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1.
Gut ; 2024 Jul 05.
Article in English | MEDLINE | ID: mdl-38969490

ABSTRACT

OBJECTIVE: Precancerous metaplasia transition to dysplasia poses a risk for subsequent intestinal-type gastric adenocarcinoma. However, the molecular basis underlying the transformation from metaplastic to cancerous cells remains poorly understood. DESIGN: An integrated analysis of genes associated with metaplasia, dysplasia was conducted, verified and characterised in the gastric tissues of patients by single-cell RNA sequencing and immunostaining. Multiple mouse models, including homozygous conditional knockout Klhl21-floxed mice, were generated to investigate the role of Klhl21 deletion in stemness, DNA damage and tumour formation. Mass-spectrometry-based proteomics and ribosome sequencing were used to elucidate the underlying molecular mechanisms. RESULTS: Kelch-like protein 21 (KLHL21) expression progressively decreased in metaplasia, dysplasia and cancer. Genetic deletion of Klhl21 enhances the rapid proliferation of Mist1+ cells and their descendant cells. Klhl21 loss during metaplasia facilitates the recruitment of damaged cells into the cell cycle via STAT3 signalling. Increased STAT3 activity was confirmed in cancer cells lacking KLHL21, boosting self-renewal and tumourigenicity. Mechanistically, the loss of KLHL21 promotes PIK3CB mRNA translation by stabilising the PABPC1-eIF4G complex, subsequently causing STAT3 activation. Pharmacological STAT3 inhibition by TTI-101 elicited anticancer effects, effectively impeding the transition from metaplasia to dysplasia. In patients with gastric cancer, low levels of KLHL21 had a shorter survival rate and a worse response to adjuvant chemotherapy. CONCLUSIONS: Our findings highlighted that KLHL21 loss triggers STAT3 reactivation through PABPC1-mediated PIK3CB translational activation, and targeting STAT3 can reverse preneoplastic metaplasia in KLHL21-deficient stomachs.

2.
Mar Drugs ; 22(6)2024 Jun 19.
Article in English | MEDLINE | ID: mdl-38921596

ABSTRACT

Omega-3 fatty acids are in high demand due to their efficacy in treating hypertriglyceridemia and preventing cardiovascular diseases. However, the growth of the industry is hampered by low purity and insufficient productivity. This study aims to develop an efficient RP-MPLC purification method for omega-3 fatty acid ethyl esters with high purity and capacity. The results indicate that the AQ-C18 featuring polar end-capped silanol groups outperformed C18 and others in retention time and impurity separation. By injecting pure fish oil esters with a volume equivalent to a 1.25% bed volume on an AQ-C18 MPLC column using a binary isocratic methanol-water (90:10, v:v) mobile phase at 30 mL/min, optimal omega-3 fatty acid ethyl esters were obtained, with the notable purity of 90.34% and a recovery rate of 74.30%. The total content of EPA and DHA produced increased from 67.91% to 85.27%, meeting the acceptance criteria of no less than 84% set by the 2020 edition of the Pharmacopoeia of the People's Republic of China. In contrast, RP-MPLC significantly enhanced the production efficiency per unit output compared to RP-HPLC. This study demonstrates a pioneering approach to producing omega-3 fatty acid ethyl esters with high purity and of greater quantity using AQ-C18 RP-MPLC, showing this method's significant potential for use in industrial-scale manufacturing.


Subject(s)
Chromatography, Reverse-Phase , Esters , Fatty Acids, Omega-3 , Fish Oils , Fatty Acids, Omega-3/chemistry , Fatty Acids, Omega-3/isolation & purification , Esters/chemistry , Esters/isolation & purification , Fish Oils/chemistry , Chromatography, Reverse-Phase/methods , Chromatography, High Pressure Liquid/methods , Docosahexaenoic Acids/chemistry , Docosahexaenoic Acids/isolation & purification , Eicosapentaenoic Acid/chemistry , Eicosapentaenoic Acid/isolation & purification
3.
BMC Med Genomics ; 17(1): 156, 2024 Jun 06.
Article in English | MEDLINE | ID: mdl-38844949

ABSTRACT

BACKGROUND: Recurrent pregnancy loss (RPL) is a common pregnancy complication that brings great pain to pregnant women and their families. Genetic factors are an important cause reason of RPL. However, clinical research on monogenic diseases with recurrent miscarriage is insufficient. CASE PRESENTATION: Here we reported a Chinese family with RPL and genetic analysis of the abortion and parents. A paternally inherited heterozygous missense variant c.1415T > G (p.V472G) and a maternally inherited heterozygous nonsense variant c.2314del (p.M772*) in TMEM67 gene were identified by trio-exome sequencing. c.2314del (p.M772*) generated a premature stop codon and truncated protein, was classified as "pathogenic". c.1415T > G (p.V472G) located in extra-cellular region, was classified as "likely pathogenic". Biallelic variants in TMEM67 gene cause lethal Meckel syndrome 3, consistent with the proband's prenatal phenotype. CONCLUSION: The current study of the Chinese family expands the pathogenic variant spectrum of TMEM67 and emphasizes the necessity of exome sequencing in RPL condition.


Subject(s)
Abortion, Habitual , Membrane Proteins , Pedigree , Humans , Female , Membrane Proteins/genetics , Abortion, Habitual/genetics , Pregnancy , Adult , Asian People/genetics , Male , Exome Sequencing , China , East Asian People
4.
Food Chem ; 456: 140033, 2024 Jun 08.
Article in English | MEDLINE | ID: mdl-38870822

ABSTRACT

Myosin from bighead carp (Aristichthys nobilis) as a main type of fish protein possesses a good emulsifying ability. However, whether bighead carp myosin (BCM) could construct stable Pickering emulsions is still unclear. Therefore, myosin particles and Pickering emulsions stabilized by bighead carp myosin (BCMPEs) were analyzed. The surface structure of BCM particles at 0.6 mol/L NaCl treatment was uniform and compact with a contact angle of 86.4 ± 2.7°, exhibiting the potential ability to construct O/W Pickering emulsions. The size and flocculation index (FI) of BCMPEs decreased with the increase in BCM concentrations of 1%-4% (w/v). Reversely, the size of BCMPEs increased with the increase in oil-water ratios. BCM particles could uniformly distribute at the oil-water interface to stabilize BCMPEs at a BCM concentration of 4% (w/v) and an oil-water ratio of 6:4 (v/v). This study could help explore fish proteins to construct Pickering emulsions for the deep processing of fish products.

5.
Proc Natl Acad Sci U S A ; 121(24): e2321532121, 2024 Jun 11.
Article in English | MEDLINE | ID: mdl-38830102

ABSTRACT

Cannabis sativa is known for its therapeutic benefit in various diseases including pain relief by targeting cannabinoid receptors. The primary component of cannabis, Δ9-tetrahydrocannabinol (THC), and other agonists engage the orthosteric site of CB1, activating both Gi and ß-arrestin signaling pathways. The activation of diverse pathways could result in on-target side effects and cannabis addiction, which may hinder therapeutic potential. A significant challenge in pharmacology is the design of a ligand that can modulate specific signaling of CB1. By leveraging insights from the structure-function selectivity relationship (SFSR), we have identified Gi signaling-biased agonist-allosteric modulators (ago-BAMs). Further, two cryoelectron microscopy (cryo-EM) structures reveal the binding mode of ago-BAM at the extrahelical allosteric site of CB1. Combining mutagenesis and pharmacological studies, we elucidated the detailed mechanism of ago-BAM-mediated biased signaling. Notably, ago-BAM CB-05 demonstrated analgesic efficacy with fewer side effects, minimal drug toxicity and no cannabis addiction in mouse pain models. In summary, our finding not only suggests that ago-BAMs of CB1 provide a potential nonopioid strategy for pain management but also sheds light on BAM identification for GPCRs.


Subject(s)
Cryoelectron Microscopy , Receptor, Cannabinoid, CB1 , Signal Transduction , Receptor, Cannabinoid, CB1/metabolism , Receptor, Cannabinoid, CB1/genetics , Receptor, Cannabinoid, CB1/chemistry , Animals , Allosteric Regulation/drug effects , Mice , Humans , Signal Transduction/drug effects , GTP-Binding Proteins/metabolism , GTP-Binding Proteins/genetics , HEK293 Cells , Structure-Activity Relationship , Dronabinol/pharmacology , Dronabinol/chemistry , Dronabinol/analogs & derivatives , Cannabis/chemistry , Cannabis/metabolism
6.
Adv Sci (Weinh) ; : e2401396, 2024 Jun 10.
Article in English | MEDLINE | ID: mdl-38859590

ABSTRACT

Despite the initial efficacy of enzalutamide in castration-resistant prostate cancer (CRPC), inevitable resistance remains a significant challenge. Here, the synergistic induction of copper-dependent cell death (cuproptosis) in CRPC cells is reported by enzalutamide and copper ionophores (elesclomol/disulfiram). Mechanistically, enzalutamide treatment increases mitochondrial dependence in CRPC cells, rendering them susceptible to cuproptosis, as evidenced by specific reversal with the copper chelator tetrathiomolybdate. This susceptibility is characterized by hallmarks of cuproptosis, including lipoylated protein aggregation and iron-sulfur cluster protein instability. Interestingly, the mitochondrial matrix reductase, FDX1, specifically correlates with elesclomol sensitivity, suggesting a potential mechanistic divergence between the two copper ionophores. Notably, this synergistic effect extends beyond in vitro models, demonstrating efficacy in 22Rv1 xenografts, mouse Pten p53 knockout organoids. Importantly, enzalutamide significantly enhances copper ionophore-mediated cytotoxicity in enzalutamide-resistant cells. Collectively, these findings indicate that enzalutamide and copper ionophores synergistically induce cuproptosis, offering a promising therapeutic avenue for CRPC, potentially including enzalutamide-resistant cases.

7.
Acta Pharmacol Sin ; 2024 Jun 28.
Article in English | MEDLINE | ID: mdl-38942954

ABSTRACT

C/EBP homologous protein (CHOP) triggers the death of multiple cancers via endoplasmic reticulum (ER) stress. However, the function and regulatory mechanism of CHOP in liver cancer remain elusive. We have reported that late endosomal/lysosomal adapter, mitogen-activated protein kinase and mTOR activator 5 (LAMTOR5) suppresses apoptosis in various cancers. Here, we show that the transcriptional and posttranscriptional inactivation of CHOP mediated by LAMTOR5 accelerates liver cancer growth. Clinical bioinformatic analysis revealed that the expression of CHOP was low in liver cancer tissues and that its increased expression predicted a good prognosis. Elevated CHOP contributed to destruction of LAMTOR5-induced apoptotic suppression and proliferation. Mechanistically, LAMTOR5-recruited DNA methyltransferase 1 (DNMT1) to the CpG3 region (-559/-429) of the CHOP promoter and potentiated its hypermethylation to block its interaction with general transcription factor IIi (TFII-I), resulting in its inactivation. Moreover, LAMTOR5-enhanced miR-182/miR-769 reduced CHOP expression by targeting its 3'UTR. Notably, lenvatinib, a first-line targeted therapy for liver cancer, could target the LAMTOR5/CHOP axis to prevent liver cancer progression. Accordingly, LAMTOR5-mediated silencing of CHOP via the regulation of ER stress-related apoptosis promotes liver cancer growth, providing a theoretical basis for the use of lenvatinib for the treatment of liver cancer.

8.
Small ; : e2402338, 2024 Jun 24.
Article in English | MEDLINE | ID: mdl-38924259

ABSTRACT

A frozen-temperature (below -28 °C) laser tuning way is developed to optimize metal halide perovskite (MHP)'s stability and opto-electronic properties, for emitter, photovoltaic and detector applications. Here freezing can adjust the competitive laser irradiation effects between damaging and annealing/repairing. And the ligand shells on MHP surface, which are widely present for many MHP materials, can be frozen and act as transparent solid templates for MHP's re-crystallization/re-growth during the laser tuning. With model samples of different types of CsPbBr3 nanocube arrays,an attempt is made to turn the dominant exposure facet from low-energy [100] facet to high-energy [111], [-211], [113] and [210] ones respectively; selectively removing the surface impurities and defects of CsPbBr3 nanocubes to enhance the irradiation durability by 101 times; and quickly (tens of seconds) modifying a Ruddlesden-Popper (RP) boundary into another type of boundary like twinning, and so on. The laser tuning mechanism is revealed by an innovative in situ cryo-transmission electron microscope (cryo-TEM) exploration at atomic resolution.

9.
J Am Chem Soc ; 146(19): 12901-12906, 2024 May 15.
Article in English | MEDLINE | ID: mdl-38701349

ABSTRACT

Cholesterol-rich membranes play a pivotal role in cancer initiation and progression, necessitating innovative approaches to target these membranes for cancer inhibition. Here we report the first case of unnatural peptide (1) assemblies capable of depleting cholesterol and inhibiting cancer cells. Peptide 1 self-assembles into micelles and is rapidly taken up by cancer cells, especially when combined with an acute cholesterol-depleting agent (MßCD). Click chemistry has confirmed that 1 depletes cell membrane cholesterol. It localizes in membrane-rich organelles, including the endoplasmic reticulum, Golgi apparatus, and lysosomes. Furthermore, 1 potently inhibits malignant cancer cells, working synergistically with cholesterol-lowering agents. Control experiments have confirmed that C-terminal capping and unnatural amino acid residues (i.e., BiP) are essential for both cholesterol depletion and potent cancer cell inhibition. This work highlights unnatural peptide assemblies as a promising platform for targeting the cell membrane in controlling cell fates.


Subject(s)
Cholesterol , Peptides , Humans , Cholesterol/chemistry , Cholesterol/metabolism , Peptides/chemistry , Peptides/pharmacology , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Cell Line, Tumor , Cell Membrane/drug effects , Cell Membrane/metabolism , Cell Proliferation/drug effects
10.
Commun Biol ; 7(1): 545, 2024 May 07.
Article in English | MEDLINE | ID: mdl-38714724

ABSTRACT

CircRNAs are covalently closed, single-stranded RNA that form continuous loops and play a crucial role in the initiation and progression of tumors. Cancer stem cells (CSCs) are indispensable for cancer development; however, the regulation of cancer stem cell-like properties in gastric cancer (GC) and its specific mechanism remain poorly understood. We elucidate the specific role of Circ-0075305 in GC stem cell properties. Circ-0075305 associated with chemotherapy resistance was identified by sequencing GC cells. Subsequent confirmation in both GC tissues and cell lines revealed that patients with high expression of Circ-0075305 had significantly better overall survival (OS) rates than those with low expression, particularly when treated with postoperative adjuvant chemotherapy for GC. In vitro and in vivo experiments confirmed that overexpression of Circ-0075305 can effectively reduce stem cell-like properties and enhance the sensitivity of GC cells to Oxaliplatin compared with the control group. Circ-0075305 promotes RPRD1A expression by acting as a sponge for corresponding miRNAs. The addition of LF3 (a ß-catenin/TCF4 interaction antagonist) confirmed that RPRD1A inhibited the formation of the TCF4-ß-catenin transcription complex through competitive to ß-catenin and suppressed the transcriptional activity of stem cell markers such as SOX9 via the Wnt/ß-catenin signaling pathway. This leads to the downregulation of stem cell-like property-related markers in GC. This study revealed the underlying mechanisms that regulate Circ-0075305 in GCSCs and suggests that its role in reducing ß-catenin signaling may serve as a potential therapeutic candidate.


Subject(s)
Down-Regulation , Gene Expression Regulation, Neoplastic , Neoplastic Stem Cells , RNA, Circular , SOX9 Transcription Factor , Stomach Neoplasms , Transcription Factor 4 , beta Catenin , Stomach Neoplasms/genetics , Stomach Neoplasms/metabolism , Stomach Neoplasms/pathology , Humans , SOX9 Transcription Factor/metabolism , SOX9 Transcription Factor/genetics , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , beta Catenin/metabolism , beta Catenin/genetics , RNA, Circular/genetics , RNA, Circular/metabolism , Transcription Factor 4/genetics , Transcription Factor 4/metabolism , Animals , Mice , Cell Line, Tumor , Mice, Nude , Male , Female , Drug Resistance, Neoplasm/genetics , Mice, Inbred BALB C , Middle Aged
11.
Sci Total Environ ; 937: 173421, 2024 Aug 10.
Article in English | MEDLINE | ID: mdl-38788955

ABSTRACT

The health risks induced by chronic exposure to low concentrations of imidacloprid (IMI) to zebrafish were investigated in this study. The results indicated that the growth of zebrafish was inhibited after being exposed to 10, 100, and 500 µg/L of IMI for 90 days. Moreover, the blood glucose levels in the IMI-exposed groups were significantly higher compared to the control group. Investigation into the development of zebrafish larvae revealed that IMI exposure hindered the development of the liver and pancreatic islets, organs crucial for glucose metabolism. In addition, the IMI-exposed groups exhibited reduced liver glycogen and plasma insulin levels, along with changes in the activity of enzymes and the transcription levels of genes associated with liver glucose metabolism. These findings suggest that IMI induces glycometabolic disorders in zebrafish. The analysis of intestinal flora revealed that several key bacteria associated with an elevated risk of diabetes were significantly altered in IMI-exposed fish. Specifically, a remarkable decrease was found in the abundance of the genera Aeromonas and Shewanella, which have been found closely related to the development of pancreatic islets. This implies that the alteration of key bacteria in the fish gut by IMI, which in turn affects the development of organs such as the pancreatic islets, may be the initial trigger for abnormalities in glucose metabolism. Our results revealed that chronic exposure to low concentrations of IMI led to glycometabolic disorder in fish. Therefore, considering the pervasive existence of IMI residues in the environment, the health hazards posed by low-concentration IMI to fish cannot be overlooked.


Subject(s)
Insecticides , Neonicotinoids , Nitro Compounds , Water Pollutants, Chemical , Zebrafish , Animals , Nitro Compounds/toxicity , Water Pollutants, Chemical/toxicity , Neonicotinoids/toxicity , Insecticides/toxicity , Blood Glucose
12.
Clin Interv Aging ; 19: 639-654, 2024.
Article in English | MEDLINE | ID: mdl-38706634

ABSTRACT

Background: The triglyceride-glucose (TYG) index is a novel and reliable marker reflecting insulin resistance. Its predictive ability for cardiovascular disease onset and prognosis has been confirmed. However, for advanced chronic heart failure (acHF) patients, the prognostic value of TYG is challenged due to the often accompanying renal dysfunction (RD). Therefore, this study focuses on patients with aHF accompanied by RD to investigate the predictive value of the TYG index for their prognosis. Methods and Results: 717 acHF with RD patients were included. The acHF diagnosis was based on the 2021 ESC criteria for acHF. RD was defined as the eGFR < 90 mL/(min/1.73 m2). Patients were divided into two groups based on their TYG index values. The primary endpoint was major adverse cardiovascular events (MACEs), and the secondary endpoints is all-cause mortality (ACM). The follow-up duration was 21.58 (17.98-25.39) months. The optimal cutoff values for predicting MACEs and ACM were determined using ROC curves. Hazard factors for MACEs and ACM were revealed through univariate and multivariate COX regression analyses. According to the univariate COX regression analysis, high TyG index was identified as a risk factor for MACEs (hazard ratio = 5.198; 95% confidence interval [CI], 3.702-7.298; P < 0.001) and ACM (hazard ratio = 4.461; 95% CI, 2.962-6.718; P < 0.001). The multivariate COX regression analysis showed that patients in the high TyG group experienced 440.2% MACEs risk increase (95% CI, 3.771-7.739; P < 0.001) and 406.2% ACM risk increase (95% CI, 3.268-7.839; P < 0.001). Kaplan-Meier survival analysis revealed that patients with high TyG index levels had an elevated risk of experiencing MACEs and ACM within 30 months. Conclusion: This study found that patients with high TYG index had an increased risk of MACEs and ACM, and the TYG index can serve as an independent predictor for prognosis.


Subject(s)
Blood Glucose , Heart Failure , Triglycerides , Humans , Male , Female , Heart Failure/blood , Heart Failure/mortality , Aged , Triglycerides/blood , Prognosis , Middle Aged , Blood Glucose/analysis , Risk Factors , Biomarkers/blood , ROC Curve , Retrospective Studies , Insulin Resistance , Proportional Hazards Models , Glomerular Filtration Rate , Chronic Disease , Predictive Value of Tests
14.
J Robot Surg ; 18(1): 229, 2024 May 29.
Article in English | MEDLINE | ID: mdl-38809383

ABSTRACT

The aim of this study is to evaluate the predictive ability of MRI-based radiomics combined with tumor markers for TN staging in patients with rectal cancer and to develop a prediction model for TN staging. A total of 190 patients with rectal adenocarcinoma who underwent total mesorectal excision at the First Affiliated Hospital of the Air Force Medical University between January 2016 and December 2020 were included in the study. An additional 54 patients from a prospective validation cohort were included between August 2022 and August 2023. Preoperative tumor markers and MRI imaging data were collected from all enrolled patients. The 190 patients were divided into a training cohort (n = 133) and a validation cohort (n = 57). Radiomics features were extracted by outlining the region of interest (ROI) on T2WI sequence images. Feature selection and radiomics score (Rad-score) construction were performed using least absolute shrinkage and selection operator regression analysis (LASSO). The postoperative pathology TNM stage was used to differentiate locally advanced rectal cancer (T3/4 or N1/2) from locally early rectal cancer (T1/2, N0). Logistic regression was used to construct separate prediction models for T stage and N stage. The models' predictive performance was evaluated using DCA curves and calibration curves. The T staging model showed that Rad-score, based on 8 radiomics features, was an independent predictor of T staging. When combined with CEA, tumor diameter, mesoretal fascia (MRF), and extramural venous invasion (EMVI), it effectively differentiated between T1/2 and T3/4 stage rectal cancers in the training cohort (AUC 0.87 [95% CI: 0.81-0.93]). The N-staging model found that Rad-score, based on 10 radiomics features, was an independent predictor of N-staging. When combined with CA19.9, degree of differentiation, and EMVI, it effectively differentiated between N0 and N1/2 stage rectal cancers. The training cohort had an AUC of 0.84 (95% CI: 0.77-0.91). The calibration curves demonstrated good precision between the predicted and actual results. The DCA curves indicated that both sets of predictive models could provide net clinical benefits for diagnosis. MRI-based radiomics features are independent predictors of T staging and N staging. When combined with tumor markers, they have good predictive efficacy for TN staging of rectal cancer.


Subject(s)
Biomarkers, Tumor , Magnetic Resonance Imaging , Neoplasm Staging , Rectal Neoplasms , Humans , Rectal Neoplasms/pathology , Rectal Neoplasms/diagnostic imaging , Rectal Neoplasms/surgery , Magnetic Resonance Imaging/methods , Neoplasm Staging/methods , Male , Female , Middle Aged , Adenocarcinoma/diagnostic imaging , Adenocarcinoma/pathology , Adenocarcinoma/surgery , Aged , Prospective Studies , Predictive Value of Tests , Adult , Robotic Surgical Procedures/methods , Radiomics
15.
Gastric Cancer ; 2024 May 29.
Article in English | MEDLINE | ID: mdl-38809487

ABSTRACT

BACKGROUND: Adjuvant chemotherapy following curative surgery for locally advanced gastric cancer (AGC) significantly improves long-term patient prognosis. However, delayed chemotherapy (DC), in which patients are unable to receive timely treatment, is a common phenomenon in clinical practice for various reasons. This study aimed to investigate the impact of DC on the prognosis of patients with stage II-III locally AGC and explore the associated risk factors. METHODS: Data from four prospective studies were included in the pooled analysis. The planned chemotherapy (PC) group was defined as the time interval between surgery and the first chemotherapy ≤ 49 d, while the DC group was defined as the time interval between surgery and chemotherapy > 49 d. The prognosis, recurrence, and risk factors were compared, and a nomogram for predicting DC was established. RESULTS: In total, 596 patients were included, of whom 531 (89.1%) had PC and 65 (10.9%) had DC. Survival analysis revealed that the 5-year overall survival (OS) and disease-free survival (DFS) were significantly lower in the DC group than those in the PC group (log-rank P < 0.001). Cox univariable and multivariable analyses showed that DC was an independent risk factor for OS and DFS in stage II-III patients (P < 0.05). Based on the significant factors for DC, a prediction model was established that had a good fit, high accuracy (AUC = 0.780), and clinical applicability in both the training and validation sets. CONCLUSION: Delayed chemotherapy after gastrectomy is associated with poor long-term prognosis in patients with locally advanced stage II-III GC disease. But standardized, full-cycle adjuvant chemotherapy after surgery may play a remedial role, and can to a certain extent compensate the poor effects caused by delayed chemotherapy.

16.
Mar Drugs ; 22(5)2024 Apr 29.
Article in English | MEDLINE | ID: mdl-38786597

ABSTRACT

Abnormal melanogenesis can lead to hyperpigmentation. Tyrosinase (TYR), a key rate-limiting enzyme in melanin production, is an important therapeutic target for these disorders. We investigated the TYR inhibitory activity of hydrolysates extracted from the muscle tissue of Takifugu flavidus (TFMH). We used computer-aided virtual screening to identify a novel peptide that potently inhibited melanin synthesis, simulated its binding mode to TYR, and evaluated functional efficacy in vitro and in vivo. TFMH inhibited the diphenolase activities of mTYR, reducing TYR substrate binding activity and effectively inhibiting melanin synthesis. TFMH indirectly reduced cAMP response element-binding protein phosphorylation in vitro by downregulating melanocortin 1 receptor expression, thereby inhibiting expression of the microphthalmia-associated transcription factor, further decreasing TYR, tyrosinase related protein 1, and dopachrome tautomerase expression and ultimately impeding melanin synthesis. In zebrafish, TFMH significantly reduced black spot formation. TFMH (200 µg/mL) decreased zebrafish TYR activity by 43% and melanin content by 52%. Molecular dynamics simulations over 100 ns revealed that the FGFRSP (T-6) peptide stably binds mushroom TYR via hydrogen bonds and ionic interactions. T-6 (400 µmol/L) reduced melanin content in B16F10 melanoma cells by 71% and TYR activity by 79%. In zebrafish, T-6 (200 µmol/L) inhibited melanin production by 64%. TFMH and T-6 exhibit good potential for the development of natural skin-whitening cosmetic products.


Subject(s)
Melanins , Melanoma, Experimental , Monophenol Monooxygenase , Takifugu , Zebrafish , Animals , Melanins/biosynthesis , Takifugu/metabolism , Monophenol Monooxygenase/antagonists & inhibitors , Monophenol Monooxygenase/metabolism , Mice , Melanoma, Experimental/drug therapy , Melanoma, Experimental/metabolism , Cell Line, Tumor , Microphthalmia-Associated Transcription Factor/metabolism , Muscles/drug effects , Muscles/metabolism , Intramolecular Oxidoreductases/metabolism , Receptor, Melanocortin, Type 1/metabolism , Molecular Dynamics Simulation , Cyclic AMP Response Element-Binding Protein/metabolism
17.
Sci Total Environ ; 934: 173112, 2024 Jul 15.
Article in English | MEDLINE | ID: mdl-38734090

ABSTRACT

Fenton reaction has been widely used for efficient treatment of organic wastewater. However, its applications are limited by such key factors as pH < 3. In this study, we developed, tested, and optimized an alginate/C3N4porphyrin bead (C3N4por-SA) as a recyclable photocatalyst in a photocatalysis-self-Fenton process to overcome these limitations. Porphyrin-modified C3N4 (C3N4por) was used as the H2O2 donator, while Fe(III) nodes served as the Fenton reagent. The as-prepared floating alginate/C3N4por bead utilized the light source as a driving force for the catalysis. Under visible light irradiation for 6 h, the model pollutant atrazine was degraded by 70.96 % by the optimized photocatalyst (named as C3N4por-SA-Fe1Ca5), demonstrating better photocatalytic performance than alginate/C3N4 beads. This improvement was attributed to the higher H2O2 yield from C3N4por. The alginate/C3N4por bead showed better photocatalytic activity even after several consecutive cycles and could easily be recovered for reuse. Furthermore, Fe(III)/Ca(II) bimetallic alginate bead exhibited better photocatalytic activity and a higher content of •OH radicals than the Ca(II) monometallic alginate beads, due to the ability of Fe(III) nodes to serve as a Fenton reagent. The influences of light sources, and commonly existing matters (namely SO42-, Cl-, CO32-, NO3-, and humic acid) were investigated. Moreover, the alginate/C3N4por bead demonstrated good photocatalytic performance in a simulated natural environment without the addition of extra H2O2, with an atrazine removal percentage of up to 96.3 % after 3-h irradiation. These findings indicated the great potential of alginate/C3N4por bead in practical applications.

18.
J Robot Surg ; 18(1): 172, 2024 Apr 13.
Article in English | MEDLINE | ID: mdl-38613728

ABSTRACT

The purpose of this research was to investigate the potential predictive value of preoperative systemic inflammatory indexes in identifying lymph node metastasis among patients diagnosed with small bowel cancer. A retrospective analysis of clinical data was conducted on small bowel cancer patients who underwent surgical treatment at the gastrointestinal surgery department of our hospital between January 2010 and June 2021. Patients were divided into groups based on the presence or absence of lymph node metastasis as confirmed by postoperative pathological results. The study compared the differences in preoperative inflammatory indexes and clinical data between the two groups using single factor analysis and multifactorial Logistic regression analysis. Furthermore, a nomogram model for predicting lymph node metastasis in colorectal cancer was constructed using R software and internally validated. The study sample consisted of 140 small bowel cancer patients,postoperative pathology confirmed lymph node metastasis in 72 cases. Univariate analysis results indicated associations between preoperative inflammatory indexes and clinical data with lymph node metastasis in small bowel cancer. Multifactorial logistic regression analysis revealed that gender, PLR, number of lymph node dissection, and lymphovascular invasion independently influenced lymph node metastasis in small bowel cancer patients. The developed nomogram model demonstrated a C-index of 0.855 (95% CI 0.792-0.917), with a calibrated prediction curve closely resembling the ideal curve. An elevated PLR is an independent risk factor for LNM in patients with small bowel cancer.


Subject(s)
Colorectal Neoplasms , Robotic Surgical Procedures , Humans , Lymphatic Metastasis , Retrospective Studies , Robotic Surgical Procedures/methods , Lymphocytes
19.
Genes (Basel) ; 15(4)2024 04 17.
Article in English | MEDLINE | ID: mdl-38674435

ABSTRACT

In gene quantification and expression analysis, issues with sample selection and processing can be serious, as they can easily introduce irrelevant variables and lead to ambiguous results. This study aims to investigate the extent and mechanism of the impact of sample selection and processing on ribonucleic acid (RNA) sequencing. RNA from PBMCs and blood samples was investigated in this study. The integrity of this RNA was measured under different storage times. All the samples underwent high-throughput sequencing for comprehensive evaluation. The differentially expressed genes and their potential functions were analyzed after the samples were placed at room temperature for 0h, 4h and 8h, and different feature changes in these samples were also revealed. The sequencing results showed that the differences in gene expression were higher with an increased storage time, while the total number of genes detected did not change significantly. There were five genes showing gradient patterns over different storage times, all of which were protein-coding genes that had not been mentioned in previous studies. The effect of different storage times on seemingly the same samples was analyzed in this present study. This research, therefore, provides a theoretical basis for the long-term consideration of whether sample processing should be adequately addressed.


Subject(s)
High-Throughput Nucleotide Sequencing , RNA , Sequence Analysis, RNA , Humans , High-Throughput Nucleotide Sequencing/methods , Sequence Analysis, RNA/methods , RNA/genetics , RNA/blood , Leukocytes, Mononuclear/metabolism , Gene Expression Profiling/methods , Male , Specimen Handling/methods , Blood Specimen Collection/methods , Female
20.
Foods ; 13(8)2024 Apr 16.
Article in English | MEDLINE | ID: mdl-38672886

ABSTRACT

This study compared collagens from cold-water and warm-water fish for their structural, rheological, and functional properties, and explored their potential applications, aiming to realize the high-value utilization of marine biological resources. To this end, chum salmon skin collagen (CSSC) and Nile tilapia skin collagen (NTSC) were both successfully extracted. Collagens from the two species had different primary and secondary structures, with NTSC having a higher molecular weight, imino acid content, and α-helices and ß-turns content. The denaturation temperatures were 12.01 °C for CSSC and 31.31 °C for NTSC. CSSC was dominated by viscous behavior and its structure varied with temperature, while NTSC was dominated by elastic behavior and its structure remained stable with temperature. Both collagens had good oil holding capacity, foaming capacity, and emulsifying activity, but NTSC had better water holding capacity and foaming and emulsifying stability. Their different properties make CSSC more suitable for the preservation of frozen and chilled foods and the production of sparkling beverages, and give NTSC greater potential in biofunctional materials and solid food processing.

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