Solute carrier organic anion transporter family member 4A1 promotes colorectal cancer progression and is regulated by miR-1224-5p.

Colorectal cancer (CRC) is one of the most common malignant tumors, and pharmacological treatments of CRC are unsatisfactory. Increasing evidence shows that solute carrier organic anion transporter family member 4A1 (SLCO4A1) is abnormally expressed in numerous cancer types and may be correlated with cancer development and metastasis. However, the roles of SLCO4A1 in CRC are incompletely understood. This study utilized the GSE110224 dataset and other databases to analyze SLCO4A1 expression levels in CRC tissues. The expression levels of SLCO4A1 in CRC cell lines were evaluated by quantitative real-time polymerase chain reaction and western blotting. The roles of SLCO4A1 in CRC cell proliferation, migration, invasion, and epithelial-mesenchymal transition were assessed. The interaction between SLCO4A1 and microRNA-1224-5p was verified using a dual-luciferase reporter assay. The effect of SLCO4A1 in vivo was investigated using a BALB/c mouse model. The level of SLCO4A1 expression was increased in CRC tissues and cell lines. Moreover, high SLCO4A1 expression was positively associated with a poor prognosis. The results of gain- and loss-of-function experiments showed that SLCO4A1 knockdown suppressed CRC cell proliferation, migration, invasion, and epithelial-mesenchymal transition while SLCO4A1 overexpression had opposite effects in vitro. Furthermore, SLCO4A1 knockdown could suppress tumor growth in vivo. Further analyses showed that SLCO4A1 was downregulated by miR-1224-5p. Rescue experiments confirmed that SLCO4A1 reversed the effect of miR-1224-5p on cell function. These results suggested that SLCO4A1 acted as an oncogene to regulate CRC development and was a potential target for CRC treatment.

Multi-centre study of the clinical features and gene variant spectrum of Gitelman syndrome in Chinese children.

Based on the Chinese Children Genetic Kidney Disease Database (CCGKDD), we established a pediatric Gitelman syndrome (GS) cohort to explore the phenotype and genotype characteristics. Thirty-two patients with SLC12A3 gene variants were collected. Five cases (16%) were homozygous, 16 (50%) were compound heterozygous, 10 (31%) carried only a single variant, and the other one harbored two de novo variants beyond classification. p.(T60M) was found in eight patients. The average diagnosis age was 7.79 ± 3.54 years. A total of 31% of the patients were asymptomatic. Muscle weakness was the most common symptom, accounting for 50%. Earlier age of onset (4.06 ± 1.17 yr vs. 8.10 ± 3.46 yr vs. 8.61 ± 3.56 yr, p< 0.05) and lower urinary calcium-creatinine ratio (p = 0.024) were found in the homozygous group than those in the heterozygous and compound heterozygous group. Patients with p.(T60M) variant had an earlier age of onset (4.01 ± 2.83 yr vs. 6.92 ± 3.07 yr, p = 0.025) and lower urinary calcium-creatinine ratio (p = 0.056). Thus, more than 30% of GS children have no clinical symptoms. Homozygous variant and the p.(T60M) variant may be associated with earlier onset and lower urinary calcium excretion in Chinese pediatric GS.

Screening and identification of a specific peptide binding to breast cancer cells from a phage-displayed peptide library.

OBJECTIVES: Breast cancer is a popular fatal malignant tumor for women with high of rates incidence and mortality. Development of the new approaches for breast cancer targeted diagnosis and chemotherapy is emergently needed by the current clinical practice, the important first step is finding a breast cancer specifically binding molecule or fragment as early clinical indicators. RESULTS: By a phage-displayed peptide library, a 12-mer peptide, CSB1 was screened out using MCF-7 cells as the target. The consequently results under immunofluorescence and laser scanning confocal microscope (LSCM) indicated that CSB1 bound MCF-7 cells and breast cancer tissues specifically and sensitively with high affinity. Bioinformatics analysis suggested that the peptide CSB1 targets the 5-Lipoxygenase-Activating Protein (FLAP), which has been implicated in breast cancer progression and prognosis. CONCLUSIONS: The peptide, CSB1 is of the potential as a candidate to be used for developing the new approaches of molecular imaging detection and targeting chemotherapy of breast cancer in the future.

Clinical Analysis of Primary Nephrotic Syndrome Complicated by Plastic Bronchitis in Children.

OBJECTIVE: To summarize the clinical features of primary nephrotic syndrome (PNS) complicated by plastic bronchitis (PB) in children to provide guidance for treatment. METHODS: We conducted a retrospective review of the clinical data of 25 children hospitalized with NS complicated by PB in our Hospital between 10/2016 and 03/2019, and summarized the clinical manifestations, imaging and fiberoptic bronchoscopy (FOB) examinations, treatment course and outcome of them. RESULTS: 1). The 25 children, with a nephrotic syndrome (NS) course of one to 36 months, were all diagnosed with PB after FOB, among which 8 cases (32%) had respiratory failure and required ventilatory support. All of them started with respiratory symptoms such as fever and cough, and then suffered from dyspnea and progressive aggravation after 1-3 day(s) of onset, with rapid occurrence of bidirectional dyspnea and even respiratory failure in severe cases. 2). Laboratory test for pathogens: influenza A virus H1N1 (11 cases), influenza B virus (9 cases), adenovirus (3 cases) and mycoplasma pneumoniae (2 cases). There was no statistically significant difference (P>0.05) between children with common NS complicated by influenza virus (IV) infection (not accompanied by dyspnea) and those with kidney disease who developed PB in the white blood cell count, lymphocyte count, the inflammatory biomarkers C-reactive protein (CRP), procalcitonin (PCT) and humoral immunity (IgG level), yet the total IgG level was found significantly higher and the blood albumin level lower in the latter (P<0.05). 3). The 25 children were all examined with the FOB and treated with lavage, 15 of which had typical bronchial tree-like casts and 10 broken and stringy casts. Based on histopathological classification, all children were of Type I. 4). Twenty children (80%) with influenza were administered the antiviral drug Oseltamivir, 20 (80%) were treated with antibiotics, oral hormones were replaced with the same dosage of intravenous Methylprednisolone for 5 cases (20%), and 20 (80%) were intravenously administered gamma globulins (400-500 mg/kg x 3 days). These children showed a remarkable improvement after treatment and there were no deaths. CONCLUSION: NS children are at high risk of influenza virus infection. Children with a severe case of NS are more susceptible to PB. If symptoms like shortness of breath, wheezing and progressive bidirectional dyspnea occur, FOB examination and lavage treatment should be performed as early as possible. Hyper-IgE-emia and hypoproteinemia may be the high risk factors for PNS complicated by PB in children. ZIEL: Ziel der Studie war es, durch Zusammenfassung der klinischen Merkmale des primären nephrotischen Syndroms (PNS) mit komplizierender plastischer Bronchitis (PB) im Kindesalter eine Orientierungshilfe für die Therapie der Erkrankung zu geben. METHODIK: Wir führten eine retrospektive Prüfung der klinischen Daten von 25 Kindern durch, die zwischen Oktober 2016 und März 2019 in unser Krankhaus aufgenommen wurden, und erstellten eine Zusammenfassung der klinischen Symptome, Untersuchungen mit bildgebenden Verfahren und fiberoptischer Bronchoskopie (FOB), des Therapieverlaufs und des Outcomes der Patienten. ERGEBNISSE: 1). Bei den 25 Kindern bestand ein nephrotisches Syndrom (NS) über einen Zeitraum von einem bis 36 Monaten. Bei allen Patienten wurde die Diagnose PB nach FOB gestellt, wobei in 8 Fällen (32%) eine beatmungspflichtige respiratorische Insuffizienz vorlag. Alle Patienten zeigten anfänglich Symptome einer Atemwegserkrankung wie Fieber und Husten, gefolgt von Atemnot und progredienter Verschlechterung 1 bis 3 Tage nach Erkrankungsbeginn. Dabei kam es rasch zum Auftreten bidirektionaler Atemnot, in schweren Fällen bis hin zur respiratorischen Insuffizienz. 2). Laboruntersuchung auf Erreger: Influenza-A-Virus H1N1 (11 Fälle), Influenza-B-Virus (9 Fälle), Adenovirus (3 Fälle) und Mycoplasma pneumoniae (2 Fälle). Es fand sich kein statistisch signifikanter Unterschied (P>0,05) zwischen Kindern, die ein "gewöhnliches" NS mit komplizierender Influenza-Virus (IV)-Infektion (ohne begleitende Atemnot) aufwiesen, und Kindern mit Nierenerkrankung, die eine PB entwickelten, hinsichtlich der Leukozyten- und Lymphozytenwerte sowie der Entzündungsmarker C-reaktives Protein (CRP), Procalcitonin (PCT) und humorale Immunität (IgG-Wert). Allerdings wurde bei der letzteren Patientengruppe ein signifikant höherer Gesamt-IgG-Wert und ein signifikant niedriger Albumin-Spiegel im Blut nachgewiesen (P<0.05). 3). Bei allen 25 Kindern erfolgte eine FOB und Therapie mit Lavage, bei 15 Kinder fanden sich typische verzweigte Ausgüsse der Bronchialäste und bei 10 Patienten desintegrierte und zähe Ausgüsse. Gemäß der histopathologischen Klassifikation waren alle Kinder vom Typ I. 4). Zwanzig Kinder (80%) mit Influenza erhielten das Virostatikum Oseltamivir, 20 Kinder (80%) eine Antibiotikatherapie, in 5 Fällen (20%) wurden oral gegebene Hormone durch intravenös in derselben Dosis verabreichtes Methylprednisolon ersetzt und 20 Kinder (80%) erhielten intravenös verabreichte Gammaglobuline (400-500 mg/kg Körpergewicht x 3 Tage). Diese Kinder zeigten eine bemerkenswerte Verbesserung nach der Therapie und es traten keine Todesfälle auf. SCHLUSSFOLGERUNG: Bei Kindern mit NS besteht ein hohes Risiko für eine Influenza-Virus-Infektion. Kinder mit schwerem NS sind anfälliger für PB. Bei Auftreten von Symptomen wie Atemnot, Giemen und Brummern sowie progredienter bidirektionaler Dyspnoe sollte baldmöglichst eine FOB-Untersuchung und eine therapeutische Lavage durchgeführt werden. Erhöhte IgE-Werte im Blut und Hypoproteinämie stellen möglicherweise Risikofaktoren für PNS mit komplizierender PB im Kindesalter dar.

Study on the damage of sperm induced by nickel nanoparticle exposure.

As a new type of nanomaterials, nickel nanoparticles (Ni NPs) have been widely used by human beings, whose exposure probability was greatly increasing. Many studies have shown that Ni NPs can induce apoptosis, oxidative stress and DNA damage. Nowadays, male reproductive health is an important public health problem, which is a hot topic in toxicological research. In the present study, to protect reproductive health, the effect of Ni NPs exposure on spermatogenesis injury was assessed, understanding the toxicity and safety of Ni NPs. Sixty ICR male mice with 20 ± 2 g were randomly divided into five groups. The experimental groups were treated with 5 mg/kg, 15 mg/kg and 45 mg/kg Ni NPs. The reproductive toxicity of Ni NPs on male mice was evaluated by the indexes of testicular organ coefficient, testicular marker enzyme, sperm motility and histopathology. As a result, the somatic index of testis and epididymis increased in each group. Compared with the control group, the activity of testicular markers increased and the sperm motility index decreased in the low-, middle- and high-dose groups. Pathological results indicated that various cell apoptosis and disordered arrangement of cells occurred in the seminiferous tubules of the exposed groups. In conclusion, the findings of this study suggest that Ni NPs have certain damage to spermatogenesis in mice.

[Clinical feature and variant analysis of a case with hereditary hypophosphatemic rickets with hypercalciuria].

OBJECTIVE: To explore the clinical features and genetic basis for a patient with hereditary hypophosphatemic rickets with hypercalciuria(HHRH). METHODS: Clinical data of the patient was collected. The patient was subjected to whole exome capture and next generation sequencing (NGS). Suspected variants were verified by Sanger sequencing. RESULTS: The patient presented with hypophosphatemic rickets, short stature, hypercalciuria, and renal stones. NGS showed that he has carried compound heterozygous variants of the SLC34A3 gene, namely c.532_533delCA(p.Q178Vfs*6) and c.894_925+69del(splicing). His parents were asymptomatic heterozygous carriers of one of the variants. Based on ACMG guidelines, both variants were classified as pathogenic. CONCLUSION: The compound heterozygous variants c.532_533delCA (p.Q178Vfs*6) and c.894_925+69del(splicing) of the SLC34A3 gene probably underlie the disease in this child. Above finding has enriched the variant spectrum for HHRH. Based on the results, prenatal diagnosis may be provided for the family.

Reproductive toxicity induced by nickel nanoparticles in Caenorhabditis elegans.

To investigate the reproductive toxicity and underlying mechanism of nickel nanoparticles (Ni NPs), Caenorhabditis elegans (C. elegans) were treated with/without 1.0, 2.5, and 5.0 µg cm-2 of Ni NPs or nickel microparticles (Ni MPs). Generation time, fertilized egg numbers, spermatide activation and motility were detected. Results indicated, under the same treatment doses, that Ni NPs induced higher reproductive toxicity to C. elegans than Ni MPs. Reproductive toxicities observed in C. elegans included a decrease in brood size, fertilized egg and spermatide activation, but an increase in generation time and out-of-round spermatids. The reproductive toxicity of Ni NPs on C. elegans may be induced by oxidative stress. The reproductive toxicity in C. elegans induced by Ni NPs is consistent with our previous results in the rats. Therefore, C. elegans can be used as an alternative model to detect the early reproductive toxicity of Ni NPs exposure. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1530-1538, 2017.

The further characterization of the peptide specifically binding to gastric cancer.

Targeting peptide has been considered to be useful as a small molecule probe leading to multifunctional properties for both imaging detection and targeting therapy. Thus, the identification of novel targets is urgently needed to develop innovative agents to effectively control gastric cancer metastasis and progression. Previously, we reported a novel 12-mer peptide, GP-5 (IHKDKNAPSLVP), binding to gastric carcinoma (GC) cells specifically and sensitively, and it was screened by using a phage displayed peptide library and primarily analyzed. In this study, it was further identified via fluorescence microscopy, flow cytometry, tissue chip and other methods. Our results indicated that the peptide GP-5 presents a particularly high affinity and specificity to GC cells and tissues, whereas only background detection occurred with other control cancer cells, cancer tissues or normal tissues. Taken together, all results support that the peptide GP-5 is a potential candidate to be developed as a useful molecule fragment for the imaging detection and targeting therapy of GC.

Mechanisms involved in reproductive toxicity caused by nickel nanoparticle in female rats.

Nickel nanoparticles (Ni NPs) are associated with reproductive toxicity. However, the mechanisms of reproductive toxicity are unclear. Our goal was to explore further reproductive toxicity induced by nickel nanoparticle and mechanisms involved in this process, including the role of oxidative stress and apoptosis. According to the one-generation reproductive toxicity standard, rats were exposed to nickel nanoparticles by gavage and we selected indicators including ultrastructural, reactive oxygen species (ROS), oxidant and antioxidant enzymes, and cell apoptosis-related factors. Ultrastructural results of ovaries showed mitochondrion swelling, disappearance of mitochondrial cristae, and enlargement of the endoplasmic reticulum in the exposure groups. NiNPs had significantly decreased the activity of SOD and CAT, and had increased the levels of ROS, MDA, and NO in comparison with the control groups. The mRNA expressions of caspase-3, caspase-8, and caspase-9 and the expressions of Fas, Cyt c, Bax, and Bid protein on the ovaries significantly increased. At the same time, the expressions of Bcl-2 protein were significantly decreased. Based on these results, oxidative stress and cell apoptosis may play the important roles in inducing reproductive toxicity after NiNPs treatment. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1674-1683, 2016.

Evaluation of the Bitterness of Traditional Chinese Medicines using an E-Tongue Coupled with a Robust Partial Least Squares Regression Method.

To accurately, safely, and efficiently evaluate the bitterness of Traditional Chinese Medicines (TCMs), a robust predictor was developed using robust partial least squares (RPLS) regression method based on data obtained from an electronic tongue (e-tongue) system. The data quality was verified by the Grubb's test. Moreover, potential outliers were detected based on both the standardized residual and score distance calculated for each sample. The performance of RPLS on the dataset before and after outlier detection was compared to other state-of-the-art methods including multivariate linear regression, least squares support vector machine, and the plain partial least squares regression. Both R² and root-mean-squares error (RMSE) of cross-validation (CV) were recorded for each model. With four latent variables, a robust RMSECV value of 0.3916 with bitterness values ranging from 0.63 to 4.78 were obtained for the RPLS model that was constructed based on the dataset including outliers. Meanwhile, the RMSECV, which was calculated using the models constructed by other methods, was larger than that of the RPLS model. After six outliers were excluded, the performance of all benchmark methods markedly improved, but the difference between the RPLS model constructed before and after outlier exclusion was negligible. In conclusion, the bitterness of TCM decoctions can be accurately evaluated with the RPLS model constructed using e-tongue data.

Screening of a specific peptide binding to esophageal squamous carcinoma cells from phage displayed peptide library.

To select a specifically binding peptide for imaging detection of human esophageal squamous cell carcinoma (ESCC), a phage-displayed 12-mer peptide library was used to screen the peptide that bind to ESCC cells specifically. After four rounds of bio-panning, the phage recovery rate gradually increased, and specific phage clones were effectively enriched. The 60 randomly selected phage clones were tested using cellular enzyme-linked immunosorbent assay (ELISA), and 41 phage clones were identified as positive clones with the over 2.10 ratio of absorbance higher than other clones, IRP and PBS controls. From the sequencing results of the positive clones, 14 peptide sequences were obtained and ESCP9 consensus sequence was identified as the peptide with best affinity to ESCC cells via competitive inhibition, fluorescence microscopy, and flow cytometry. The results indicate that the peptide ESCP9 can bind to ESCC cells specifically and sensitively, and it is a potential candidate to be developed as an useful molecule to the imaging detection and targeting therapy for ESCC.

Toxoplasma gondii infection in the peritoneal macrophages of rats treated with glucocorticoids.

It is well known that toxoplasmosis can be life threatening to immunocompromised individuals such as AIDS and organ transplantation patients. Glucocorticoids (GCs) are widely used in the clinic for the treatment of autoimmune diseases and organ transplantation resulting in acute toxoplasmosis in these patients. However, the interaction and mechanism between the development of acute toxoplasmosis and GC therapy are still unknown. The aims of this study were to investigate the infection of Toxoplasma gondii in the peritoneal macrophages of rats treated with glucocorticoids. Our results showed that the growth rate of T. gondii RH strain was significantly increased in the peritoneal macrophages of rats treated with glucocorticoids in vivo. For instance, 242 (±16) tachyzoites were found in 100 macrophages from the rats treated with methylprednisolone (MP), while only 16 (±4) tachyzoites were counted in the macrophages from the non-treated control rats 24 h after infection (P < 0.01). We also demonstrated that a significant inhibition of nitric oxide (NO) production was detected in the macrophages collected from the rats post-treated with GCs with 12.90 µM (±0.99 µM) of nitrite production from the rats treated with MP, while 30.85 µM (±1.62 µM) was found in the non-treated control rats 36 h after incubation (P < 0.01). Furthermore, glucocorticoids could significantly inhibit the expression of inducible nitric oxide synthase mRNA and its protein in the rat peritoneal macrophages. Our results strongly indicate that the decrease of NO in the rat peritoneal macrophages is closely linked to the cause of acute toxoplasmosis in the host. Additionally, there was a significant increase in the number of cysts produced by the naturally cyst forming, T. gondii Prugniaud strain with an average of 2,795 (±422) cysts of the parasite being detected in the brains of the rats treated with dexamethasone, while only 1,356 (±490) cysts were found in the non-treated control animals (P < 0.01). As rats and humans are both naturally resistant to T. gondii infection, these novel data could lead to a better understanding of the development of acute toxoplasmosis during glucocorticoid therapy in humans.

Correlation Between Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio with Risk Stratification Indicators and Thrombus Burden in Patients with Moderate-to-High Risk Acute Pulmonary Embolism, and Changes After Treatment.

OBJECTIVE: To investigate the correlation between neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and risk stratification indicators as well as thrombus burden in patients with moderate-to-high risk acute pulmonary embolism (APE), and to assess the changes in these parameters following interventional therapy. METHODS: This study retrospectively included patients with moderate-to-high risk APE who were admitted to the Department of Interventional Vascular Surgery at Putian First Hospital from May 2020 to May 2024. All patients received anticoagulation therapy, pulmonary artery catheter-directed thrombolysis, and/or mechanical thrombectomy. Patients were further divided into subgroup A if they did not present with any of the following conditions at admission: a) acute inflammatory diseases (including lung infections); b) malignant tumors; c) history of trauma or surgery within the past 2 months. Patients with any of the aforementioned conditions were classified as subgroup B. Additionally, 50 healthy individuals were randomly selected as the healthy control group. RESULTS: The NLR and PLR in subgroup A were significantly lower than those in subgroup B (P < .01). Compared with the healthy control group, the NLR in the APE group and subgroup A was significantly higher (P < .001). There were no significant differences in NLR and PLR between the troponin I-negative and troponin I-positive groups (P > .05), or between the N-terminal pro-B-type natriuretic peptide (NT-proBNP)-negative and NT-proBNP-positive groups (P > .05). There were no significant correlations between NLR and PLR with risk stratification indicators and pulmonary artery embolism index (P > .05). Compared with before treatment, NLR, troponin I, NT-proBNP, right ventricular diameter/left ventricular diameter ratio, and pulmonary artery embolism index were significantly reduced after treatment (P < .05), while there was no significant difference in PLR before and after treatment (P > .05). CONCLUSION: Elevated NLR in patients with APE, which decreases after effective treatment, may be used for assessing disease status and treatment efficacy. However, there is no correlation between NLR and risk stratification indicators or thrombus burden. PLR does not demonstrate significant value in assessing APE.

Lean-rich combustion characteristics of methane and ammonia in the combined porous structures for carbon reduction and alternative fuel development.

Ammonia as a carbon-free alternative fuel has received much attention with the consumption of fossil fuels. In order to explore the mixed combustion of methane and ammonia, a combined porous media burner was designed with pellets embedded in annular ceramic foam. And the effects of operating parameters on combustion characteristics were investigated. The results showed that the ammonia addition increased the combustion temperature and reduced carbon dioxide emissions at the equivalence ratio of <1. And the ammonia promoted the conversion of CO2 to CO for an equivalence ratio of >1. With the increasing of the ammonia ratio, the CO selectivity increased but the CO2 selectivity decreased. In addition, the mixed combustion of ammonia and methane improved the hydrogen production. The fuel ratio of methane to ammonia (0.80: 0.20) resulted in higher syngas production and lower CO2 mole fraction. The flame propagated faster in ceramic foam with lower pore densities (20 PPI) so the preheating time was greatly reduced. Moreover, the 40 PPI ceramic foam was conducive to the stability of the flame position in the upstream zone, and the H2 mole fraction achieved 10.60 % at the inlet velocity of 14 cm/s.

Study on the toxicity prediction model ofacetolactate synthase inhibitor herbicides based on human serum albumin and superoxide dismutase binding information.

Toxicity significantly influences the successful development of drugs. Based on the toxicity prediction method (carrier protein binding information-toxicity relationship) previously established by the our group, this paper introduces information on the interaction between pesticides and environmental markers (SOD) into the model for the first time, so that the toxicity prediction model can not only predict the toxicity of pesticides to humans and animals, but also predict the toxicity of pesticides to the environment. Firstly, the interaction of acetolactate synthase inhibitor herbicides (ALS inhibitor herbicides) with human serum albumin (HSA) and superoxide dismutase (SOD) was investigated systematically from theory combined with experiments by spectroscopy methods and molecular docking, and important fluorescence parameters were obtained. Then, the fluorescence parameters, pesticides acute toxicity LD50 and structural splitting information were used to construct predictive modeling of ALS inhibitor herbicides based on the carrier protein binding information (R2 = 0.977) and the predictive modeling of drug acute toxicity based on carrier protein binding information and conformational relationship (R2 = 0.991), which had effectively predicted pesticides toxicity in humans and animals. To predict potential environmental toxicity, the predictive modeling of drug acute toxicity based on superoxide dismutase binding information was established (R2 = 0.883) by ALS inhibitor herbicides-SOD binding information, which has a good predictive ability in the potential toxicity of pesticides to the environment. This study lays the foundation for developing low toxicity pesticides.

One of the major challenges of masking the bitter taste in medications: an overview of quantitative methods for bitterness.

Objective: The aim of the present study was to carry out a systematic research on bitterness quantification to provide a reference for scholars and pharmaceutical developers to carry out drug taste masking research. Significance: The bitterness of medications poses a significant concern for clinicians and patients. Scientifically measuring the intensity of drug bitterness is pivotal for enhancing drug palatability and broadening their clinical utility. Methods: The current study was carried out by conducting a systematic literature review that identified relevant papers from indexed databases. Numerous studies and research are cited and quoted in this article to summarize the features, strengths, and applicability of quantitative bitterness assessment methods. Results: In our research, we systematically outlined the classification and key advancements in quantitative research methods for assessing drug bitterness, including in vivo quantification techniques such as traditional human taste panel methods, as well as in vitro quantification methods such as electronic tongue analysis. It focused on the quantitative methods and difficulties of bitterness of natural drugs with complex system characteristics and their difficulties in quantification, and proposes possible future research directions. Conclusion: The quantitative methods of bitterness were summarized, which laid an important foundation for the construction of a comprehensive bitterness quantification standard system and the formulation of accurate, efficient and rich taste masking strategies.

A genomic association study revealing subphenotypes of childhood steroid-sensitive nephrotic syndrome in a larger genomic sequencing cohort.

Dissecting the genetic components that contribute to the two main subphenotypes of steroid-sensitive nephrotic syndrome (SSNS) using genome-wide association studies (GWAS) strategy is important for understanding the disease. We conducted a multicenter cohort study (360 patients and 1835 controls) combined with a GWAS strategy to identify susceptibility variants associated with the following two subphenotypes of SSNS: steroid-sensitive nephrotic syndrome without relapse (SSNSWR, 181 patients) and steroid-dependent/frequent relapse nephrotic syndrome (SDNS/FRNS, 179 patients). The distribution of two single-nucleotide polymorphisms (SNPs) in ANKRD36 and ALPG was significant between SSNSWR and healthy controls, and that of two SNPs in GAD1 and HLA-DQA1 was significant between SDNS/FRNS and healthy controls. Interestingly, rs1047989 in HLA-DQA1 was a candidate locus for SDNS/FRNS but not for SSNSWR. No significant SNPs were observed between SSNSWR and SDNS/FRNS. Meanwhile, chromosome 2:171713702 in GAD1 was associated with a greater steroid dose (>0.75 mg/kg/d) upon relapse to first remission in patients with SDNS/FRNS (odds ratio = 3.14; 95% confidence interval, 0.97-9.87; P = 0.034). rs117014418 in APOL4 was significantly associated with a decrease in eGFR of greater than 20% compared with the baseline in SDNS/FRNS patients (P = 0.0001). Protein-protein intersection network construction suggested that HLA-DQA1 and HLA-DQB1 function together through GSDMA. Thus, SSNSWR belongs to non-HLA region-dependent nephropathy, and the HLA-DQA/DQB region is likely strongly associated with disease relapse, especially in SDNS/FRNS. The study provides a novel approach for the GWAS strategy of SSNS and contributes to our understanding of the pathological mechanisms of SSNSWR and SDNS/FRNS.

α-Stereoselective 3-Deoxy-d-manno-oct-2-ulosonoic Acid (Kdo) O-Glycosylation with a p-Toluenethioglycoside Donor by the (p-Tol)2SO/Tf2O Preactivation Strategy.

A convenient and efficient approach was developed to synthesize α-Kdo O-glycosides based on the Tf2O/(p-Tol)2SO preactivation strategy using peracetylated Kdo thioglycoside as a donor. Under the optimized reaction conditions, several O-glycoside products, including α-(2 → 1)-, α-(2 → 2)-, α-(2 → 3)-, and α-(2 → 6)-Kdo products, were stereoselectively synthesized in high yields. Remarkably, a series of aromatic α-Kdo O-glycosides were first and successfully constructed in high yields. An SN2-like mechanism was revealed by DFT calculations and experimental results.