Chemoproteomic strategy identifies PfUCHL3 as the target of halofuginone.

The human malaria parasite Plasmodium falciparum (P. falciparum) continues to pose a significant public health challenge, leading to millions of fatalities globally. Halofuginone (HF) has shown a significant anti-P. falciparum effect, suggesting its potential as a therapeutic agent for malaria treatment. In this study, we synthesized a photoaffinity labeling probe of HF to identify its direct target in P. falciparum. Our results reveal that ubiquitin carboxyl-terminal hydrolase 3 (PfUCHL3) acts as a crucial target protein of HF, which modulates parasite growth in the intraerythrocytic cycle. In particular, we discovered that HF potentially forms hydrogen bonds with the Leu10, Glu11, and Arg217 sites of PfUCHL3, thereby inducing an allosteric effect by promoting the embedding of the helix 6' region on the protein surface. Furthermore, HF disrupts the expression of multiple functional proteins mediated by PfUCHL3, specifically those that play crucial roles in amino acid biosynthesis and metabolism in P. falciparum. Taken together, this study highlights PfUCHL3 as a previously undisclosed druggable target of HF, which contributes to the development of novel anti-malarial agents in the future.

Metabolomic profiles of breath odor compounds for prognostic prediction in patients with acute-on-chronic liver failure: A pilot study.

AIM: The aim of this study was to use a metabonomics approach to identify potential biomarkers of exhaled breath condensate (EBC) for predicting the prognosis of acute-on-chronic liver failure (ACLF). METHODS: Using liquid chromatography mass spectrometry, EBC metabolites of ACLF patients surviving without liver transplantation (n = 57) and those with worse outcomes (n = 45), and controls (n = 15) were profiled from a specialized liver disease center in Beijing. The metabolites were used to identify candidate biomarkers, and the predicted performance of potential biomarkers was tested. RESULTS: Forty-one metabolites, involving glycerophospholipid metabolism, sphingolipid metabolism, arachidonic acid metabolism, and amino acid metabolism, as candidate biomarkers for discriminating the different outcomes of ACLF were selected. A prognostic model was constructed by a panel of four metabolites including phosphatidylinositol [20:4(5Z,8Z,11Z,14Z)/13:0], phosphatidyl ethanolamine (12:0/22:0), L-metanephrine and ethylbenzene, which could predict the worse prognosis in ACLF patients with sensitivity (84.4%) and specificity (89.5%) (area under the receiver operating characteristic curve [AUC] = 0.859, 95% confidence interval [CI] = 0.787-0.931). Compared with Model for End-Stage Liver Disease (MELD) score (AUC = 0.639, 95% CI = 0.526-0.753) and MELD-sodium (MELD-Na) score (AUC = 0.692, 95% CI = 0.582-0.803), EBC-associated metabolite signature model could better predict worse outcomes in patients with ACLF (p < 0.05). Using the MELD-Na score and EBC metabolite signatures, a decision tree model was built for predicting the prognosis of ACLF identified on logistic regression analyses (AUC = 0.906, 95% CI = 0.846-0.965). CONCLUSION: EBC metabolic signatures show promise as potential biomarkers for predicting worse prognosis of ACLF.

Salivary metabolites are promising noninvasive biomarkers of drug-induced liver injury.

BACKGROUND: Drug-induced liver injury (DILI) is one of the most common adverse events of medication use, and its incidence is increasing. However, early detection of DILI is a crucial challenge due to a lack of biomarkers and noninvasive tests. AIM: To identify salivary metabolic biomarkers of DILI for the future development of noninvasive diagnostic tools. METHODS: Saliva samples from 31 DILI patients and 35 healthy controls (HCs) were subjected to untargeted metabolomics using ultrahigh-pressure liquid chromatography coupled with tandem mass spectrometry. Subsequent analyses, including partial least squares-discriminant analysis modeling, t tests and weighted metabolite coexpression network analysis (WMCNA), were conducted to identify key differentially expressed metabolites (DEMs) and metabolite sets. Furthermore, we utilized least absolute shrinkage and selection operato and random fores analyses for biomarker prediction. The use of each metabolite and metabolite set to detect DILI was evaluated with area under the receiver operating characteristic curves. RESULTS: We found 247 differentially expressed salivary metabolites between the DILI group and the HC group. Using WMCNA, we identified a set of 8 DEMs closely related to liver injury for further prediction testing. Interestingly, the distinct separation of DILI patients and HCs was achieved with five metabolites, namely, 12-hydroxydodecanoic acid, 3-hydroxydecanoic acid, tetradecanedioic acid, hypoxanthine, and inosine (area under the curve: 0.733-1). CONCLUSION: Salivary metabolomics revealed previously unreported metabolic alterations and diagnostic biomarkers in the saliva of DILI patients. Our study may provide a potentially feasible and noninvasive diagnostic method for DILI, but further validation is needed.

Precise delivery of multi-stimulus-responsive nanocarriers based on interchangeable visual guidance.

Cancer treatment is imminent, and controlled drug carriers are an important development direction for future clinical chemotherapy. Visual guidance is a feasible means to achieve precise treatment, reduce toxicity and increase drug efficacy. However, the existing visual control methods are limited by imaging time-consuming, sensitivity and side effects. In addition, the ability of the carrier to respond to environmental stimuli in vivo is another difficulty that limits its application. Here, we propose a highly stimulus-responsive GC liposome with precise tracing and sensitive feedback capabilities. It combines magnetic resonance imaging and fluorescence imaging, and addresses the need for precise visualization by alternating imaging modalities. More importantly, GC liposomes are a carrier that can accumulate stimuli. In this paper, by tracking the fragmentation process of empty GC and drug-loaded D-GC liposomes, we confirm the synergistic effect between multiple stimuli, which can result in a more efficient drug release performance. Finally, in mice models we examined the GC liposome imaging approach and the D-GC + UV group guided by this visualization exhibited the highest tumor inhibition efficiency (6.85-fold). This study highlights the advantages of alternate visualization-guided and co-stimulation treatment strategies, and provides design ideas and potential materials for efficient and less toxic cancer treatments.

Chemical fingerprinting techniques for the differentiation of polysaccharides from genus Astragalus.

A generic strategy based on chemical fingerprinting is proposed for the differentiation of polysaccharides from Astragalus membranaceus (AEP) and A. mongholicus (AOP), using multiple chromatographic and mass spectrometric techniques. Complete and mild acid hydrolysis and Smith degradation were employed for the depolymerization of polysaccharides. The corresponding digested products were efficiently separated and detected using GC-MS, HILIC-ELSD and HR-ESI--MS. The resulting bottom-up fingerprinting reflected the variations in native polysaccharides, which may be attributed to the three structural levels, which are monosaccharide compositions, glycosidic linkages, and skeletal structure. Similarity analysis from GC-MS and HILIC-ELSD fingerprinting showed that the correlation coefficients from homologous species were more than 0.914, whereas those from heterologous species were less than 0.796. It also noted that characteristic peak area ratio of Man/Gal in Smith fingerprinting could be used a feasible parameter for direct discrimination of AEP and AOP. Principal component analysis from m/z fingerprinting data resulted in clear clustering of AEP and AOP based on changes of oligosaccharides in mild acid hydrolyzates. By combining the accurate m/z, ESI--MS/MS and methylation assays, the structures of a series of hexose glycopolymers in mild acid hydrolyzates were characterized by predominant 1,6 glycosidic linkages along with minor 1,4 glycosidic linkages. The established chemical fingerprinting is not only an interconnected structure mapping but also a powerful approach for the evaluation of polysaccharides from traditional Chinese medicines.

Exploring an Integrative Therapy for Treating COVID-19: A Randomized Controlled Trial.

OBJECTIVES: To develop a new Chinese medicine (CM)-based drug and to evaluate its safety and effect for suppressing acute respiratory distress syndrome (ARDS) in COVID-19 patients. METHODS: A putative ARDS-suppressing drug Keguan-1 was first developed and then evaluated by a randomized, controlled two-arm trial. The two arms of the trial consist of a control therapy (alpha interferon inhalation, 50 µg twice daily; and lopinavir/ritonavir, 400 and 100 mg twice daily, respectively) and a testing therapy (control therapy plus Keguan-1 19.4 g twice daily) by random number table at 1:1 ratio with 24 cases each group. After 2-week treatment, adverse events, time to fever resolution, ARDS development, and lung injury on newly diagnosed COVID-19 patients were assessed. RESULTS: An analysis of the data from the first 30 participants showed that the control arm and the testing arm did not exhibit any significant differences in terms of adverse events. Based on this result, the study was expanded to include a total of 48 participants (24 cases each arm). The results show that compared with the control arm, the testing arm exhibited a significant improvement in time to fever resolution (P=0.035), and a significant reduction in the development of ARDS (P=0.048). CONCLUSIONS: Keguan-1-based integrative therapy was safe and superior to the standard therapy in suppressing the development of ARDS in COVID-19 patients. (Trial registration No. NCT04251871 at www.clinicaltrials.gov ).

Structural characteristics and hepatoprotective potential of Aralia elata root bark polysaccharides and their effects on SCFAs produced by intestinal flora metabolism.

The structural characteristics of the polysaccharides from Aralia elata root barks (AERP) were systematically investigated by FT-IR, HPSEC-ELSD and colorimetric methods as well as by GCMS based monosaccharide compositions, Smith degradations, and methylation analysis. The result showed average molecular weights of AERP were between 42.7 kDa and 93.9 kDa. AERP was composed of Ara, Rha, GlcA, Man, Glc, and Gal in a molar ratio of 22.2: 10.3: 8.1: 32.7: 5.7: 21.2 along with a small number of sulfate (3.38%) and acetyl (4.87%) groups. The abundant glycosidic linkages of Man, Ara, Gal, and Rha were observed as more than 90% of all the monosaccharides detected. Studies to evaluate hepatoprotective potentials of AERP showed that they had potent hepatoprotective effects in vivo in carbon tetrachloride-induced acute liver injury (CIALI) in mice by histopathological evaluation, biochemical examinations and ELISA assays. GCMS was further used to determine the effects of AERP on the chemical profiles of nine common short-chain fatty acids (SCFAs) produced by intestinal flora metabolism in CIALI mice. These findings not only provide novel insights into the pharmacological actions of AERP on the protection from CIALI in mice, but they also demonstrate that determining SCFA profiles by targeted GC-MS metabolomics is an effective technique to investigate the molecular mechanisms of the effects of plant polysaccharides on intestinal flora metabolism.

Predictors of poor outcomes in 488 patients with herb-induced liver injury.

BACKGROUND/AIMS: Herb-induced liver injury (HILI) can lead to chronic liver injury, liver transplantation, or even death. This study aimed to identify the predictors of poor HILI outcomes, especially chronic HILI. MATERIALS AND METHODS: Clinical data of 488 patients with HILI were retrospectively analyzed from a Chinese center between January 2010 and January 2014. Logistic regression and C-statistic were used to identify risk factors and prognostic models for HILI outcomes. RESULTS: In all patients, 69 (14.1%) developed chronic HILI, and 20 (4.1%) died due to liver injury or underwent liver transplantation. To predict the fatal HILI prognosis, the model for end-stage liver disease (MELD) with a C-statistic of 0.981 (95%CI 0.968-0.995) was better than Hy's law (C-statistic 0.569; 95%CI 0.449-0.689). The latency, course of peak alanine aminotransferase decreasing >50% after discontinuation of herb application, peak triglyceride value, and platelet count at liver injury onset were identified as independent risk factors for chronicity with the adjusted odds ratios of 1.268 (95% confidence interval [CI] 1.034-1.554), 2.303 (95%CI 1.588-3.340), 0.580 (95%CI 0.343-0.978), and 0.183 (95%CI 0.091-0.368), respectively. A prognostic model for chronic HILI based on these four factors yielded the best prediction with a C-statistic of 0.812 (95%CI 0.755-0.868), compared with MELD (C-statistic 0.506; 95%CI 0.431-0.581) and Hy's law (C-statistic 0.418; 95%CI 0.343-0.492). CONCLUSION: Model for end-stage liver disease can be used to predict the fatal prognosis of HILI. A long latency, slow recovery, and low triglyceride value and platelet counts are important determinants for chronic HILI.

Association between the concurrence of pre-existing chronic liver disease and worse prognosis in patients with an herb- Polygonum multiflorum thunb. induced liver injury: a case-control study from a specialised liver disease center in China.

OBJECTIVES: The present study aimed to evaluate the association between the concurrence of pre-existing chronic liver diseases (CLD) and worse prognosis in patients with HILI. DESIGN: A case-control study. SETTING: Tertiary hospital specialising in liver diseases in China. PARTICIPANTS: 145 hospitalised HILI patients were assessed with respect to prognosis by comparing HILI with or without pre-existing CLD from February 2007 to January 2017. Twenty-five HILI cases with pre-existing alcoholic liver disease (ALD) or non-alcoholic fatty liver disease (NAFLD) and 200 ALD or NAFLD controls matched 1:8 for sex, age (±4 years old), body mass index (±2 kg/m2), the type of CLD, alcohol intake (±5 g/d) and the presence or absence of cirrhosis. PRIMARY OUTCOME MEASURES: Mortality and chronicity in HILI patients with or without pre-existing CLD, and matched CLD patients. RESULTS: Of the 193 714 hospitalised patients with liver diseases, 5703 patients met the diagnostic criteria for drug-induced liver injury (DILI), which was attributed to Polygonum multiflorum Thunb. (PMT) in 145 patients. Among these HILI patients, 22.8% (33 of 145) had pre-existing CLD, including 17 (51.5%) with ALD, 8 (24.2%) with NAFLD, 5 (15.2%) with chronic viral hepatitis and 3 (9.1%) with autoimmune liver disease. Compared with HILI patients without CLD, HILI patients with pre-existing CLD showed higher mortality (0.9% vs 9.1%, p=0.037) and higher chronicity (12.5% vs 30.3%, p=0.016). Compared with matched ALD (136 patients) or NAFLD (64 patients) patients, HILI patients with pre-existing ALD showed higher chronicity (35.3% vs 11.8%, p=0.019). Multivariate logistic regression analysis found that concurrence of pre-existing CLD was an independent risk factor for both of chronicity and mortality (OR 3.966, 95% CI 1.501 to 10.477, p=0.005), especially the chronicity (OR 3.035, 95% CI 1.115 to 8.259, p=0.030). CONCLUSIONS: Concurrence of pre-existing CLD could be an independent risk factor for worse prognosis, especially chronicity, in PMT-related HILI.