Prognostic significance of pan-immune-inflammation value in hepatocellular carcinoma treated by curative radiofrequency ablation: potential role for individualized adjuvant systemic treatment.

BACKGROUND: This study aimed to explore the prognostic role of pan-immune-inflammation value (PIV) and develop a new risk model to guide individualized adjuvant systemic treatment following radiofrequency ablation (RFA) for early-stage hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Patients with early-stage HCC treated by RFA were randomly divided into training cohort A (n = 65) and testing cohort B (n = 68). Another 265 counterparts were enrolled into external validating cohort C. Various immune-inflammatory biomarkers (IIBs) were screened in cohort A. Prognostic role of PIV was evaluated and validated in cohort B and C, respectively. A nomogram risk model was built in cohort C and validated in pooled cohort D. Clinical benefits of adjuvant anti-angiogenesis therapy plus immune checkpoint inhibitor (AA-ICI) following RFA was assessed in low- and high-risk groups. RESULTS: The cutoff point of PIV was 120. High PIV was an independent predictor of unfavorable recurrence-free survival (RFS) and overall survival (OS). RFS and OS rates of patients with high PIV were significantly lower than those with low PIV both in cohort B (PRFS=0.016, POS=0.011) and C (PRFS<0.001, POS<0.001). The nomogram model based on PIV, tumor number and BCLC staging performed well in risk stratification in external validating cohort C. Adjuvant AA-ICI treatment showed an added benefit in OS (p = 0.011) for high-risk patients. CONCLUSIONS: PIV is a feasible independent prognostic factor for RFS and OS in early-stage HCC patients who received curative RFA. The proposed PIV-based nomogram risk model could help clinicians identify high-risk patients and tailor adjuvant systemic treatment and disease follow-up scheme.

Key findingsHigh pan-immune-inflammation value (PIV) is an independent indicator of unfavorable recurrence-free survival (RFS) and overall survival (OS) for early-stage hepatocellular carcinoma (HCC) patients who received curative radiofrequency ablation (RFA).Adjuvant anti-angiogenesis target therapy plus immune checkpoint inhibitor (AA-ICI) treatment showed added benefit in OS for the high-risk patients defined by a nomogram risk model based on PIV, tumor number and BCLC staging.What is known and what is new?Inflammation and impaired host immunity are associated with carcinogenesis and progression of HCC. Increasing evidences showed that immune-inflammatory biomarkers (IIBs) had prognostic roles in early-stage HCC patients who received RFA. However, prognostic potential of PIV has not been determined in this setting.Herein, high PIV was first reported to be an independent risk factor of poor RFS and OS in early-stage HCC patients treated by curative RFA and helped to discriminate patients between low- and high-risk groups. Adjuvant AA-ICI treatment following RFA was beneficial to OS of patients in the high-risk group.What is the implication, and what should change now?For early-stage HCC with high-risk factors (high PIV, multiple tumor foci and more advanced BCLC stage), intensive follow-up and adjuvant systemic therapy following curative RFA were warranted.

CircRNA Interference Pathway: A New Target for Intervention in Different Stages of Heart Failure.

Cardio-cerebrovascular disease has seen a rapid rise in recent years, with Heart Failure (HF) -- a terminal stage of various cardiovascular diseases -- also on the rise. HF has a complex pathogenesis involving multiple factors, such as inflammation, fibrosis, and oxidative stress. Due to its unique reverse shear mechanism, HF exhibits distinct expression patterns across different diseases. CircRNA has been linked to conditions like cancer, diabetes, and osteoarthritis. This article briefly introduces the mechanisms of circRNA biogenesis and its associated biological functions, focusing on CircSLC8A1-1, CircRNA_000203, and others at the early stage of HF, CircRNA PAN3, CircRNA (ACR), and others during the progression of HF, and CircHIPK3, CircNfix, and others at the end stage of HF. These circRNAs play a participatory role in the exact mechanism. As a research method, circRNA can be utilized to study the pathogenesis of heart failure and serve as a target for drug discovery and development. Therefore, circRNA's ability to mark the disease at different stages has significant guiding implications for HF monitoring, treatment, and prognosis.

Pretreatment of wastepaper with an aqueous solution of amino acid-derived ionic liquid for biochar production as adsorbent.

The carbonization of lignocellulosic biomass with ionic liquids (ILs) are considered as an advantageous approach for the preparation of carbonaceous materials. The commonly used imidazolium and pyridinium based ILs have drawbacks such as toxicity, resistance to biodegradation, high cost and viscosity. These issues can be mitigated by diluting ILs with water, although excessive water content above 1 wt% can reduce the solubility of biomass. This research aims to investigate the potential of pretreating wastepaper with a "fully green" ILs, amino acid-based IL with high water content, followed by pyrolysis without IL, in enhancing the properties of biochar. For this purpose, the paper was treated with an aqueous solution of IL cysteine nitrate ([Cys][NO3]), and the IL was not involved in the pyrolysis process to prevent the formation of secondary gaseous pollutants. The findings revealed that the hemicellulose and mineral filler in the paper were eliminated during pretreatment, leading to higher carbon content but lower oxygen content. As a result, the biochar exhibited micropores of 0.42 cm3g-1 and a specific surface area of 1011.21 m2 g-1. The biochar demonstrated high adsorption capacities for Cd2+, enrofloxacin, bisphenol A, ciprofloxacin, and tetracycline, with values of 45.20 mg g-1, 49.82 mg g-1, 49.90 mg g-1, 49.88 mg g-1, and 49.65 mg g-1, respectively. The proposed mechanism for the adsorption of enrofloxacin by the biochar primarily involves physical adsorption such as pore filling and electrostatic interactions, along with chemical adsorption facilitated by graphitic nitrogen.

Liver-directed moderately hypo-fractionated radiotherapy combined with pembrolizumab and bevacizumab for advanced hepatocellular carcinoma: a retrospective observational study of 23 cases.

Background: Programmed cell death protein 1 (PD-1) or its ligand (PD-L1) monoclonal antibody combined with bevacizumab (a monoclonal antibody targeting vascular endothelial growth factor) has been established as first-line systemic treatment for advanced hepatocellular carcinoma (HCC). Radiotherapy is a crucial local treatment for HCC. Mutual efficacy enhancement has been reported between radiotherapy, anti-angiogenesis therapy and immunotherapy in preclinical researches, but not been validated in clinical practice. Whether radiotherapy can enhance efficacy of anti-PD-1 immunotherapy plus bevacizumab for HCC remains unclear. This retrospective observational study aimed to appraise efficacy and safety of the combination of radiotherapy with pembrolizumab (a PD-1 monoclonal antibody) and bevacizumab for advanced HCC for the first time. Methods: Patients with advanced HCC treated by intrahepatic tumor-directed moderately hypo-fractionated radiotherapy combined with pembrolizumab and bevacizumab were consecutively included. Clinicopathological characteristics, therapeutic outcomes and treatment-related adverse events (TRAEs) were recorded and evaluated. Results: A total of 23 patients were eventually enrolled. Median cycles of pembrolizumab and bevacizumab were 4 (median, 1-8) and 4 (median, 1-9) cycles. The objective response rates and disease control rates of irradiated intrahepatic HCC and non-irradiated extrahepatic HCC were 34.8% [95% confidence interval (CI), 16.4-57.3%] vs. 10.0% (95% CI, 1.2-31.7%), and 91.3% (95% CI, 72.0-98.9%) vs. 70.0% (95% CI, 45.7-88.1%), respectively. The median progression-free survival (PFS) and overall survival (OS) were 6.6 (95% CI, 4.7-8.5) and 18.3 (95% CI, 8.2-33.6) months, and 12-month PFS and OS rates were 17.5% (95% CI, 7.0-28.0%) and 60.9% (95% CI, 50.7-71.1%). Two patients (8.7%) with locally advanced, unresectable HCC eventually underwent curative resection of tumors after this trimodal treatment. Eighteen patients (78.3%) had ≥ grade 3 TRAEs, with myelosuppression and transaminase increase as the most common. Conclusions: This study firstly reported that combining radiotherapy with pembrolizumab and bevacizumab was preliminarily a feasible and effective therapeutic choice for advanced HCC in despite of more TRAEs. This tri-modal regimen may be a potential conversion therapy for unresectable, locally advanced HCC. The limitations of this study are its retrospective nature and small sample size; therefore, big-sample prospective studies are warranted to further investigate this tri-modal regimen.

Efficient regulation of cadmium accumulation by carboxymethylammonium chloride in rice: Correlation analysis and expression of transporter gene OsGLR3.

The mechanism of carboxymethylammonium chloride (CC) regulating cadmium (Cd) accumulation in rice was studied in field and hydroponic experiments. Field experiments showed that 0.2-1.2 mmol L-1 CC spraying effectively reduced Cd accumulation by 44 %-77 % in early rice grains and 39 %-78 % in late rice grains, significantly increased calcium (Ca) content and amino acids content in grains, as well as alleviated Cd-induced oxidative damage in leaves. Hydroponic experiments further verified the inhibition effect of CC on Cd accumulation. 1.2 mmol L-1 CC made the highest decrease of Cd content in shoots and roots of hydroponic seedlings by 45 % and 53 %, respectively. Exogenous CC significantly increased glutamate (Glu), glycine (Gly) and glutathione (GSH) content, and improved the activities of catalase (CAT) and superoxide dismutase (SOD) by 41-131 % and 11-121 % in shoots of hydroponic seedlings, respectively. Exogenous CC also increased the relative expression of OsGLR3.1-3.5 in the shoots and roots of hydroponic seedlings. The quantum computational chemistry was used to clarify that the Gly radical provided by CC could form various complexes with Cd through carboxyl oxygen atoms. These results showed that exogenous application of CC improved the tolerance to Cd by enhancing the antioxidant capacity; inhibited the absorption, transport and accumulation of Cd in rice by (1) promoting chelation, (2) increasing the GLRs activity through upregulating the content of Glu, Gly, as well as the expression of OsGLR3.1-3.5.

Kinetic and thermodynamic-based studies on the interaction mechanism of novel R. roxburghii seed peptides against pancreatic lipase and cholesterol esterase.

Pancreatic lipase (PL) and cholesterol esterase (CE) are vital digestive enzymes that regulate lipid digestion. Three bioactive peptides (LFCMH, RIPAGSPF, YFRPR), possessing enzyme inhibitory activities, were identified in the seed proteins of R. roxburghii. It is hypothesized that these peptides could inhibit the activities of these enzymes by binding to their active sites or altering their conformation. The results showed that LFCMH exhibited superior inhibitory activity against these enzymes compared to the other peptides. The inhibition mechanisms of the three peptides were identified as either competitive or mixed, according to inhibition models. Further studies have shown that peptides could bind to the active sites of enzymes, thus affecting their spatial conformation and restricting substrate entry into the active site. Molecular simulation further proved that hydrogen bonds and hydrophobic interactions played a vital role in the binding of peptides to enzymes. This study enriches our understanding of interaction mechanisms of peptides on PL and CE.

Contrast-enhanced ultrasound for the preoperative prediction of pathological characteristics in breast cancer.

Objective: We aimed to investigate the value of contrast-enhanced ultrasound (CEUS) in the preoperative prediction of the histological grades and molecular subtypes of breast cancer. Methods: A total of 183 patients with pathologically confirmed breast cancer were included. Contrast enhancement patterns and quantitative parameters were compared in different groups. The receiver operating characteristic (ROC) curve was used to analyze the efficacy of CEUS in the preoperative prediction of pathological characteristics, including histologic grade and molecular subtypes. Results: Heterogeneous enhancement, perfusion defects, and peripheral radial vessels were mostly observed in higher histologic grade (grade III) breast cancer. Heterogeneous enhancement and perfusion defect were the most effective indicators for grade III breast cancer, with the areas under the ROC curve of 0.768 and 0.756, respectively. There were significant differences in the enhancement intensity, post-enhanced margin, perfusion defects, and peripheral radial vessel among the different molecular subtypes of breast cancer (all P < 0.01). Perfusion defects and clear edge after enhancement were the best qualitative criteria for the diagnosis of HER-2 overexpressed and triple-negative breast cancers, and the corresponding areas under the ROC curves were 0.804 and 0.905, respectively. There were significant differences in PE, WiR, WiPI, and WiWoAUC between grade III vs grade I and II breast cancer (P < 0.05). PE, WiR, WiPI, and WiWoAUC had good efficiency in the diagnosis of high-histologic-grade breast cancer. PE had the highest diagnostic efficiency in Luminal A, while WiPI had the highest diagnostic efficiency in Luminal B subtype breast cancer, and the areas under the ROC curve were 0.825 and 0.838, respectively. WiWoAUC and WiR were the most accurate parameters for assessing triple-negative subtype breast cancers, and the areas under the curve were 0.932 and 0.922, respectively. Conclusion: Qualitative and quantitative perfusion analysis of contrast-enhanced ultrasound may be useful in the non-invasive prediction of the histological grade and molecular subtypes of breast cancers.

Combined Influence of Eight Lifestyle Factors on Metabolic Syndrome Incidence: A Prospective Cohort Study from the MECH-HK Study.

Although previous studies have shown significant associations between individual lifestyles and metabolic syndrome, limited studies have explored the combined effect of lifestyles. The purpose of this study was to investigate whether a combined lifestyle score was associated with metabolic syndrome incidence in Hong Kong Chinese women. This prospective cohort study included 1634 women (55.9 ± 8.6 years) without baseline metabolic syndrome, diabetes, myocardial infarction, or stroke. Eight lifestyle factors (smoking, physical activity, sedentary time, sleep, stress, fatigue, diet, and alcohol) were included by assigning 0 (unhealthy) or 1 point (healthy). The overall score was the sum of these points, ranging from 0 (the least healthy) to 8 points (the healthiest). Metabolic syndrome was diagnosed by the joint interim statement. During a 1.16-year follow-up, 179 (11.0%) new metabolic syndrome cases were identified. The incidences for the 0-3-point, 4-point, 5-point, and 6-8-point groups were 12.8% (79/618), 11.5% (42/366), 9.4% (29/309), and 8.5% (29/341), respectively. Compared to the lowest combined lifestyle score group, the highest group had a 47% reduced metabolic syndrome incidence, with an adjusted odds ratio and 95% confidence interval of 0.53 (0.33-0.86) (p = 0.010). These findings indicate that a higher combined lifestyle score was associated with a lower metabolic syndrome incidence in this population.

Unveiling Epigenetic Vulnerabilities in Triple-Negative Breast Cancer through 3D Organoid Drug Screening.

Triple-negative breast cancer (TNBC) poses a therapeutic challenge due to its aggressive nature and lack of targeted therapies. Epigenetic modifications contribute to TNBC tumorigenesis and drug resistance, offering potential therapeutic targets. Recent advancements in three-dimensional (3D) organoid cultures, enabling precise drug screening, hold immense promise for identifying novel compounds targeting TNBC. In this study, we established two patient-derived TNBC organoids and implemented a high-throughput drug screening system using these organoids and two TNBC cell lines. Screening a library of 169 epigenetic compounds, we found that organoid-based systems offer remarkable precision in drug response assessment compared to cell-based models. The top 30 compounds showing the highest drug sensitivity in the initial screening were further assessed in a secondary screen. Four compounds, panobinostat, pacritinib, TAK-901, and JIB-04, targeting histone deacetylase, JAK/STAT, histone demethylases, and aurora kinase pathways, respectively, exhibited potent anti-tumor activity in TNBC organoids, surpassing the effect of paclitaxel. Our study highlights the potential of these novel epigenetic drugs as effective therapeutic agents for TNBC and demonstrates the valuable role of patient-derived organoids in advancing drug discovery.

Carrier-free self-assembled nanomedicine based on celastrol and galactose for targeting therapy of hepatocellular carcinoma via inducing ferroptosis.

Triggering ferroptosis is a potential therapeutic pathway and strategy for the prospective treatment of lethal hepatocellular carcinoma (HCC). The asialo-glycoprotein receptor (ASGPR) is an over-expressed receptor on the membranes of hepatocellular carcinoma cells (HCCs) and binds specifically to galactose (Gal) ligand. Celastrol (CE) is a potent anticancer natural product, but its poor water solubility and severe toxicity restrict its clinical application. In this study, a carrier-free self-assembled nanoparticles, CE-Gal-NPs, were designed and prepared by nanoprecipitation method, which could recognize ASGPR receptor by active targeting (Gal ligand) and passive targeting (EPR effect), access to the cell through the clathrin pathway and finally internalize to lysosomes. CE-Gal-NPs triggered reactive oxygen species (ROS)-mediated ferroptosis pathway and exerted anti-HCC effects in vitro and in vivo by down-regulating GPX4 and up-regulating COX-2 expression, depleting glutathione (GSH) levels, and increasing lipid peroxidation levels in cells and tumor tissues. In the H22 xenograft mouse model, the CE-Gal-NPs group exhibited dramatically superior tumor inhibition than the CE group, while Gal conjugating diminished the systemic toxicity of CE. Consequently, this study presented a promising strategy for CE potentiation and toxicity reduction, as well as a potential guideline for the development of clinically targeted therapeutic agents for HCC.

A selenium-based NIR-II photosensitizer for a highly effective and safe phototherapy plan.

High efficiency, stability, long emission wavelength (NIR-II), and good biocompatibility are crucial for photosensitizers in phototherapy. However, current Food and Drug Administration (FDA)-approved organic fluorophores exhibit poor chemical stability and photostability as well as short emission wavelength, limiting their clinical usage. To address this, we developed Se-IR1100, a novel organic photosensitizer with a photostable and thermostable benzobisthiadiazole (BBTD) backbone. By incorporating selenium as a heavy atom and constructing a D-A-D structure, Se-IR1100 exhibits a maximum fluorescence emission wavelength of 1100 nm. Compared with FDA-approved indocyanine green (ICG), DSPE-PEGylated Se-IR1100 nanoparticles exhibit prominent photostability and long-lasting photothermal effects. Upon 808 nm laser irradiation, Se-IR1100 NPs efficiently convert light energy into heat and reactive oxygen species (ROS), inducing cancer cell death in cellular studies and living organisms while maintaining biocompatibility. With salient photostability and a photothermal conversion rate of 55.37%, Se-IR1100 NPs hold promise as a superior photosensitizer for diagnostic and therapeutic agents in oncology. Overall, we have designed and optimized a multifunctional photosensitizer Se-IR1100 with good biocompatibility that performs NIR-II fluorescence imaging and phototherapy. This dual-strategy method may offer novel approaches for the development of multifunctional probes using dual-strategy or even multi-strategy methods in bioimaging, disease diagnosis, and therapy.

Resveratrol Enhances Anticancer Effects of Silybin on HepG2 Cells and H22 Tumor-bearing Mice via Inducing G2/M Phase Arrest and Increasing Bax/Bcl-2 Ratio.

BACKGROUND: Silybin, a major flavonoid extracted from the seeds of milk thistle, has a strong hepatoprotective but weak anti-hepatoma activity. Screening another natural ingredient and combining it with silybin is expected to improve the anti-hepatoma efficacy of silybin. OBJECTIVE: The objective of this study was to investigate the synergistic anti-hepatoma effect of resveratrol and silybin on HepG2 cells and H22 tumor-bearing mice in hepatocellular carcinoma (HCC) in vitro and in vivo, respectively. METHODS: Cell viability, scratch wound, clone formation, cell apoptosis, cell cycle, and western blot analysis of HepG2 cells were used to investigate the synergistic effects in vitro of the combination resveratrol with silybin. Growth rates, tumor weights, organ indexes, and histological pathological examination in H22 tumor-bearing mice were used to investigate the synergistic effects in vivo. RESULTS: The combination of resveratrol (50 µg/mL) and silybin (100 µg/mL) significantly suppressed cell viability, whose combination index (CI) was 1.63 (>1.15), indicating the best synergism. The combination exhibited the synergistic effect in blocking the migration and proliferative capacity of HepG2 cells in the measurement in vitro. In particular, resveratrol enhanced the upregulation of Bcl-2 expression and the downregulation of Bax expression with a concurrent increase in the Bax/Bcl-2 ratio. The combination of resveratrol (50 mg/kg) and silybin (100 mg/kg) reduced the tumor weight, inhibited the growth rate, increased the organ indexes, and destroyed the tumor tissue morphology in H22 tumor-bearing mice. CONCLUSION: Resveratrol was found to exhibit synergistic anti-cancer effects with silybin on HepG2 cells and H22 tumor-bearing mice.

Chitosan coatings with different degrees of deacetylation regulate the postharvest quality of sweet cherry through internal metabolism.

In this study, chitosan coatings with different degrees of deacetylation (DD, 88.1 % and 95.2 %) were electrostatically sprayed on sweet cherries to evaluate their impacts on postharvest characteristics and internal metabolism. The results showed that chitosan coating could effectively delay the change of weight, color, firmness, and maintain the content of total phenols, flavonoids and titratable acids, and inhibit the activities of ß-galactosidase and polyphenol oxidase during cold storage. The storage qualities and physiological activities of sweet cherry were significantly correlated with the contents of sorbitol, 4-hydroxycinnamic acid, hydrogenated hydroxycinnamic acid, tyrosine, proline, glutamine, phenylalanine, and other metabolites. Chitosan coating may modulate fruit quality by inhibiting the energy metabolism, accelerating the accumulation of carbohydrates, and promoting the metabolism of phenylalanine and flavonoid. Especially, chitosan coating with 88.1 % DD had better wettability on sweet cherry's peel and displayed more obvious preservation effect through stronger metabolic regulation ability.

Novel sulfonyl-substituted tetrandrine derivatives for colon cancer treatment by inducing mitochondrial apoptosis and inhibiting PI3K/AKT/mTOR pathway.

Tetrandrine (TET) possesses multiple pharmacological activities and could suppress tumor proliferation via PI3K pathway inhibition. However, inferior antitumor activity and potential toxicity limit its clinical application. In the present study, a series of 14-sulfonamide and sulfonate TET derivatives were designed, synthesized, and evaluated for biological activities. Through structural-activity relationship studies, compound 3c with α, ß-unsaturated carbonyl group exhibited the most potent activity against all tested tumor cell lines (including Hela, HCT116, HepG2, MCF-7, and SHSY5Y), as well as negligible toxicity against normal cell lines LO2 and HEK293. Additionally, compound 3c effectively inhibited HCT116 and CT26 cell proliferation in vitro with increased cell proportion in the G2/M phase, activated the mitochondrial apoptosis pathway, and induced colon cancer cell apoptosis by suppressing the PI3K/AKT/mTOR pathway. The further molecular docking results confirmed that compound 3c is potentially bound to multiple residues in PI3K with a stronger binding affinity than TET. Ultimately, compound 3c dramatically suppressed tumor growth in the CT26 xenograft tumor model, without noticeable visceral toxicity detected in the high-dose group. In summary, compound 3c might present new insights for designing new PI3K inhibitors and be a potential candidate for colon cancer treatment.

Chemical constitutes from Tuber indicum with immunosuppressive activity uncovered by transcriptome analysis.

Three previously undescribed compounds including a polyketide (1) and two lactams (2 and 3) were obtained from Tuber indicum. The structures of new findings were elucidated by HRESIMS, NMR as well as NMR and ECD calculations. Transcriptome analysis through RNA-seq revealed that compound 2 exhibits immunosuppressive activity. Lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages were employed as a model to explore the effect of these compounds in immunosuppressive activity. The results showed that 2 could reduce the generation of inflammatory mediators including nitric oxide (NO), reactive oxygen species (ROS), interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), cyclooxygenase 2 (COX-2) and inducible nitric oxide synthase (iNOS). Western blotting analysis demonstrated that 2 could suppressed the PI3K pathway by decreasing the levels of p-PI3K and p-Akt, while increasing the levels of p-PTEN. The anti-inflammatory activity of 2 was further confirmed using a zebrafish in vivo model.

HDAC1: An Essential and Conserved Member of the Diverse Zn2+-Dependent HDAC Family Driven by Divergent Selection Pressure.

Zn2+-dependent histone deacetylases (HDACs) are enzymes that regulate gene expression by removing acetyl groups from histone proteins. These enzymes are essential in all living systems, playing key roles in cancer treatment and as potential pesticide targets. Previous phylogenetic analyses of HDAC in certain species have been published. However, their classification and evolutionary origins across biological kingdoms remain unclear, which limits our understanding of them. In this study, we collected the HDAC sequences from 1451 organisms and performed analyses. The HDACs are found to diverge into three classes and seven subclasses under divergent selection pressure. Most subclasses show species specificity, indicating that HDACs have evolved with high plasticity and diversification to adapt to different environmental conditions in different species. In contrast, HDAC1 and HDAC3, belonging to the oldest class, are conserved and crucial in major kingdoms of life, especially HDAC1. These findings lay the groundwork for the future application of HDACs.

LITAF Promotes Atherosclerotic Plaque Formation by Stimulating the NF-κB Inflammatory Pathway.

OBJECTIVE: Lipopolysaccharide-induced tumor necrosis factor-α factor (LITAF) protein is a newly discovered inflammatory protein. This study aims to study the role of LITAF in the formation of atherosclerosis. METHODS: A total of 10 C57BL/6J mice and 10 C57BL/6J mice with knockout of LITAF gene (C57BL/6J-LITAF-) were divided into two groups: the control group and the LITAF-/- group. The animals were accommodated for 16 weeks and then euthanized with their hearts and aortas isolated thereafter. Next, the roots of the mouse aorta were cryosectioned and stained with Oil Red O staining and immunohistochemical staining (CD68, α-SMA, and Masson), respectively. The area of Oil Red O staining and the proportion of positive expression after immunohistochemical staining were then compared between the control and LITAF-/- groups. At the same time, the blood of mice was collected for the extraction of proteins and RNA. The proteins and RNA were used to detect the expression of major molecules of the NF-κB inflammatory pathway in mice in the control group and the LITAF-/- group by Western blotting and RT-PCR. RESULTS: Oil Red O staining of the aortic root sections of the mice in each group revealed that the area of atherosclerotic plaques in the LITAF-/- group was substantially lower than that in the control group (P<0.05). Moreover, immunohistochemical staining determined that the expression level of α-SMA and CD68 in the LITAF-/- group was significantly lower than that in the control group, whereas the results were reversed following Masson staining (P<0.05). The expression levels of P65 and caspase 3 were significantly lower in the LITAF-/- group than in the control group (P<0.05), whereas the expression level of IκB was higher in the LITAF-/- group. CONCLUSION: LITAF might participate in the formation of atherosclerotic plaque through the NF-κB pathway and play a promoting role in the formation of atherosclerosis.

Formation, Evolution, and Antioxidant Activity of Melanoidins in Black Garlic under Different Storage Conditions.

Melanoidins (MLDs) are formed through the reaction of carbonyl compounds and amino compounds in the Maillard reaction (MR) during the heating or storage of food. In this study, the formation, chemical composition, and structural characteristics of black garlic (BG) MLDs stored at different temperatures (4 °C, 20 °C, and 35 °C) over a period of 6 months were investigated. The initial products of the MR formed more often at 4 °C and 20 °C, while higher temperatures (35 °C) promoted the reaction in the middle and late stages of the MR. The higher temperature promoted an increase in molecular weight and MLD content, which can be attributed to the increase in protein and phenolic content. Elemental analysis confirmed an increase in nitrogen (N) content and the continuous incorporation of nitrogen-rich substances into the skeleton. Amino acids, particularly aspartic acid and threonine, were the primary N-containing compounds involved in MLD formation. Additionally, the infrared analysis revealed that the changes in MLDs during storage were characterized by amide I and amide II groups. The MR enhanced the yields of heterocyclic compounds (from 56.60% to 78.89%), especially that of O-heterocyclic compounds, at the higher temperature according to Py-GC-MS analysis. Furthermore, the higher temperature enhanced the molecular weight, maximum height, and roughness of MLDs compared to the control. The antioxidant ability of MLDs was positively correlated with storage temperatures. In summary, temperature had an impact on the formation, evolution, and antioxidant activity of MLDs.

Effect of age and sex on hematological and biochemical parameters in Chinese rhesus monkeys (Macaca mulatta) anesthetized with ketamine.

OBJECTIVE: Rhesus monkeys are increasingly used in biomedical research, which makes their hematological and biochemical parameters increasingly important in preclinical research. Since age and sex can influence blood parameters, establishing reference intervals for such parameters based on age and sex becomes along with identifying the effect of age and sex on those parameters. METHODS: A total of 1385 healthy Chinese rhesus monkeys (548 males and 837 females) anesthetized with ketamine were selected and segregated by age (six groups) and sex. A total of 21 hematological and 26 biochemical parameters were measured, and the effects of age and sex were analyzed. RESULTS: We established baseline indices for hematological and biochemical parameters based on age and sex, separately, and observed significant impacts of age, sex, and age-sex interactions on blood parameters. Among different age groups, significant differences were found in WBC, NEUT%, LYM%, EO%, LYM#, EO#, MCV, RDW-CV, PLT, MPV, PDW, PCT, TP, Alb, GLB, A/G, ALT, AST, ALP, TBIL, GGT, BUN, Cre, GLU, CK, TRIG, LDL, HCY, IL-6 FOL, Vit B12, VIT D-T, PTH, and AMH. Additionally, significant differences were observed in RBC, HGB, HCT, MPV, Alb, BUN, Cre, GLU, CHOL, TRIG, HDL, LDL, HCY, and VIT D-T between the two sexes. An age-sex interaction exerted a significant effect on WBC, NEUT#, MCV, MCHC, PDW, GLB, ALP, Cre, CHOL, TRIG, HDL, LDL, HCY, IL-6, Vit B12, VIT D-T. However, neither age, sex, and age-sex interactions exerted significant effects on MO%, MOMO#, MCH, RDW-SD, CRP, and CT. CONCLUSION: Our study investigated the blood parameters of rhesus monkeys to provide a reference basis for rhesus monkey-related scientific experimental research.

Multi-target responsive nanoprobe with cellular-level accuracy for spatiotemporally selective photodynamic therapy.

Photodynamic therapy is known for its non-invasiveness to significantly reduce undesired side effects on patients. However, the infiltration and invasiveness of tumor growth are still beyond the specificity of traditional light-controlled photodynamic therapy (PDT), which lacks cellular-level accuracy to tumor cells, possibly leading to "off-target" damage to healthy tissues such as the skin or immune cells infiltrated. Here, upconversion nanoparticles (UCNPs) were co-encapsulated with manganese dioxide (MnO2) by amphiphilic polymers poly(styrene-co-methyl acrylate) (PSMA) and further coated with photosensitizer (riboflavin)-loaded mesoporous silica (C@S/V). The C@S/V nanoprobes exhibited shielded upconversion luminescence in normal conditions (pH 7.4, no hydroperoxide (H2O2)) under 980-nm irradiation and thus minimal reactive oxygen production from riboflavin. However, the excess H2O2 (1 mM) and acidic environment (pH 5.5) could decompose the MnO2 within the C@S/V, resulting in remarkable enhancement of upconversion luminescence and a favorable hypoxia-relieving condition for PDT, providing a spatiotemporal signal for therapy initiation. The C@S/V nanoprobes were applied to the co-culture of normal cells (HEK293) and pancreatic cancer cells (Panc02) and performed a selective killing on Panc02 under the 980-nm irradiation. By using the "double-safety" strategy, a responsive C@S/V nanoprobe was designed by the selective activation of acidic and H2O2-rich conditions and 980-nm irradiation for spatiotemporally selective photodynamic therapy with cellular-level accuracy.