Piezo1 and its inhibitors: Overview and perspectives.

The cation channel Piezo1, a crucial mechanotransducer found in various organs and tissues, has gained considerable attention as a therapeutic target in recent years. Following this trend, several Piezo1 inhibitors have been discovered and studied for potential pharmacological properties. This review provides an overview of the structural and functional importance of Piezo1, as well as discussing the biological activities of Piezo1 inhibitors based on their mechanism of action. The compounds addressed include the toxin GsMTx4, Aß peptides, certain fatty acids, ruthenium red and gadolinium, Dooku1, as well as the natural products tubeimoside I, salvianolic acid B, jatrorrhzine, and escin. The findings revealed that misexpression of Piezo1 can be associated with a number of chronic diseases, including hypertension, cancer, and hemolytic anemia. Consequently, inhibiting Piezo1 and the subsequent calcium influx can have beneficial effects on various pathological processes, as shown by many in vitro and in vivo studies. However, the development of Piezo1 inhibitors is still in its beginnings, with many opportunities and challenges remaining to be explored.

Identification of novel phenylalanine derivatives bearing a hydroxamic acid moiety as potent quorum sensing inhibitors.

Phenylalanine derivatives are a well-known small moiety responsible for controlling the virulence factors of several bacteria. Herein, for the first time, we report novel structures of phenylalanine derivatives bearing a hydroxamic acid moiety which were designed, synthesized, and evaluated for use as quorum sensing inhibitors. Biological results reveal that six compounds showed good quorum sensing inhibitors properties with an IC50 ranging from 7.12 ± 2.11 µM-92.34 ± 2.09 µM (4NPO, a reference compound, IC50 = 29.13 ± 0.88 µM). In addition, three out of the six compounds (4a, 4c, 4h) showed strong anti-biofilm formation and CviR inhibitory activity when compared to that of 4NPO. These biological data were also confirmed by computational studies. In this series of compounds, 4h is the most promising compound for future drug development targeting quorum sensing. Our results concluded that the fragment-based drug design is a good approach for the discovery of novel quorum-sensing inhibitors in the future.

The Impact of Fluorination on the Design of Histone Deacetylase Inhibitors.

In recent years, histone deacetylases (HDACs) have emerged as promising targets in the treatment of cancer. The approach is to inhibit HDACs with drugs known as HDAC inhibitors (HDACis). Such HDACis are broadly classified according to their chemical structure, e.g., hydroxamic acids, benzamides, thiols, short-chain fatty acids, and cyclic peptides. Fluorination plays an important role in the medicinal-chemical design of new active representatives. As a result of the introduction of fluorine into the chemical structure, parameters such as potency or selectivity towards isoforms of HDACs can be increased. However, the impact of fluorination cannot always be clearly deduced. Nevertheless, a change in lipophilicity and, hence, solubility, as well as permeability, can influence the potency. The selectivity towards certain HDACs isoforms can be explained by special interactions of fluorinated compounds with the structure of the slightly different enzymes. Another aspect is that for a more detailed investigation of newly synthesized fluorine-containing active compounds, fluorination is often used for the purpose of labeling. Aside from the isotope 19F, which can be detected by nuclear magnetic resonance spectroscopy, the positron emission tomography of 18F plays a major role. However, to our best knowledge, a survey of the general effects of fluorination on HDACis development is lacking in the literature to date. Therefore, the aim of this review is to highlight the introduction of fluorine in the course of chemical synthesis and the impact on biological activity, using selected examples of recently developed fluorinated HDACis.

Comparison of the University Pharmacy Education Programs in Germany and Vietnam.

During the global COVID pandemic, the importance of professionals in the health care sector has been put in a new light, including pharmacists. In this context, the focus is also on how pharmacists are trained in different countries. Through an exchange of pharmacy teaching staff from a German to a Vietnamese university, the pharmacy education programs in both countries were compared. Aspects such as access to studies, structure of studies, and further training opportunities were considered. Differences and similarities emerged. In both countries, students first acquire basic knowledge and then delve deeper into pharmaceutical content in main studies. There is, expectedly, a great overlap in the content of the courses. Overall, the education at Vietnamese universities seems to be more practice-oriented due to a large number of placements. This also allows a specialization, which can be pursued in Germany with self-interest after graduation. There, the preparation for everyday work in the community pharmacy is separated from the university by a mandatory practical year. For the future, efforts are being made in both countries to strengthen the importance of clinical pharmacy in the curriculum. To this end, the Vietnamese are taking their inspiration from abroad in many cases, including Germany.

Increased Expressions of Programmed Death Ligand 1 and Galectin 9 in Transplant Recipients Who Achieved Tolerance After Immunosuppression Withdrawal.

Programmed death 1 (PD1)/its ligand PD-L1 concomitant with T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3)/its ligand galectin 9 (Gal-9) and the forkhead box P3 (FOXP3) might be involved in tolerance after liver transplantation (LT). Liver biopsies from 38 tolerant, 19 nontolerant (including 16 samples that triggered reintroduction of immunosuppression [IS] and 19 samples after IS reintroduction), and 38 control LT patients were studied. The expressions of PD1, PD-L1, Gal-9, and FOXP3 were determined by immunohistochemical and immunofluorescence (IF) staining. The success period of IS withdrawal was calculated using Kaplan-Meier curve analysis. Tolerant and control patients exhibited higher PD-L1, Gal-9, and FOXP3 levels than nontolerant patients at the moment of triggering IS reintroduction. High expressions of PD-L1 and Gal-9 were associated with prolonged success of tolerance (83.3% versus 36.7% [P < 0.01] and 73.1% versus 42.9% [P = 0.03]). A strong correlation between PD-L1 and Gal-9 expression levels was detected (Spearman r = 0.73; P ≤ 0.001), and IF demonstrated colocalization of PD-L1 and Gal-9 in the cytoplasm of hepatocytes. In conclusion, the present study demonstrated that increased expressions of PD-L1 and Gal-9 were associated with sustained tolerance after IS withdrawal in pediatric liver transplantation.

Role of Dual-Energy Computed Tomography in the Identification of Monosodium Urate Deposition in Gout Patients: A Comprehensive Analysis of 828 Joints According to Structural Joint Damage.

Background Dual-energy computed tomography (DECT) has become a promising, non-invasive procedure for the visualization, characterization, and quantification of monosodium urate (MSU) crystals, which aids clinicians in the diagnosis of gout. In this study, we aimed to examine the diagnostic accuracy of DECT in the evaluation of gout. Methodology This cross-sectional retrospective study included patients who were clinically diagnosed with gout and underwent a DECT scan. Results A majority (80.4%) of the MSU deposits were found in the ankle joints. The presence of MSU deposits on DECT scan was highly correlated with bone erosion in the upper limb (odds ratio [OR] = 132; 95% confidence interval [CI] = 17.3-1004.3), bone sclerosis in the lower limb (OR = 36.4; 95% CI = 15.4-86.1), bone erosion in metacarpophalangeal joints (OR = 160; 95% CI = 42.7-600.2), and bone sclerosis in metatarsophalangeal joints (OR = 35.6; 95% CI = 15.5-81.9). Using linear regression analysis on patient-level data, correlations were found between DECT MSU crystal deposition and damage on all categories of structural joint damage showing significant association with erosion (r = 0.91, p < 0.001) and space narrowing (r = 0.75, p < 0.001) but not with joints having periarticular calcification (r = 0.52, p < 0.041). Conclusions Our study established DECT as a valid method for detecting MSU deposits and their association with structural joint deterioration in a Vietnamese population.

Utility of Mac-2 Binding Protein Glycosylation Isomer to Evaluate Graft Status After Liver Transplantation.

Mac-2 binding protein glycosylation isomer (M2BPGi) is a novel liver fibrosis biomarker, but there are few studies on M2BPGi in liver transplantation (LT) recipients. This study aimed to evaluate the utility of M2BPGi measurement in LT recipients. We collected the clinicopathological data of 233 patients who underwent a liver biopsy at Kyoto University Hospital after LT between August 2015 and June 2019. The median values of M2BPGi in patients with METAVIR fibrosis stages F0, F1, F2, and ≥F3 were 0.61, 0.76, 1.16, and 1.47, respectively, whereas those in patients with METAVIR necroinflammatory indexes A0, A1, and ≥A2 were 0.53, 1.145, and 2.24, respectively. Spearman rank correlation test suggested that the necroinflammatory index had a stronger correlation to the M2BPGi value than the fibrosis stage. The area under the receiver operating characteristic curve of M2BPGi to predict ≥A1 was 0.75, which was significantly higher than that of any other liver fibrosis and inflammation marker. Patients with a rejection activity index (RAI) of ≥3 had a higher M2BPGi value than those with RAI ≤ 2 (P = 0.001). Patients with hepatitis C virus viremia had a higher M2BPGi value than sustained virological responders or those with other etiologies. In conclusion, the present study demonstrated that M2BPGi values are more strongly influenced by necroinflammatory activity and revealed M2BPGi, which has been thought to be a so-called fibrosis marker, as a disease activity marker in transplant recipients. M2BPGi measurement may be useful to detect early stage liver inflammation that cannot be detected by routine blood examination of LT recipients.

Long-term impact and clinical significance of living donor liver transplantation with respect to donor liver restoration and spleen size: A prospective study.

This study aimed to evaluate postoperative long-term liver restoration and splenic enlargement and their clinical significance in living donor liver transplantation. One hundred and sixteen donors who had donated livers more than 5 years previously accepted the invitation to participate in this study. The liver restoration rate and the splenic enlargement rate were calculated as the rate with respect to the original volume. The mean liver restoration rate was 0.99 ± 0.12 and older age was associated with a higher incidence for liver restoration rate <0.95 (P = .005), whereas type of donor operation was not. The donors with liver restoration rate <0.95 showed lower serum albumin levels than those with liver restoration rate ≥0.95. The mean splenic enlargement rate was 1.10 ± 0.16. Right lobe donors demonstrated higher splenic enlargement rate (1.14 ± 0.18) than left lobe/lateral segment donors (1.06 ± 0.13). In the donors with splenic enlargement rate ≥1.10, platelet count was not fully restored to the preoperative level. In conclusion, older age increases the risk for incomplete postoperative liver restoration, which may be associated with a decrease in albumin more than 5 years after donation. Right lobe donation poses a risk of splenic enlargement, which is associated with incomplete restoration of platelet count.

Adlay seed extract (Coix lachryma-jobi L.) decreased adipocyte differentiation and increased glucose uptake in 3T3-L1 cells.

The aim of the present study was to investigate effects of the ethyl acetate fraction of an ethanol extract of Coix lachryma-jobi (ECLJ) on glucose uptake and adipocyte differentiation in 3T3-L1 cells. ECLJ phosphorylated AMP-activated protein kinase (AMPK) and its downstream substrate acetyl-coenzymeA carboxylase in 3T3-L1 cells in a time- and dose-dependent manner. Moreover, we discovered that compound C inhibits ECLJ-stimulated ACC phosphorylation. In addition, ECLJ exhibited a dose-dependent stimulation of glucose uptake in 3T3-L1 cells, and this increase was obviously attenuated by compound C. ECLJ also caused a decrease in the expression levels of adipogenesis factors such as fatty acid synthase, sterol-regulatory-element-binding protein-1c, peroxisome proliferator-activated receptor γ, and CAATT/enhancer binding protein α in a dose-dependent manner. Differentiation was examined by Oil red O staining activity after ECLJ treatment for 6 days. ECLJ decreased mean droplet size. These results suggest a possible role for AMPK in the process of adipose differentiation and that ECLJ targeted for adipocyte functions could be effective in improving the symptoms of metabolic syndrome.