial damage, and autophagy were determined.
RESULTS
STZ-administrated rats showed reduced body weight, increased blood glucose levels, elevated SDH activity and AGE content, suggesting successful establishment of the DC rat model. Interestingly, MFN2 expression was significantly downregulated in DC rat lens and HG-induced HLE-B3 cells. Further analysis showed that under HG conditions, MFN2 overexpression enhanced cell viability and inhibited apoptosis accompanied by decreased Bax, cleaved caspase-9 and increased Bcl-2 expression in HLE-B3 cells. MFN2 overexpression also suppressed the mitochondrial damage elicited by HG as manifested by reduced ROS production, recovered Δψm and increased mitochondrial cytochrome c (Cyto c) level. Moreover, MFN2 overexpression increased LC3BⅡ/LC3BⅠ ratio and Beclin-1 expression, but decreased p62 level, and blocked the phosphorylation of mTOR in HG-treated HLE-B3 cells. In contrast, MFN2 silencing exerted opposite effects.
CONCLUSIONS
Our findings indicate that MFN2 expression may be essential for preventing lens epithelial cell apoptosis during development of diabetic cataract.
PubMed: 38912568
DOI: 10.5603/fhc.98875 -
Heliyon Jun 2024Specific anthocyanins and phenolic compounds exhibit acetylcholinesterase inhibitory (AChEi) activity. In this study, the AChEi activity of jaboticaba peel extracts were...
Specific anthocyanins and phenolic compounds exhibit acetylcholinesterase inhibitory (AChEi) activity. In this study, the AChEi activity of jaboticaba peel extracts were investigated based on their high phenol contents. Jaboticaba peel ethanolic extract (PEX) and aqueous extract (PAX) were prepared by extracting jaboticaba peel with 95% ethanol and boiling water, respectively. Through HPLC-MS/MS and HPLC-PDA analysis, gallic acid was identified in PAX with a concentration of 598.13 ± 42.43 mg/100 g extract, and ellagic acid in PEX with a concentration of 350.47 ± 8.53 mg/100 g extract. Both PEX and PAX showed dose-dependent inhibition against AChE activity, with IC values of 3.54 and 4.07 mg/mL, respectively. The mechanism of inhibition of PEX was determined to be non-competitive inhibition based on the decreasing and relatively constant with increasing PEX concentration, as determined using a Lineweaver-Burk plot.
PubMed: 38912491
DOI: 10.1016/j.heliyon.2024.e32322 -
Frontiers in Cellular and Infection... 2024We assessed the anti-chlamydial activity of fresh vaginal secretions, deciphering the microbial and metabolic components able to counteract viability.
INTRODUCTION
We assessed the anti-chlamydial activity of fresh vaginal secretions, deciphering the microbial and metabolic components able to counteract viability.
METHODS
Forty vaginal samples were collected from a group of reproductive-aged women and their anti-chlamydial activity was evaluated by inhibition experiments. Each sample underwent 16S rRNA metabarcoding sequencing to determine the bacterial composition, as well as H-NMR spectroscopy to detect and quantify the presence of vaginal metabolites.
RESULTS
Samples characterized by a high anti-chlamydial activity were enriched in , especially and , while not-active samples exhibited a significant reduction of lactobacilli, along with higher relative abundances of and . showed an opposite behavior compared to , being more prevalent in not-active vaginal samples. Higher concentrations of several amino acids (i.e., isoleucine, leucine, and aspartate; positively correlated to the abundance of and ) lactate, and 4-aminobutyrate were the most significant metabolic fingerprints of highly active samples. Acetate and formate concentrations, on the other hand, were related to the abundances of a group of anaerobic opportunistic bacteria (including and ). Finally, glucose, correlated to and genera, emerged as a key molecule of the vaginal environment: indeed, the anti-chlamydial effect of vaginal fluids decreased as glucose concentrations increased.
DISCUSSION
These findings could pave the way for novel strategies in the prevention and treatment of chlamydial urogenital infections, such as lactobacilli probiotic formulations or lactobacilli-derived postbiotics.
Topics: Female; Humans; Vagina; RNA, Ribosomal, 16S; Lactobacillus; Chlamydia trachomatis; Adult; Streptococcus; Young Adult; Lactobacillus crispatus; Chlamydia Infections
PubMed: 38912205
DOI: 10.3389/fcimb.2024.1403782 -
Frontiers in Chemistry 2024The oxalic acid complexation method and sulfuric acid heat treatment method were used to synthesize the YMnO (YMO) and YMO-SO (YMO-SO) photocatalysts. The YMO-SO...
Synthesis and full-spectrum-responsive photocatalytic activity from UV/Vis to near-infrared region of S-O decorated YMnO nanoparticles for photocatalytic degradation of ibuprofen.
The oxalic acid complexation method and sulfuric acid heat treatment method were used to synthesize the YMnO (YMO) and YMO-SO (YMO-SO) photocatalysts. The YMO-SO photocatalyst maintained the crystal structure of YMO, but the particle size increased slightly and the optical band gap decreased significantly. The YMO-SO photocatalyst demonstrates a wide range of light absorption capabilities, covering ultraviolet, visible and near-infrared light. The photocatalytic activity of YMO-SO was investigated with ibuprofen as the target pollutant. The YMO-SO photocatalyst exhibits high ultraviolet (UV), visible and near-infrared photocatalytic activity. Experiments with different environmental parameters confirmed that the best catalyst content was 1 g/L, the best drug concentration was 75 mg/L and the best pH value was 7. The capture experiment, free radical detection experiment and photocatalytic mechanism analysis confirmed that the main active species of YMO-SO photocatalyst were hole and superoxide free radical.
PubMed: 38911994
DOI: 10.3389/fchem.2024.1424548 -
Frontiers in Plant Science 2024Manganese (Mn) plays a pivotal role in plant growth and development. Aside aiding in plant growth and development, Mn as heavy metal (HM) can be toxic in soil when...
Metabolomics and physio-chemical analyses of mulberry plants leaves response to manganese deficiency and toxicity reveal key metabolites and their pathways in manganese tolerance.
INTRODUCTION
Manganese (Mn) plays a pivotal role in plant growth and development. Aside aiding in plant growth and development, Mn as heavy metal (HM) can be toxic in soil when applied in excess. is an economically significant plant, capable of adapting to a range of environmental conditions and possessing the potential for phytoremediation of contaminated soil by HMs. The mechanism by which tolerates Mn stresses remains obscure.
METHODS
In this study, Mn concentrations comprising sufficiency (0.15 mM), higher regimes (1.5 mM and 3 mM), and deficiency (0 mM and 0.03 mM), were applied to in pot treatment for 21 days to understand Mn tolerance. Mn stress effects on the net photosynthetic rate (Pn), stomatal conductance (Gs), transpiration rate (Tr), intercellular CO concentration (Ci), chlorophyll content, plant morphological traits, enzymatic and non-enzymatic parameters were analyzed as well as metabolome signatures via non-targeted LC-MS technique.
RESULTS
Mn deficiency and toxicity decrease plant biomass, Pn, Ci, Gs, Tr, and chlorophyll content. Mn stresses induced a decline in the activities of catalase (CAT) and superoxide dismutase (SOD), while peroxidase (POD) activity, and leaf Mn content, increased. Soluble sugars, soluble proteins, malondialdehyde (MDA) and proline exhibited an elevation in Mn deficiency and toxicity concentrations. Metabolomic analysis indicates that Mn concentrations induced 1031 differentially expressed metabolites (DEMs), particularly amino acids, lipids, carbohydrates, benzene and derivatives and secondary metabolites. The DEMs are significantly enriched in alpha-linolenic acid metabolism, biosynthesis of unsaturated fatty acids, galactose metabolism, pantothenate and CoA biosynthesis, pentose phosphate pathway, carbon metabolism, etc.
DISCUSSION AND CONCLUSION
The upregulation of Galactinol, Myo-inositol, Jasmonic acid, L-aspartic acid, Coproporphyrin I, Trigonelline, Pantothenol, and Pantothenate and their significance in the metabolic pathways makes them Mn stress tolerance metabolites in . Our findings reveal the fundamental understanding of DEMs in 's response to Mn nutrition and the metabolic mechanisms involved, which may hold potential significance for the advancement of genetic improvement initiatives and phytoremediation programs.
PubMed: 38911982
DOI: 10.3389/fpls.2024.1349456 -
Frontiers in Neuroscience 2024Nicotinamide adenine dinucleotide (NAD) is a crucial molecule in cellular metabolism and signaling. Mapping intracellular NAD content of human brain has long been of...
INTRODUCTION
Nicotinamide adenine dinucleotide (NAD) is a crucial molecule in cellular metabolism and signaling. Mapping intracellular NAD content of human brain has long been of interest. However, the sub-millimolar level of cerebral NAD concentration poses significant challenges for measurement and imaging.
METHODS
In this study, we demonstrated the feasibility of non-invasively mapping NAD contents in entire human brain by employing a phosphorus-31 magnetic resonance spectroscopic imaging (P-MRSI)-based NAD assay at ultrahigh field (7 Tesla), in combination with a probabilistic subspace-based processing method.
RESULTS
The processing method achieved about a 10-fold reduction in noise over raw measurements, resulting in remarkably reduced estimation errors of NAD. Quantified NAD levels, observed at approximately 0.4 mM, exhibited good reproducibility within repeated scans on the same subject and good consistency across subjects in group data (2.3 cc nominal resolution). One set of higher-resolution data (1.0 cc nominal resolution) unveiled potential for assessing tissue metabolic heterogeneity, showing similar NAD distributions in white and gray matter. Preliminary analysis of age dependence suggested that the NAD level decreases with age.
DISCUSSION
These results illustrate favorable outcomes of our first attempt to use ultrahigh field P-MRSI and advanced processing techniques to generate a whole-brain map of low-concentration intracellular NAD content in the human brain.
PubMed: 38911598
DOI: 10.3389/fnins.2024.1389111 -
International Journal of Nanomedicine 2024Targeted therapy for infantile hemangiomas (IHs) has been extensively studied as they can concentrate drugs, increase therapeutic efficacy and reduce drug dosage.... (Review)
Review
Targeted therapy for infantile hemangiomas (IHs) has been extensively studied as they can concentrate drugs, increase therapeutic efficacy and reduce drug dosage. Meanwhile, they can extend drug release times, enhance drug stability, decrease dosing frequency, and improve patient compliance. Moreover, carriers made from biocompatible materials reduced drug immunogenicity, minimizing adverse reactions. However, current targeted formulations still face numerous challenges such as the non-absolute safety of carrier materials; the need to further increase drug loading capacity; the limitation of animal hemangioma models in fully replicating the biological properties of human infantile hemangiomas; the establishment of models for deep-seated hemangiomas with high incidence rates; and the development of more specific targets or markers. In this review, we provided a brief overview of the characteristics of IHs and summarized the past decade's advances, advantages, and targeting strategies of targeted drug delivery systems for IHs and discussed their applications in the treatment of IHs. Furthermore, the goal is to provide a reference for further research and application in this field.
Topics: Humans; Animals; Hemangioma; Infant; Drug Delivery Systems; Drug Carriers; Antineoplastic Agents
PubMed: 38911507
DOI: 10.2147/IJN.S463119 -
Clinical, Cosmetic and Investigational... 2024Psoriasis is a common chronic inflammatory disease. However, trace elements are essential to biochemical processes of the skin, it is suspected that the trace elements...
OBJECTIVE
Psoriasis is a common chronic inflammatory disease. However, trace elements are essential to biochemical processes of the skin, it is suspected that the trace elements are vital in the pathogenesis of psoriasis. Our research is aimed to investigate the association between serum levels and dietary intake levels of selenium, zinc, and copper with psoriasis.
METHODS
In this cross-sectional study, we utilized the National Health and Nutrition Examination Survey data from 2011 to 2014 to examine the association between psoriasis and serum concentration and dietary intake of trace elements including copper, zinc, and selenium in the US individuals. Our research combined two cycles and weighted the data. Student's t-tests and χ2 test were used. Subgroup analyses and interaction tests were conducted by IBM SPSS Statistics 22 and EmpowerStats.
RESULTS
This study indicates that the population with psoriasis has a lower dose of dietary intake selenium than the controls, and risk analysis showed that the men with selenium daily intake >150 mcg/day have a decreasing risk for psoriasis compared to those with daily intaking selenium <75 mcg/day. However, there are no differences on daily intake of selenium, zinc, and copper and serum levels of Zinc and Copper between psoriasis and healthy controls. The current study showed that the psoriasis group was significantly older with a bigger waist circumference, a higher education level, a higher ratio of people with smoke every day, and a higher ratio of people in USA and being non-Hispanic White.
CONCLUSION
This cross-section study showed that a high selenium intake may benefit USA adults from psoriasis, especially for males. The social and cultural background and ethnic differences between the two groups influence the eating and living models, including the trace element intake. The national recommended dietary allowances (RDAs) might be considered to be modified with more reliable investigative clinical data and certain considering the social and cultural models.
PubMed: 38911341
DOI: 10.2147/CCID.S450407