Optimizing ARA and DHA in infant formula: A systematic review of global trends, regional disparities, and considerations for precision nutrition.

In the context of precision nutrition, the addition of ARA and DHA in infant formula needs to consider more factors. This study conducted a comprehensive literature review, including 112 relevant Chinese and English articles, to summarize and analyze the global levels of ARA, DHA, and the ARA/DHA ratio in breast milk. The data were correlated with local aquatic products intake and children's IQ. The results indicated that the average level of DHA in breast milk across regions is lower than that of ARA. Variations in DHA content were identified as a primary factor influencing ARA/DHA ratio fluctuations. Breast milk ARA and DHA levels decrease with prolonged lactation periods but increase over the past 22 years. Correlation analysis revealed a significant positive relationship between aquatic products intake and breast milk DHA levels (r = 0.64, p < 0.05). Breast milk DHA levels also showed a significant positive correlation with children's IQ (r = 0.67, p < 0.01). Stable breast milk ARA content did not exhibit significant correlations with aquatic products intake or children's IQ (r = 0, p > 0.05). Among 22 infant formula products available in China, only 5 had ARA levels within the range of breast milk. Most formula products had higher ARA levels than DHA, resulting in ARA/DHA ratios generally exceeding 1. The temporal and spatial variability in breast milk ARA and DHA levels may lead to diverse health outcomes in infants. Therefore, the addition of ARA and DHA in infant formula should consider this variability, including the molecular forms and positional isomerism of the added ARA and DHA. Additionally, considering the impact of different cognitive development tests and infant's gene expression on formula assessment results, there is a need to establish a more comprehensive infant health assessment system to guide the addition of ARA and DHA in formula.

Walnut Protein: A Rising Source of High-Quality Protein and Its Updated Comprehensive Review.

Recently, plant protein as a necessary nutrient source for human beings, a common ingredient of traditional processed food, and an important element of new functional food has gained prominence due to the increasing demand for healthy food. Walnut protein (WP) is obtained from walnut kernels and walnut oil-pressing waste and has better nutritional, functional, and essential amino acids in comparison with other vegetable and grain proteins. WP can be conveniently obtained by various extraction techniques, including alkali-soluble acid precipitation, salting-out, and ultrasonic-assisted extraction, among others. The functional properties of WP can be modified for desired purposes by using some novel methods, including free radical oxidation, enzymatic modification, high hydrostatic pressure, etc. Moreover, walnut peptides play an important biological role both in vitro and in vivo. The main activities of the walnut peptides are antihypertensive, antioxidant, learning improvement, and anticancer, among others. Furthermore, WP could be applied in the development of functional foods or dietary supplements, such as delivery systems and food additives, among others. This review summarizes recent knowledge on the nutritional, functional, and bioactive peptide aspects of WP and possible future products, providing a theoretical reference for the utilization and development of oil crop waste.

Numerical Modeling and Simulation of Non-Invasive Acupuncture Therapy Utilizing Near-Infrared Light-Emitting Diode.

Acupuncture is one of the most extensively used complementary and alternative medicine therapies worldwide. In this study, we explore the use of near-infrared light-emitting diodes (LEDs) to provide acupuncture-like physical stimulus to the skin tissue, but in a completely non-invasive way. A computational modeling framework has been developed to investigate the light-tissue interaction within a three-dimensional multi-layer model of skin tissue. Finite element-based analysis has been conducted, to obtain the spatiotemporal temperature distribution within the skin tissue, by solving Pennes' bioheat transfer equation, coupled with the Beer-Lambert law. The irradiation profile of the LED has been experimentally characterized and imposed in the numerical model. The experimental validation of the developed model has been conducted through comparing the numerical model predictions with those obtained experimentally on the agar phantom. The effects of the LED power, treatment duration, LED distance from the skin surface, and usage of multiple LEDs on the temperature distribution attained within the skin tissue have been systematically investigated, highlighting the safe operating power of the selected LEDs. The presented information about the spatiotemporal temperature distribution, and critical factors affecting it, would assist in better optimizing the desired thermal dosage, thereby enabling a safe and effective LED-based photothermal therapy.

The effect of light therapy on sleep quality in cancer patients: a systematic review and meta-analysis of randomized controlled trials.

Background: Sleep problem is one of the major issues of cancer patients and may have detrimental effects on the ongoing treatment and recovery of patients. However, the evidence for the effect of light therapy on sleep problems in this population remained scarce. This study aimed to examine the effect of light therapy on self-reported and physiological measures of sleep quality of cancer patients. It also aimed to quantify the magnitude of the effect using a meta-analytical approach. Methods: Six databases were searched for randomized control trials (RCTs). The primary outcome was the sleep quality using the Pittsburgh sleep quality index (PSQI) measurement of self-reported scores, and the secondary outcomes included total sleep time and sleep efficiency measured by actigraphy. Meta-analyses were performed with the random effects model using the RevMan software. The standardized mean difference (SMD) of the PSQI scores and other measures with their 95% confidence intervals (CIs) were used for assessing the treatment effect (CRD42023370947). Results: Nine RCTs were identified and included in the study. Light therapy significantly improved the self-reported sleep quality with a reduction of the pooled PSQI score (SMD = -0.72; 95% CI: -1.24 to -0.21; p = 0.006). Regarding total sleep time (p = 0.72) and sleep efficiency (p = 0.47), no significant effects of light therapy were found. Conclusion: Light therapy could improve self-reported sleep quality in cancer patients. However, due to the heterogeneity and small sample size of the included trials, the results should be interpreted cautiously. Trials with better designs and larger sample sizes are suggested to be conducted for a more definitive conclusion.Systematic review registration:https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=370947.

Dietary palmitoleic acid reprograms gut microbiota and improves biological therapy against colitis.

Magnitude and diversity of gut microbiota and metabolic systems are critical in shaping human health and diseases, but it remains largely unclear how complex metabolites may selectively regulate gut microbiota and determine health and diseases. Here, we show that failures or compromised effects of anti-TNF-α therapy in inflammatory bowel diseases (IBD) patients were correlated with intestinal dysbacteriosis with more pro-inflammatory bacteria, extensive unresolved inflammation, failed mucosal repairment, and aberrant lipid metabolism, particularly lower levels of palmitoleic acid (POA). Dietary POA repaired gut mucosal barriers, reduced inflammatory cell infiltrations and expressions of TNF-α and IL-6, and improved efficacy of anti-TNF-α therapy in both acute and chronic IBD mouse models. Ex vivo treatment with POA in cultured inflamed colon tissues derived from Crohn's disease (CD) patients reduced pro-inflammatory signaling/cytokines and conferred appreciable tissue repairment. Mechanistically, POA significantly upregulated the transcriptional signatures of cell division and biosynthetic process of Akkermansia muciniphila, selectively increased the growth and abundance of Akkermansia muciniphila in gut microbiota, and further reprogrammed the composition and structures of gut microbiota. Oral transfer of such POA-reprogrammed, but not control, gut microbiota induced better protection against colitis in anti-TNF-α mAb-treated recipient mice, and co-administration of POA with Akkermansia muciniphila showed significant synergistic protections against colitis in mice. Collectively, this work not only reveals the critical importance of POA as a polyfunctional molecular force to shape the magnitude and diversity of gut microbiota and therefore promote the intestinal homeostasis, but also implicates a new potential therapeutic strategy against intestinal or abenteric inflammatory diseases.

The role of PIWI-interacting RNA in naringin pro-angiogenesis by targeting HUVECs.

Angiogenesis is a biological process in which resting endothelial cells start proliferating, migrating and forming new blood vessels. Angiogenesis is particularly important in the repair of bone tissue defects. Naringin (NG) is the main active monomeric component of traditional Chinese medicine, which has various biological activities, such as anti-osteoporosis, anti-inflammatory, blood activation and microcirculation improvement. At present, the mechanism of naringin in the process of angiogenesis is not clear. PIWI protein-interacting RNA (piRNA) is a small noncoding RNA (sncRNA) that has the functions of regulating protein synthesis, regulating the structure of chromatin and the genome, stabilizing mRNA and others. Several studies have demonstrated that piRNAs can mediate the angiogenesis process. Whether naringin can interfere with the process of angiogenesis by regulating piRNAs and related target genes deserves further exploration. Thus, the purpose of this study was to validate the potential angiogenic and bone regeneration properties and related mechanisms of naringin both in vivo and in vitro.

Traditional Chinese medicine Tongxie Yaofang treating irritable bowel syndrome with diarrhea and type 2 diabetes mellitus in rats with liver-depression and spleen-deficiency: A preliminary study.

Tongxie Yaofang (TXYF), a Traditional Chinese Medicine (TCM) with four components as follows: Rhizoma Atractylodis Macrocephalae (baizhu), Radix Paeoniae Alba (baishao), Pericarpium Citri Reticulatae (chenpi) and Radix Saposhnikovia Divaricata (fangfeng), benefits irritable bowel syndrome (IBS). Nonetheless, proofs of this formula ameliorating D-IBS and T2DM are required. This research aimed at investigating the efficacy of TXYF in treating inflammation in rats with D-IBS and T2DM using animal models. In this study, gavage with high-fat diet, fasciculation, and senna was given to develop rat models with target diseases. To determine intestinal inflammations, major inflammatory factors, and intestinal permeability proteins, H&E staining, ELISA, and immunohistochemistry methods were employed, respectively. This study also utilized Western blot to discover potential inflammatory targets. Results of this research illustrates that TXYF treatment reduced the level of TNF-α, IL-1ß, and IL-6, and raised the IL-10 concentration in liver-depressed spleende ficient rats with D-IBS and T2DM, indicating controlled inflammatory reactions. Staining analysis also showed improved disease states of animal models. Furthermore, efficient rebounds of claudin-1, an intestinal permeability-associated protein, were detected. Moreover, TXYF may treat D-IBS and T2DM in rats via the rage pathway.

Anticancer effects of herbal medicines in pancreatic ductal adenocarcinoma through modulation of steroid hormone response proteins.

Many individual herbs and herbal formulae have been demonstrated to provide safe and effective treatment for pancreatic ductal adenocarcinoma (PDAC); however, the therapeutic mechanisms underlying their effects have not been fully elucidated. A total of 114 herbal formulae comprising 216 single herbal medicines used to treat PDAC were identified. Cluster analysis revealed a core prescription including four herbs [Glycyrrhizae Radix et Rhizome (Gan Cao), Codonopsis Radix (Dang Shen), Citri Reticulatae Pericarpium (Chen Pi), and Pinelliae Rhizoma (Ban Xia)] in combination to treat PDAC, and 295, 256, 141, and 365 potential targets were screened for each of these four herbs, respectively. PDAC-related proteins (n = 2940) were identified from the DisGeNET database. Finally, 44 overlapping targets of herbs and PDAC were obtained, representing potential targets of the herbal medicines for PDAC treatment. GO enrichment analysis indicated that targets common to herbs and PDAC primarily functioned in response to steroid hormones. KEGG pathway enrichment analysis indicated that the herbs may prevent PDAC by influencing apoptotic, p53, and PI3K/Akt signaling pathways. Further, molecular docking analysis indicated that of identified bioactive compounds, stigmasterol, phaseol, perlolyrine, shinpterocarpin, and licopyranocoumarin have good binding ability with proteins involved in responses to steroid hormones, while stigmasterol, phaseol, perlolyrine, and DIOP have good binding ability with PTGS2(also known as COX-2), ESR1, ESR2, AR, and PGR. The anti-PDAC activity of herbal medicines may be mediated via regulation of proteins with roles in responses to steroid hormones. This study provides further evidence supporting the potential for use of herbal medicines to treat PDAC.

SiNiSan alleviates liver injury by promoting hepatic stem cell differentiation via Wnt/ß-catenin signaling pathway.

BACKGROUND: SiNiSan, a Traditional Chinese Medicine containing Radix Bupleuri, Radix Paeoniae Alba, Fructus Aurantii Immaturus, and Radix Glycyrrhizae, has been shown to be clinically effective in treating liver damage, its underlying molecular mechanisms however remains unclear. PURPOSE: The aim of the current study was to understand the molecular mechanisms of SiNiSan in the treatment of liver damage utilizing mice and cell culture models. METHODS: Here, mice were gavaged with 0.2% CCl4 to obtain acute liver injury model and with alcohol to obtain chronic liver injury model. H&E staining was performed to detect liver histomorphology. HPLC-MS was performed to analyze the composition of SiNiSan decoction and SiNiSan-medicated serum (SMS). In addition, western blots were done to analyze the representative protein expression in Wnt/ß-catenin signaling. Immunofluorescence staining was done to analyze the protein levels in WB-F344 cells. Finally, in an attempt to measure the influence of SiNiSan on liver regeneration in rats, we constructed a rats partial hepatectomy models. RESULTS: We demonstrated that SiNiSan treatment mitigated liver damage in mice, as evidenced by the decrease in serum AST and ALT levels, as well as improved liver tissue morphology. HPLC-MS results showed that SMS contained a variety of components from the SiNiSan decoction. Next, our results showed that SMS reduced the expression of α-fetoprotein (AFP) and enhanced the expression of albumin (ALB) and cytokeratin 19 (CK19) in WB-F344 cells. Further, SMS treatment induced the accumulation of ß-catenin. After 14 days of SMS treatment, ß-catenin protein underwent nuclear translocation and bound to the LEF1 receptor in the nucleus, which regulated c-Myc and Cyclin D1 factors to activate Wnt/ß-catenin signaling and promoted differentiation of WB-F344 cells. In addition, we demonstrated that SiNiSan increased liver regeneration in rat hepatectomy. CONCLUSION: Collectively, the current study revealed that SiNiSan alleviated the acute liver injury induced by CCl4 as well as the chronic liver damage triggered by alcohol and sucrose in vitro. Concurrently, SMS treatment induced hepatic stem cell differentiation by activating Wnt/ß-catenin signaling in vivo. Further study showed that SiNiSan promoted the regeneration of rats liver. The current study provides a theoretical basis for the clinical treatment of liver-related diseases with SiNiSan.

Evaluation of adalimumab biosimilar candidate (HS016) in Chinese patients with active ankylosing spondylitis based on a health survey: sub-analysis of a phase 3 study.

OBJECTIVE: The equivalence of the biosimilar HS016 to adalimumab (Humira) for the treatment of active ankylosing spondylitis (AS) patients has been previously validated. The aim was to compare the efficacy of HS016 and adalimumab in stratified subgroups at different time points using Health Assessment Questionnaire for Spondyloarthropathies (HAQ-S) and short form 36 (SF-36) questionnaires. METHODS: We carried out a multicenter, randomized, double-blind, parallel, positive control, phase 3 trial of patients with active AS. They were selected randomly to be subcutaneously administered 40 mg HS016 or adalimumab every 2 weeks for a total treatment period of 24 weeks in a 2:1 ratio. A health surveys were used to assess mental and physical improvements of patients as well as other factors. RESULTS: HAQ-S revealed that changes in scores from baseline in both groups were time dependent until 14 weeks and that during the first 4 weeks of treatment the changes declined rapidly. The SF-36 health survey revealed that both HS016 and adalimumab produced rapid beneficial effects against AS during the first 2 weeks of therapy, which gradually declined between 2 and 12 weeks and flattened out after 12 weeks until 24 weeks. CONCLUSION: This trial demonstrated that both HS016 and adalimumab produced rapid improvements in symptoms during the first 2 weeks of treatment. These findings suggest that HS016 is an alternative economical treatment for Chinese AS patients producing a rapid amelioration of symptoms, aiding them to recover their lifestyle satisfaction. TRIAL REGISTRATION: http://www.chictr.org.cn/enindex.aspx , ChiCTR1900022520, retrospectively registered. Key points • HS016 and adalimumab produced rapid AS symptom improvements during the first 2 weeks followed by a slowdown of improvements until week 4 with afterwards few improvements evaluated by HAQ-S • The improvements according to the short form of the 36 (SF-36) questionnaires revealed similar trends as for HAQ-S • There was no significant difference in HAQ-S and SF-36 scores between HS016 and adalimumab.

Long-term straw returning improve soil K balance and potassium supplying ability under rice and wheat cultivation.

The aims of the present study were to provide scientific bases for rational use of crop straw to substitute chemical potassium (K) input. The effects of potassium fertilization and straw incorporation on soil K balance and K supplying in a long-term (14 years) field experiment. Five treatments were examined: (1) no fertilization (CK); (2) mineral fertilizing (NPK); (3) straw 6000 kg h m-2 (S); (4) NPK with straw 3000 kg h m-2 (NPK1/2S); and (5) NPK with straw 6000 kg h m-2 (NPKS). K composition, K balance and quantity-intensity (Q/I) relationship were studied. Under no fertilization or low straw returned conditions, soil K was unbalanced and deficienct seriously. Straw return at 6000 kg h m-2 per season with fertilization improved the soil potassium supply and K balance. Long-term K surplus (4 or 5 years), compared with NPK, the NPKS significantly increased non-special K adsorption (Knsa) and non-exchangeable K (Kne) by 5.7-11.2 mg kg-1 and 65.7-128.1 mg kg-1, respectively. Q/I relationship showed cropping without straw K or without fertilizer K resulted in lower quantity (nonspecifically and specifically held K i.e. - ∆K0 and Kx) and intensity (equilibrium activity ratio i.e. CR0K) of K in tested soils. K-fertilization with straw maintain higher exchangeable K (EK0) and a higher difference between EK0 and minimum exchangeable K(EKmin), and would help to prevent depletion in non-exchangeable pool of soil K under intensive cropping. Additionally, The straw return mainly decreased potential buffering capacity for exchangeable pool (PBCKn), 43.92-48.22% of added K in soil might be converted to exchangeable pool while it was 25.67-29.19% be converted to non-exchangeable pool. The contribution of exchangeable K towards plant K uptake would be higher in the soil with straw than the soil without straw and the non-exchangeable K would be the long-term fixed K as a supplement to the potassium pool. K fertilizer with 6000 kg h m-2 straw return in each crop season increased soil available K and slowly available K. The findings underlined importance of the straw return and contribution for sustain K supplying ability of soils.

Comparative transcriptomics and network pharmacology analysis to identify the potential mechanism of celastrol against osteoarthritis.

INTRODUCTION: Celastrol is a promising therapeutic agent for the treatment of osteoarthritis (OA). However, the mechanism of action of celastrol is unclear. This study was aiming to identify the potential function of celastrol on OA and determine its underlying mechanism. METHOD: Celastrol targets were collected from web database searches and literature review, while pathogenic OA targets were obtained from Online Mendelian Inheritance in Man (OMIM) and GeneCards databases. Transcriptomics data was sequenced using an Illumina HiSeq 4000 platform. Celastrol-OA overlapping genes were then identified followed by prediction of the potential function and signaling pathways associated with celastrol using gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. A celastrol-target network was constructed to identify the candidate core targets of celastrol. The predictions were then validated by performing molecular docking and molecular dynamics simulation studies. RESULTS: In total, 96 genes were identified as the putative celastrol targets for treatment of OA. These genes were possibly involved in cell phenotype changes including response to lipopolysaccharide and oxidative stress as well as in cell apoptosis and aging. The genes also induced the mTOR pathway and AGE-RAGE signaling pathway at the intracellular level. Additionally, results indicated that 13 core targets including mTOR, TP53, MMP9, EGFR, CCND1, MAPK1, STAT3, VEGFA, CASP3, TNF, MYC, ESR1, and PTEN were likely direct targets of celastrol in OA. Finally, mTOR was determined as the most likely therapeutic target of celastrol in OA. CONCLUSION: This study provides a basic understanding and novel insight into the potential mechanism of celastrol against OA. Key Points • Our study provides a strong indication that further study of celastrol therapy in OA is required. • mTOR is the most likely therapeutic target of celastrol in OA.

Intranasal treatment with bacteriophage rescues mice from Acinetobacter baumannii-mediated pneumonia.

AIM: With the emergence of drug-resistant bacteria, finding alternative agents to treat antibiotic-resistant bacterial infections is imperative. MATERIALS & METHODS: A mouse pneumonia model was developed by combining cyclophosphamide pretreatment and Acinetobacter baumannii challenge, and a lytic bacteriophage was evaluated for its therapeutic efficacy in this model by examining the survival rate, bacterial load in the lung and lung pathology. RESULTS: Intranasal instillation with bacteriophage rescued 100% of mice following lethal challenge with A. baumannii. Phage treatment reduced bacterial load in the lung. Microcomputed tomography indicated a reduction in lung inflammation in mice given phage. CONCLUSION: This research demonstrates that intranasal application of bacteriophage is viable, and could provide complete protection from pneumonia caused by A. baumannii.

Effects of Huaier aqueous extract on proliferation and apoptosis in the melanoma cell line A875.

In recent years, an aqueous extract of the fungus Trametes robiniophila Murriell 1907 (Huaier) has been commonly used in China for complementary cancer therapy. However, the mechanisms of its anticancer effects are largely unknown. In the present study, we aimed to investigate the effects of Huaier extract on the inhibition of proliferation and promotion of apoptosis in a melanoma cell line, A875, and to explore the possible mechanisms of its anticancer effects. Cell proliferation was measured using a Cell Counting Kit-8 (CCK8) and PCNA-Western blot. The cell cycle distribution, and apoptosis levels were analyzed by flow cytometry, and Western blot was used to test the apoptotic pathways. We found that Huaier extract strongly inhibited cell proliferation of the A875 melanoma cells and induced G2/M arrest and apoptosis in a time- and dose-dependent manner. P53 expression was increased and cell apoptosis executed by caspase-3. Down-regulation of Bcl-2 and up-regulation of Bcl2-associated X protein (BAX) indicated that Huaier extract induced apoptosis through the mitochondrial pathway. As expected, the inhibitor Huaier decreased melanoma cell line A875 proliferation, and induced apoptosis in a time- and dose-dependent manner. Our findings indicate that Huaier extract is an effective complementary agent for cancer treatment of melanoma.

Sex-specific DNA methylation and gene expression in andromonoecious poplar.

UNLABELLED: The andromonoecious poplar is an exceptional model system for studying sex-specific flower development in dioecious plants. There is increasing evidence that epigenetic regulation, particularly DNA methylation, is an important regulatory factor during flower development. Here, methylation-sensitive amplified polymorphism (MSAP) was used to screen for sex-specific DNA methylation alterations in the andromonoecious poplar. The sequences of 27 sex-specific amplified fragments were obtained from DNA prepared from sex-specific flower tissues. PtGT2, PtPAL3, and PtCER4, which are homologous to MF26, MF29, and MF35, respectively, were cloned as candidate genes. Expression analysis and DNA methylation pattern profiling of the three candidate genes revealed that gene expression upregulation was always associated with gene body methylation. The results suggested that DNA methylation sites have the potential to regulate the genes' transcript levels. These three genes were shown to play important roles during different phases of flower development. This study will help to provide candidates for future experiments aimed at understanding the mechanism, whereby DNA methylation regulates gene expression in poplar. KEY MESSAGES: We report the first screen for sex-specific DNA methylation alterations in the andromonoecious poplar. 27 sex-specific methylation sites were identified. The gene expression levels and DNA methylation patterns were detected for three candidate genes.

Qiliqiangxin improves cardiac function in spontaneously hypertensive rats through the inhibition of cardiac chymase.

BACKGROUND: This study was designed to investigate the effects and mechanism of action of the traditional Chinese drug formula, qiliqiangxin (QLQX), on cardiac function in spontaneously hypertensive rats (SHRs). METHODS: We evaluated the effects of oral high-dose (4 g/kg/day, n = 7) and low-dose (1 g/kg/day, n = 7) QLQX on cardiac function in SHRs aged between 8 compared to control, the 8-week-old Wistar-Kyoto (WKY) rats. Echocardiography was performed to evaluate cardiac function and hemodynamic parameters. Hematoxylin and eosin (HE) and Masson's trichrome staining were performed, and the expression of myocardial angiotensin (Ang)-converting enzyme, chymase, transforming growth factor (TGF)-ß, and collagen-type I and III were evaluated with real-time reverse transcription-PCR. Myocardial chymase, Ang-converting enzyme (ACE), and Ang II activities were measured with radioimmunoassay (RIA) techniques. Cardiac mast cells were detected with toluidine blue staining. RESULTS: In SHRs, the number of chymase enzyme-positive mast cells increased in the left ventricle (LV) compared with WKY rats. QLQX significantly decreased mast cell density and cardiac chymase levels, and it improved ejection fraction values and cardiac systolic function compared with vehicle. Moreover, QLQX decreased left atrial diameters and improved the E/A ratio. QLQX suppressed collagen-type I and III and TGF-ß mRNA levels, and Ang II activity, in a dose-dependent manner. Whereas no difference in ACE activity was found between SHRs, chymase expression and activity were significantly decreased with QLQX. CONCLUSIONS: These data suggest that QLQX improves both systolic and diastolic cardiac function in SHRs through downregulating the cardiac chymase signaling pathway and chymase-mediated Ang II production.

Pharmacokinetic characterization of a natural product-inspired novel MEK1 inhibitor E6201 in preclinical species.

PURPOSE: E6201 is a natural product-inspired novel inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-1 (MEK1) and other kinases and is currently under development as an anticancer (parenteral administration) and antipsoriasis agent (topical application). In vitro and in vivo preclinical studies were performed to characterize the pharmacokinetics of E6201. Allometric scaling was applied to predict human pharmacokinetics of E6201. METHODS: In vitro metabolism studies for CYP induction and CYP inhibition were conducted using human hepatocytes and microsomes, respectively. Metabolic stability using microsomes and protein-binding studies using pooled plasma were performed for mice, rats, dogs, and human. Pharmacokinetics of E6201 and its isomeric metabolite, ER-813010, in mice, rats, and dogs was determined following single IV administration of E6201 at three dose levels. Bioanalysis was performed using LC/MS/MS. Pharmacokinetic parameters were determined using non-compartmental analysis, and allometric scaling with a two-compartment model was used to predict E6201 pharmacokinetics in humans. RESULTS: E6201 showed high plasma protein binding (>95%), and metabolic stability half-life ranged from 36 to 89 min across species. In vitro CYP inhibition (CYP1A2, 2C9, 2C19, 2D6, 2E1, and 3A) and CYP induction (CYP1A, 3A, 2C9, and 2C19) suggested no inhibitory or induction effect on the tested human CYPs up to 10 µM of E6201. Pharmacokinetics of E6201 in mice, rats, and dogs was characterized by mean clearance ranging from 3.45 to 10.92 L/h/kg, distribution volume ranging from 0.63 to 13.09 L/kg, and elimination half-life ranging from 0.4 to 1.6 h. ER-813010 was detected in all species with metabolite to parent exposure ratio (AUC(R)) ranging from 3.1 to 33.4% and exhibited fast elimination (<3 h). The allometry predicted high clearance and large volume of distribution of E6201 in humans and was in general in good agreement with the observed first human subject pharmacokinetics. CONCLUSIONS: E6201 exhibited high clearance, high to moderate distribution, and fast elimination in preclinical species. In vitro results suggested that E6201 has low risk of drug-drug interactions due to CYP inhibition and induction in humans. In the first-in-man study, E6201 exhibited high clearance, which was well predicted by allometric scaling.

Arsenic trioxide induces apoptosis of fibroblast-like synoviocytes and represents antiarthritis effect in experimental model of rheumatoid arthritis.

OBJECTIVE: recent studies have demonstrated that rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) proliferate as fiercely as tumor cells. Induction of apoptosis in RA FLS therefore provides a new approach for the inhibition of joint destruction. Arsenic trioxide (As(2)O(3)) was reported to be an effective apoptosis inducer in a variety of cell types. We investigated the possible effect of As(2)O(3) on apoptosis induction of RA FLS and the mechanisms involved in this process. METHODS: apoptosis was determined by flow cytometric analysis, terminal deoxynucleotide transferase-mediated dUTP nick end-labeling, and transmission electron microscopy. The activity and messenger RNA (mRNA) expression of nuclear factor-κB (NF-κB) was then detected by ELISA and real-time polymerase chain reaction, respectively. Activities of caspase-3 and caspase-8 were evaluated using luminogenic substrates. The effect of As(2)O(3) on the morphology of rats with collagen-induced arthritis was evaluated under a light microscope after H&E staining. RESULTS: as(2)O(3) significantly enhanced the apoptosis of RA FLS. It suppressed the DNA-binding activity and mRNA expression level of NF-κB, probably by inhibiting tumor necrosis factor-α-induced activation of NF-κB. As(2)O(3) treatment significantly increased the activity of both caspase-3 and caspase-8. Morphological analysis revealed histological recovery in the synovial membrane. Synovial hyperplasia and inflammation in the joints were effectively inhibited. CONCLUSION: as(2)O(3) represents an apoptotic effect on RA FLS through NF-κB signaling pathway, and this process is mediated by the activation of caspase cascade. Treatment with As(2)O(3) significantly improved the pathologic changes of collagen-induced arthritis and may have potential for treatment of RA.