A prospective study of zanubrutinib, a Bruton tyrosine kinase inhibitor, in relapsed/refractory idiopathic multicentric Castleman disease.

Relapsed and refractory (R/R) idiopathic multicentric Castleman disease (iMCD) is a clinical challenge with no standard treatment. In this preliminary clinical trial, we investigated the efficacy and safety profiles of a Bruton tyrosine kinase inhibitor (BTKi), zanubrutinib, in patients with R/R iMCD. The primary endpoint was the overall response rate at Week 12 according to the Castleman Disease Collaborative Network (CDCN) response criteria. The trial was terminated early due to a lack of treatment response in the first enrolled 5 patients. Although 3 patients achieved symptomatic response, none of the 5 patients had an overall response by Week 12. One patient had progressive disease and the other 4 had stable disease. The study drug was well tolerated without grade 2 or higher adverse events. Our findings suggest that BTKi therapy is not effective for iMCD, and further attempts at single-agent therapy with zanubrutinib or other BTKis for iMCD should be considered with caution and probably avoided. This trial was registered at www.clinialtrials.gov as #NCT04743687.

Scientific landscape and trend analysis of chronic urticaria: a two-decade bibliometric review.

BACKGROUND: In the past 20 years, an increasing number of studies have advanced our understanding of the pathogenic mechanism of chronic urticaria (CU), providing new treatment options. OBJECTIVES: This bibliometric study aimed to evaluate published reports of CU-related studies from a number of different angles, review the research trends of the studies, and provide future perspectives of CU. MATERIALS & METHODS: Publications related to CU from 2001-2022 were searched in the Web of Science Core Collection. The database file was imported to Excel and analysed using bibliometric software, including VOSviewer and BiblioShiny. RESULTS: A total of 4,452 publications of CU were included. The number of publications related to CU has increased steadily over time. The journal with the most published articles was Allergy, and the countries with the most publications were the United States, Germany, and Italy. The most productive author was Maurer Marcus from Germany. There was close co-authorship between authors and countries (and regions) across the world. Recent studies have focused more on the pathogenesis and treatment of CU. Future hotspots may include emerging biologics for treatment. CONCLUSION: This study shows the research development of CU over the past two decades, which may provide beneficial reference for publication and future trends in CU research.

Bortezomib plus dexamethasone as first-line therapy for patients with POEMS syndrome.

POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome is a rare plasma cell dyscrasia without standard front-line treatment. Merely, few studies have reported the responses and outcomes of bortezomib plus dexamethasone (BDex) in POEMS syndrome. In this study, a total of 69 patients (40 males) treated with front-line BDex were included. The median age at diagnosis was 50 years (range, 30-78 years). After a median of 9 cycles BDex (range 1-9), fifty-two (88.1%), thirty-two (46.4%), and forty-seven (71.2%) patients achieved the best neurologic response, hematological complete response, and serum vascular endothelial growth factor (VEGF) response, respectively. The extravascular overload, pulmonary hypertension, and renal impairment also substantially improved. No treatment-related death occurred. Two patients developed grade-1 bortezomib-induced peripheral neuropathy and were reversible after drug withdrawal. After a median follow-up of 22.5 months, the estimated 2-year overall survival and time to next treatment were 95.7% and 65.6%, respectively. In conclusion, the combination of bortezomib and dexamethasone is effective, with a high response rate and safety profile for patients with newly diagnosed POEMS syndrome.

[Latest Progresses in Surgical Treatment of Median Arcuate Ligament Syndrome].

Median arcuate ligament syndrome(MALS)is compression of the celiac trunk by the median arcuate ligament.Median arcuate ligament release is the corner stone for the surgical treatment of MALS.Open surgery,laparoscopic surgery,and robot-assisted surgery have been developed,among which laparoscopic surgery has been proposed as the preferred approach in view of its minimal trauma and short hospital stay.Auxiliary celiac plexus neurolysis could further alleviate the patient's discomfort.Moreover,vascular reconstitution is of vital importance in the case of persistent stenosis in the celiac artery despite of median arcuate ligament decompression.Vascular reconstruction has satisfactory long-term patency rate,while endovascular treatment is less invasive.This article aims to summarize the consensuses and advances and shed light on the surgical treatment of MALS.

The antityrosinase and antioxidant activities of flavonoids dominated by the number and location of phenolic hydroxyl groups.

BACKGROUND: Compounds with the ability to scavenge reactive oxygen species (ROS) and inhibit tyrosinase may be useful for the treatment and prevention from ROS-related diseases. The number and location of phenolic hydroxyl of the flavonoids will significantly influence the inhibition of tyrosinase activity. Phenolic hydroxyl is indispensable to the antioxidant activity of flavonoids. Isoeugenol, shikonin, baicalein, rosmarinic acid, and dihydromyricetin have respectively one, two, three, four, or five phenolic hydroxyls. The different molecular structures with the similar structure to l-3,4-dihydroxyphenylalanine (l-DOPA) were expected to the different antityrosinase and antioxidant activities. METHODS: This investigation tested the antityrosinase activity, the inhibition constant, and inhibition type of isoeugenol, shikonin, baicalein, rosmarinic acid, and dihydromyricetin. Molecular docking was examined by the Discovery Studio 2.5 (CDOCKER Dock, Dassault Systemes BIOVIA, USA). This experiment also examined the antioxidant effects of the five compounds on supercoiled pBR322 plasmid DNA, lipid peroxidation in rat liver mitochondria in vitro, and DPPH, ABTS, hydroxyl, or superoxide free radical scavenging activity in vitro. RESULTS: The compounds exhibited good antityrosinase activities. Molecular docking results implied that the compounds could interact with the amino acid residues in the active site center of antityrosinase. These compounds also exhibited antioxidant effects on DPPH, ABTS, hydroxyl, or superoxide free radical scavenging activity in vitro, lipid peroxidation in rat liver mitochondria induced by Fe2+/vitamin C system in vitro, and supercoiled pBR322 plasmid DNA. The activity order is isoeugenol < shikonin < baicalein < rosmarinic acid < dihydromyricetin. The results showed the compounds with more phenolic hydroxyls have more antioxidant and antityrosinase activities. CONCLUSION: This was the first study of molecular docking for modeling the antityrosinase activity of compounds. This was also the first study of the protective effects of compounds on supercoiled pBR322 plasmid DNA, the lipid peroxidation inhibition activity in liver mitochondria. These results suggest that the compounds exhibited antityrosinase and antioxidant activities may be useful in skin pigmentation and food additives.

Hepatoprotective effects and antioxidant, antityrosinase activities of phloretin and phloretin isonicotinyl hydrazone.

BACKGROUND: Acute liver damage is primarily induced by one of several causes, among them viral exposure, alcohol consumption, and drug and immune system issues. Agents with the ability to inhibit tyrosinase and protect against DNA damage caused by reactive oxygen species (ROS) may be therapeutically useful for the prevention or treatment of ROS-related diseases. METHODS: This investigation examined the hepatoprotective effects of phloretin and phloretin isonicotinyl hydrazone (PIH) on d-galactosamine (D-GalN)-induced acute liver damage in Kunming mice, as well as the possible mechanisms. The serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyl transferase (γ-GT), alkaline phosphatase (ALP), and total bilirubin (TB) as well as the histopathological changes in mouse liver sections were determined. The antioxidant effects of phloretin, quercetin, and PIH on lipid peroxidation in rat liver mitochondria in vitro, 1,1-diphenyl-2-picrylhydrazyl (DPPH) or 2,2-azino-bis-(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS) free radical scavenging activity in vitro, and supercoiled pBR322 plasmid DNA were confirmed. The experiment also examined the antityrosinase activity, inhibition type, and inhibition constant of phloretin and PIH. RESULTS: Phloretin, quercetin, or PIH significantly prevented the increase in serum ALT, AST, γ-GT, ALP, and TB in acute liver damage induced by D-GalN, and produced a marked reduction in the histopathological hepatic lesions. Phloretin, quercetin, or PIH also exhibited antioxidant effects on lipid peroxidation in rat liver mitochondria in vitro, DPPH or ABTS free radical scavenging activity in vitro, and supercoiled pBR322 plasmid DNA. Phloretin, quercetin, or PIH also exhibited good antityrosinase activity. CONCLUSION: To the best of our knowledge, this was the first study of the hepatoprotective effects of phloretin and PIH on D-GalN-induced acute liver damage in Kunming mice as well as the possible mechanisms. This was also the first study of the lipid peroxidation inhibition activity of phloretin and PIH in liver mitochondria induced by the Fe(2+)/vitamin C (Vc) system in vitro, the protective effects on supercoiled pBR322 plasmid DNA, and the antityrosinase activity of phloretin and PIH.

Synthesis, characterization and biological evaluation of paeonol thiosemicarbazone analogues as mushroom tyrosinase inhibitors.

A series of hydroxy- and methoxy-substituted paeonol thiosemicarbazone analogues were synthesized as potential tyrosinase inhibitors and their inhibitory effects on mushroom tyrosinase and inhibitory mechanism were evaluated. Paeonol thiosemicarbazone analogues have been found exhibiting more remarkable inhibition than their indexcompounds on mushroom tyrosinase. Among them, compound 2,4-dihydroxy acetophenone-4-phenyl-3-thiosemicarbazone (d1) had the most potent inhibition activity with the IC50 value of 0.006 ± 0.001 mM, displayed as a reversible competitive inhibitor. The inhibitory ability of o- or p-substituted acetophenone thiosemicarbazones was: di-substituted acetophenone thiosemicarbazones>mono-substituted acetophenone thiosemicarbazones>non-substituted acetophenone thiosemicarbazones. Copper ions chelation assay explained that compound d1 exhibited competitive inhibition by forming a chelate with the copper ions at the catalytic domain of tyrosinase as well as indicate a 1.5:1 binding ratio of compound d1 with copper ions. In the fluorescence spectrum study, compound d1 behaved stronger fluorescence quenching on tyrosinase towards d1-Cu(2+) complex, inhibiting tyrosinase mainly by means of chelating the two copper ions in the active site. The newly synthesized compounds may serve as structural templates for designing and developing novel tyrosinase inhibitors.

[Study on the interactions of genisten esterified derivatives with bovine serum albumin].

Under the imitated physiological conditions (pH = 7.4), the interactions of two novel genistein esterified derivatives, genistein 7-acetylferulic acid ester and genistein 7, 4'-di-acetylferulic acid ester (1 and 2), with bovine serum albumin (BSA) were investigated by the fluorescence and UV-Vis spectroscopy. It was observed that both of them can effectively quench the intrinsic fluorescence of BSA. The results suggested that the fluorescence quenching process of BSA at low concentrations of the compounds may be mainly governed by static quenching mechanisms. The binding constants (KA) and the number of binding sites (n) at different temperatures were calculated. From the thermodynamic parameters, it can be judged that the binding of 1 to BSA involved electrostatic interactions, whereas the binding of 2 to BSA involved hydrogen bonds and Van der Waals forces. The binding average distances r between BSA (donor) and the compounds (acceptor) were determined to be 2.63 nm and 2.92 nm respectively based on the Forster theory. Besides, the interactions of BSA with the compounds did not change the conformation of BSA and the binding of compounds to BSA is near tryptophan subunit via synchronous fluorescence spectrometry.

[Research on the interactions between genistein and its glucosides with DNA].

The interactions of genistein (GEN), genistein glucoside (GENG) and genistein 7,4'-di-O-beta-D- glucoside(GEND) with calf thymus DNA (ctDNA) in Tris (pH 7.2) buffer were investigated by UV spectra, fluorescence spectra and viscosity. From the absorption titration experiments, no obvious red shifts were found, but the notable hypochromicities were observed. The pi-->pi* transitions of GEN at 262 nm showed a 10% decrease in intensity at [GEN]/[DNA] = 2, and for the GENG and GEND, the decreases were 24.8% and 18% at 260 and 258 nm, respectively. These results indicated that there were intercalations between these compounds and ctDNA, involving a strong pi-stacking interacting. The hypochromism of the two glucosides was bigger than that of GEN, which suggested that the two glucosides intercalated deeply into the DNA base pairs. The emission intensity of DNA-EB system at 600 nm decreased remarkably with increasing the three compounds, indicating that these compounds could intercalate into DNA and replace EB from the DNA-EB system. And at 25 and 37 degrees C, the fluorescence quenching curves of these compounds with DNA-EB system were not linear curves. According to the classical Stern-Volmer equation, it was not single static or dynamic quenching model, so there would be hydrogen bonding besides intercalation. Viscosity experiments were carried out by an Ubbelodhe viscometer at (20.0 +/- 0.1) degrees C. The relative viscosity of ctDNA increased steadily with increasing these compounds. The results clearly showed that these compounds could intercalate between DNA base pairs, causing an extension of the helix, and thus increased the viscosity of DNA. And because of the greatest increase in viscosity of the DNA, the interaction of GENG with DNA was the strongest, followed by GEND, and then GEN. The results were consistent with the above spectral results. These results suggested that genistein and its glucosides could bind to ctDNA partly by intercalation and hydrogen bonding mode, and the binding ability to ctDNA followed the order of GENG > GEND > GEN from which, the authors speculated that 7 or 4'-O-glycosylation modification maybe an effective way to improve medicinal activity of genistein, and its glucoside modified derivatives may be a promising candidate for anticancer drug, which deserves further research.

[Research on the interaction of Cr(III) complex of genistein with DNA].

The interaction of the Cr(III) complex of genistein (GEN-Cr) with calf thymus DNA (ctDNA) in Tris (pH 7.2) buffer was investigated using UV spectra, DNA melting, fluorescence spectra and viscosity. From the absorption titration experiment, no obvious red shift was found, but the notable hypochromicities were observed. When C(DNA)/C(GEN-Cr) = 3, the pi-pi* transitions of the complex at 272 nm showed a decrease in intensity of 29.1%, which indicated that there was remarkable intercalation between complex and DNA base pairs, involving a strong pi-stacking interacting between them. The binding constant for the complex was K = 1.9 x 10(5) mol x L(-1). From the melting curves of ctDNA in the absence and presence of the complex, the melting temperature of ctDNA was found to increase by 5.5 degrees C from 74 to 79.5 degrees C, owing to the increased stability of the helix in the presence of the complex that was intercalated into the double helix. The complex could emit weak luminescence in Tris buffer. The emission intensity of the complex at 340 nm increased steadily with the addition of ctDNA. The result suggested that the complex got into a hydrophobic environment inside the DNA and avoided the effect of solvent water molecules. The strong interaction of the complex and ctDNA also resulted in greatly enhanced intensity of the resonance light scattering spectra. The emission intensity of DNA-EB system at 600 nm decreased remarkably with increasing the complex concentration, which indicated that the complex could be intercalated into DNA and replace EB from the DNA-EB system. According to the classical Stern-Volmer equation, the quenching plots at 25 and 37 degrees C both appeared approximately linear. These results showed that there was one predominant quenching style in this process. Viscosity experiments were carried out by an Ubbelodhe viscometer at 20.0 (+/- 0.1) degrees C. The relative viscosity of ctDNA increased steadily with the increased in the complex. The result clearly showed that the complex could be intercalated between DNA base pairs, causing an extension of the helix, and thus increased the viscosity of DNA. The results above indicated that there is a relatively strong interaction between the GEN-Cr complex and ctDNA, and the complex could bind ctDNA mainly by intercalation. The research suggested that the GEN-Cr complex may be a promising candidate for anticancer, which deserves further research.