Metabolic activation of tyrosine kinase inhibitors: recent advance and further clinical practice.

At present, receptor tyrosine kinase signaling-related pathways have been successfully mediated to inhibit tumor proliferation and promote anti-angiogenesis effects for cancer therapy. Tyrosine kinase inhibitors (TKIs), a group of novel chemotherapeutic agents, have been applied to treat diverse malignant tumors effectively. However, the latent toxic and side effects of TKIs, such as hepatotoxicity and cardiotoxicity, limit their use in clinical practice. Metabolic activation has the potential to lead to toxic effects. Numerous TKIs have been demonstrated to be transformed into chemically reactive/potentially toxic metabolites following cytochrome P450-catalyzed activation, which causes severe adverse reactions, including hepatotoxicity, cardiotoxicity, skin toxicity, immune injury, mitochondria injury, and cytochrome P450 inactivation. However, the precise mechanisms of how these chemically reactive/potentially toxic species induce toxicity remain poorly understood. In addition, we present our viewpoints that regulating the production of reactive metabolites may decrease the toxicity of TKIs. Exploring this topic will improve understanding of metabolic activation and its underlying mechanisms, promoting the rational use of TKIs. This review summarizes the updated evidence concerning the reactive metabolites of TKIs and the associated toxicities. This paper provides novel insight into the safe use of TKIs and the prevention and treatment of multiple TKIs adverse effects in clinical practice.

A strategy combining solid-phase extraction, multiple mass defect filtering and molecular networking for rapid structural classification and annotation of natural products: characterization of chemical diversity in Citrus aurantium as a case study.

Medicinal plants are complex chemical systems containing thousands of secondary metabolites. The rapid classification and characterization of the components in medicinal plants using mass spectrometry (MS) remains an immense challenge. Herein, a novel strategy is presented for MS through the combination of solid-phase extraction (SPE), multiple mass defect filtering (MMDF) and molecular networking (MN). This strategy enables efficient classification and annotation of natural products. When combined with SPE and MMDF, the improved analytical method of MN can perform the rapid annotation of diverse natural products in Citrus aurantium according to the tandem mass spectrometry (MS/MS) fragments. In MN, MS2LDA can be initially applied to recognize substructures of natural products, according to the common fragmentation patterns and neutral losses in multiple MS/MS spectra. MolNetEnhancer was adopted here to obtain chemical classifications provided by ClassyFire. The results suggest that the integrated SPE-MMDF-MN method was capable of rapidly annotating a greater number of natural products from Citrus aurantium than the classical MN strategy alone. Moreover, SPE and MMDF enhanced the effectiveness of MN for annotating, classifying and distinguishing different types of natural products. Our workflow provides the foundation for the automated, high-throughput structural classification and annotation of secondary metabolites with various chemical structures. The developed approach can be widely applied in the analysis of constituents in natural products.

Discovery and validation of quality markers of Fructus Aurantii against acetylcholinesterase using metabolomics and bioactivity assays.

Fructus Aurantii is a traditional medicated diet in East Asia. To determine the underlying chemical markers responsible for the quality and efficacy of Fructus Aurantii, a sensitive metabolomic method was applied to distinguish Fructus Aurantii in Jiangxi Province from other two geographical locations (Hunan Province and Chongqing City) in China. In the present study, multivariate analyses were adopted to compare chemical compositions in 21 batches of Fructus Aurantii samples. Among three geographical origins, 23 differential compounds were structurally identified. Serum pharmacochemistry exhibited that 22 components could be detected in rat serum. Six differential and absorbed components were selected as six potential markers. Statistical analysis revealed that the content of six markers varied widely in three origins of Fructus Aurantii. Six differential and absorbed components were evaluated further by biological activity. Neohesperidin, naringin, and meranzin showed inhibitory effect on acetylcholinesterase that regulates gastrointestinal motility in vitro and in silico, suggesting that these three components may be determined as the active biomarkers of Fructus Aurantii. These findings demonstrate the potential of biomarkers for identification and quality control of Fructus Aurantii.

Three-Dimensional Interpenetrating Frameworks Based on {P4Mo6} Tetrameric Clusters and Filled with In Situ Generated Alkyl Viologens.

Four novel three-dimensional interpenetrating frameworks based on {P4Mo6} units, H[C12H14N2]4[TM4(PO4)(H2O)4Na6][TM2(Mo6O12(HPO4)3(PO4)(OH)3)4]·8H2O (1, 2) and H[C14H18N2]4[TM4(PO4)(H2O)4Na6][TM2(Mo6O12(HPO4)3(PO4)(OH)3)4]·8H2O (3, 4) (TM = Co2+ (1, 3), Mn2+ (2, 4)) were synthesized and characterized using infrared spectroscopy, elemental analyses, thermogravimetric analysis, and single-crystal X-ray diffraction. In situ generated methyl viologen (compounds 1 and 2) or ethyl viologen (compounds 3 and 4) cations function as templates to induce the generation of 2-fold interpenetrating structures in which the {P4Mo6} tetrameric clusters with [TM4(PO4)Na6] (TM = Co2+ (1, 3) and Mn2+ (2, 4)) as the core were bridged by transition metal ions. Compounds 1-4 possess high thermal stabilities and the decomposition temperature of the inorganic frameworks were all >500 °C. It is worth noting that the four compounds all exhibited the bifunctional catalytic performance that they not only had an excellent photocatalytic activity for the reduction of hexavalent chromium (Cr(VI)) under visible light irradiation but also showed a good electrocatalytic activity for the reduction reaction of hydrogen peroxide.

Metabolic profiling of coumarins by the combination of UPLC-MS-based metabolomics and multiple mass defect filter.

Coumarins have aroused high interests due to their diverse bioactivities. Understanding of its metabolism contributes to determine the druggability of coumarin in vivo.A sensitive and efficient strategy based on ultra-performance liquid chromatography-mass spectrometer (UPLC-MS) analysis combined with various data-processing techniques including metabolomics and multiple mass defect filter (MMDF) was established for the comprehensive screening and elucidation of potential coumarin metabolites.Total 20 metabolites of scoparone were identified in this study, including 14 undescribed metabolites. The metabolism of two other similar coumarins scopoletin and esculetin also could be determined using this strategy.By the established strategy, this study gives the insights about the major metabolic pathways of scoparone in vivo and in vitro metabolism, including demethylation, hydroxylation, hydration, cysteine conjugation, glucuronide conjugation and sulfate conjugation. Additionally, the metabolic pathways of scopoletin and esculetin were determined as hydroxylation, glucuronidation and sulfation. These results contribute to the understanding of metabolic characterization of coumarins, and demonstrate that the combination of UPLC-MS-based metabolomics and MMDF is a powerful approach to determine the metabolic pathways of coumarin compounds.

Metabolic Activation of Elemicin Leads to the Inhibition of Stearoyl-CoA Desaturase 1.

Elemicin is a constituent of natural aromatic phenylpropanoids present in many herbs and spices. However, its potential to cause toxicity remains unclear. To examine the potential toxicity and associated mechanism, elemicin was administered to mice for 3 weeks and serum metabolites were examined. Enlarged livers were observed in elemicin-treated mice, which were accompanied by lower ratios of unsaturated- and saturated-lysophosphatidylcholines in plasma, and inhibition of stearoyl-CoA desaturase 1 (Scd1) mRNA expression in liver. Administration of the unsaturated fatty acid oleic acid reduced the toxicity of 1'-hydroxylelemicin, the primary oxidative metabolite of elemicin, while treatment with the SCD1 inhibitor A939572 potentiated its toxicity. Furthermore, the in vitro use of recombinant human CYPs and chemical inhibition of CYPs in human liver microsomes revealed that CYP1A1 and CYP1A2 were the primary CYPs responsible for elemicin bioactivation. Notably, the CYP1A2 inhibitor α-naphthoflavone could attenuate the susceptibility of mice to elemicin-induced hepatomegaly. This study revealed that metabolic activation of elemicin leads to SCD1 inhibition in liver, suggesting that upregulation of SCD1 may serve as potential intervention strategy for elemicin-induced toxicity.

A metabolomic perspective of pazopanib-induced acute hepatotoxicity in mice.

To elucidate the metabolism of pazopanib, a metabolomics approach was performed based on ultra-performance liquid chromatography coupled with electrospray ionization quadrupole mass spectrometry. A total of 22 pazopanib metabolites were identified in vitro and in vivo. Among these metabolites, 17 were novel, including several cysteine adducts and aldehyde derivatives. By screening using recombinant CYPs, CYP3A4 and CYP1A2 were found to be the main forms involved in the pazopanib hydroxylation. Formation of a cysteine conjugate (M3), an aldehyde derivative (M15) and two N-oxide metabolites (M18 and M20) from pazopanib could induce the oxidative stress that may be responsible in part for pazopanib-induced hepatotoxicity. Morphological observation of the liver suggested that pazopanib (300 mg/kg) could cause liver injury. The aspartate transaminase and alanine aminotransferase in serum significantly increased after pazopanib (150, 300 mg/kg) treatment; this liver injury could be partially reversed by the broad-spectrum CYP inhibitor 1-aminobenzotriazole (ABT). Metabolomics analysis revealed that pazopanib could significantly change the levels of L-carnitine, proline and lysophosphatidylcholine 18:1 in liver. Additionally, drug metabolism-related gene expression analysis revealed that hepatic Cyp2d22 and Abcb1a (P-gp) mRNAs were significantly lowered by pazopanib treatment. In conclusion, this study provides a global view of pazopanib metabolism and clues to its influence on hepatic function.

[UPLC-Q-TOF-MS-based metabolomics study of celastrol].

The mass spectrometry-based metabolomics method was used to systematically investigate the formation of celastrol metabolites,and the effect of celastrol on endogenous metabolites. The mice plasma,urine and feces samples were collected after oral administration of celastrol. Ultra-high performance liquid chromatography with quadrupole time-of-flight mass spectrometry( UPLC-QTOF-MS) was applied to analyze the exogenous metabolites of celastrol and its altered endogenous metabolites. Mass defect filtering was adopted to screen for the exogenous metabolites of celastrol. Multivariate statistical analysis was used to identify the endogenous metabolites affected by celastrol. Celastrol and its eight metabolites were detected in urine and feces of mice,and 5 metabolites of them were reported for the first time. The hydroxylated metabolites were observed in the metabolism of both human liver microsomes and mouse liver microsomes. Further recombinant enzyme experiments revealed CYP3 A4 was the major metabolic enzyme involved in the formation of hydroxylated metabolites. Urinary metabolomics revealed that celastrol can affect the excretion of intestinal bacteria-related endogenous metabolites,including hippuric acid,phenylacetylglycine,5-hydroxyindoleacetic acid,urocanic acid,cinnamoylglycine,phenylproplonylglycine and xanthurenic acid. These results are helpful to elucidate the metabolism and disposition of celastrol in vivo,and its mechanism of action.

Two new compounds from the green peel of Juglans mandshurica.

A new cyclic diarylheptanoid (1) and a new flavone glucoside (2), along with seven known compounds, were isolated from the green peel of Juglans mandshurica. Their structures were elucidated based on extensive spectroscopic analyses. Moreover, the cytotoxicity against NCI-H460, A549, and K562 cancer cells of compounds 1-6 was evaluated. The results showed that compound 3 exhibited moderate inhibitory potency against the growth of three cell lines.

[Tissue Intrinsic Fluorescence Spectrum Recovering Based on Diffusion Theory].

Tissue intrinsic fluorescence spectrum refers to the fluorescence that is not impaired by tissue absorption and scattering which has the ability to reflect tissue biochemical properties. In order to reduce the influence of tissue absorption and scattering properties on tissue fluorescence spectrum, and then recover tissue intrinsic fluorescence spectrum, a tissue spectrum detection system based on fiber-optic probe was developed for the measurement of tissue fluorescence spectrum and diffusion reflectance spectrum at the same place. On the other hand, diffusion theory was introduced to extract the tissue physiological parameters from the measurement tissue diffusion reflectance spectrum, which included blood volume fraction, oxyhemoglobin saturation, melanin content, reduce scattering coefficient at 500 nm and the ratio of rayleigh scattering and the total scattering. Then tissue optical parameters in visible wavelengths were calculated. According to the tissue optical parameters and measured tissue diffusion spectrum, the intrinsic fluorescence spectrum was recovered from the measured fluorescence. Based on this, clinical trials were conducted to measure human skin fluorescence spectrum and diffusion reflectance spectrum, and then to recover skin intrinsic fluorescence spectrum. Finally, the accumulation of Advanced Glycation End products (AGE) in human skin was evaluated and the probability of diabetes mellitus was predicted. The result shows that the sensitivity and specificity were 69% and 0.75% respectively, when the measured fluorescent was used to screening diabetes mellitus. At the same specificity, the sensitivity was 90% when the recovered intrinsic fluorescence was employed to screening diabetes mellitus.

Rapid and Noninvasive Detection of Skin Cholesterol with Diffuse Reflectance Spectroscopy Technology.

Due to the urgent need for noninvasive detection of skin cholesterol, a portable, intelligent and real-time skin diffuse reflectance spectroscopy measurement system was designed based on a micro-spectrometer. Digitonin-horseradish peroxidase copolymer solution was prepared. According to the properties digitonin binds to the hydroxy of cholesterol molecular specifically and the horseradish peroxidase reacts with TMB color solution (the main component is 3,3',5,5'-tetramethylbenzidine ) a color change was produced, by which the skin cholesterol was identified and instructed with high sensitivity and high specificity, and the concentration of skin cholesterol was quantified by measuring the degree of color change. In order to validate the feasibility of this method, pig skin which is similar to human skin was taken as the experimental subject, and cholesterol samples of gradient concentration were achieved through the extraction. After that the spectroscopy measurement system was adopted to detect the cholesterol concentration. The experiment result showed that, relative diffuse reflectance can distinguish the cholesterol samples with different concentrations, and the diffuse reflectance intensity factor can quantity the concentrations of cholesterol at characteristic wavelengths (442, 450 and 463 nm) and characteristic wavelength band of 442~500 nm. Linear fitting curves were obtained with the determination coefficient R2 were 0.960, 0.959, 0.958 and 0.958, respectively. The study has shown that, using diffuse reflectance spectroscopy technology can realize noninvasive rapid detection of skin cholesterol, and applying it to the risk assessment of atherosclerotic diseases would contribute to the prevention and control of such diseases significantly.

[Research on noninvasive risk evaluation of diabetes mellitus based on neural network pattern recognition].

Advanced glycation end products (AGEs) are highly associated with hyperglycemia in human skin tissue, and they also have the autofluorescence characteristic. A self-developed optical noninvasive detection device was used to measure the autofluorescence in human skin tissue, and then a neural network pattern recognition model was used to assess the risk of diabetes mellitus of the subject under survey. After the fluorescence spectra were acquired and processed with principal component analysis, four of the leading principal components were chosen to represent a whole spectrum. The established neural network pattern recognition model has 4 input nodes, 6 hidden nodes and 1 output node. A dataset consisting of 487 cases collected in Anhui Provincial Hospital was used to train the model. Seventy percent cases were used as the training set, 15% as the validation set and 15% as the test set. The model can output subject's risk of diabetes mellitus, or a dichotomous judgment. Receiver operating characteristic curve can be drawn with the area under curve of 0. 81, with standard error of 0. 02. When using 0. 5 as the threshold between diabetes mellitus and non-diabetes mellitus, the sensitivity and specificity of this model is 72. 4% and 77. 6% respectively, and the overall accuracy is 74. 9%. The method using human skin autofluorescence spectrum combined with neural network pattern recognition model is proposed for the first time, and the results show that this method has a better screening effect compared with currently used fasting plasma glucose and HbAlc.

Biocontrol and Growth Promotion Potential of Bacillus subtilis CTXW 7-6-2 against Rhizoctonia solani that Causes Tobacco Target Spot Disease.

Fungal diseases form perforated disease spots in tobacco plants, resulting in a decline in tobacco yield and quality. The present study investigated the antagonistic effect of Bacillus subtilis CTXW 7-6-2 against Rhizoctonia solani, its ability to promote the growth of tobacco seedlings, and the expression of disease resistance-related genes for efficient and eco-friendly plant disease control. Our results showed that CTXW 7-6-2 had the most vigorous growth after being cultured for 96 h, and its rate of inhibition of R. solani growth in vitro was 94.02%. The volatile compounds produced by CTXW 7-6-2 inhibited the growth of R. solani significantly (by 96.62%). The fungal growthinhibition rate of the B. subtilis CTXW 7-6-2 broth obtained after high-temperature and no-high-temperature sterile fermentation was low, at 50.88% and 54.63%, respectively. The lipopeptides extracted from the B. subtilis CTXW 7-6-2 fermentation broth showed a 74.88% fungal growth inhibition rate at a concentration of 100 mg/l. Scanning and transmission electron microscopy showed some organelle structural abnormalities, collapse, shrinkage, blurring, and dissolution in the R. solani mycelia. In addition, CTXW 7-6-2 increased tobacco seedling growth and improved leaf and root weight compared to the control. After CTXW 7-6-2 inoculation, tobacco leaves showed the upregulation of the PDF1.2, PPO, and PAL genes, which are closely related to target spot disease resistance. In conclusion, B. subtilis CTXW 7-6-2 may be an efficient biological control agent in tobacco agriculture and enhance plant growth potential.

The ethnopharmacology, phytochemistry and pharmacology of the genus Hericium.

ETHNOPHARMACOLOGICAL RELEVANCE: Mushrooms in the genus Hericium are used as functional food and traditional medicines for a long history in East Asian countries such as China, India, Japan, and Korea. Some species of Hericium are called as monkey head mushroom (Houtougu) in China and Yamabushitake in Japan, which are traditionally considered as rare and precious health promoting food and medicinal materials for the treatment of dyspepsia, insomnia, chronic gastritis, and digestive tract tumors. THE AIM OF THE REVIEW: This review aims to summarize the ethnopharmacology and structural diversity of secondary metabolites from Hericium species, as well as the pharmacological activities of the crude extracts and pure compounds from Hericium species in recent years. MATERIALS AND METHODS: All the information was gathered by searching Scifinder, PubMed, Web of Science, ScienceDirect, Springer, Wiley, ACS, CNKI, Baidu Scholar, Google Scholar databases and other published materials (books and Ph.D. and M. Sc. Dissertations) using the keywords "Hericium", "Traditional uses", "Chemical composition", "Quality control" and "Pharmacological activity" (1971-May 2023). The species name was checked with https://www.mycobank.org/. RESULTS: The traditional uses of Hericium species were summarized, and 230 secondary metabolites from Hericium species were summarized and classified into six classes, mainly focusing on their chemical diversity, biosynthesis, biological activities. The modern pharmacological experiments in vivo or in vitro on their crude and fractionated extracts showed that the chemical components from Hericium species have a broad range of bioactivities, including neuroprotective, antimicrobial, anticancer, α-glucosidase inhibitory, antioxidant, and anti-inflammatory activities. CONCLUSIONS: The secondary metabolites discovered from Hericium species are highly structurally diverse, and they have the potential to be rich resources of bioactive fungal natural products. Moreover, the unveiled bioactivities of their crude extracts and pure compounds are closely related to critical human health concerns, and in-depth studies on the potential lead compounds, mechanism of pharmacological effects and pharmaceutical properties are clearly warranted.

[Effect of downregulation of prostate cancer antigen-1 expression on malignant biological behavior of prostate cancer LNCaP cells].

OBJECTIVE: To detect the expression of prostate cancer antigen-1 (PCA-1) in prostate cancer, and to analyze the effects of downregulation of PCA-1 expression on malignant biological behavior of prostate cancer LNCaP cells, and to explore their possible molecular mechanisms. METHODS: PCA-1-siRNA and control siRNA were transfected into LNCaP cells with lipofectamine 2000. The cell cycle, proliferation and migration were determined by methyl thiazolyl tetrazolium (MTT) assay, flow cytometry and Transwell chambers, respectively. Western blotting was used to detect the expression of cyclin E, matrix metallopeptidase 9 (MMP-9) and p21. Immunohistochemistry was used to detect the expression of PCA-1 protein in 126 cases of prostate cancer and 88 cases of benign prostatic hyperplasia (BPH). RESULTS: The positive rate of PCA-1 expression was 77.8% (98/126) in prostate cancer, and 10.2% (9/88) in BPH, and its expression was not significantly related to age, prostate specific antigen (PSA), Eastern Cooperative Oncology Group (ECOG) score (P > 0.05), and was associated with Gleason score, TNM staging and bone metastasis (P < 0.05). Downregulation of PCA-1 expression inhibited cell proliferation, arrested cell cycle at S phase and decreased cell migration of LNCaP cells. The downregulation of PCA-1 expression decreased the expression of Bcl-xl, cyclin E and MMP-9 proteins, but increased the expression of p21 proteins. CONCLUSIONS: PCA-1 may play an important role in the development of prostate cancer. The downregulation of PCA-1 expression can lead to changes in the proliferation, cell cycle and migration of prostate cancer LNCaP cells, and these effects may be associated with the decrease of Bcl-xl, cyclin E and MMP-9 proteins and increase of p21 protein.

[Remediation of Soil Cadmium Contamination by Solanum nigrum L. Enhanced by the Combination of Exogenous Bacteria and Citric Acid].

To determine how to strengthen the Cd-enriched plant Solanum nigrum L. to remediate cadmium(Cd)-contaminated soil, a pot experiment was conducted with five treatments:control treatment(CK), Glomus mosseae(GM), G. mosseae+citric acid(GM+CA), G. mosseae+Bacillus megaterium(GM+BM), and G. mosseae+B. megaterium+citric acid(GM+BM+CA). We measured soil total Cd, available Cd, plant Cd uptake, and microbial community changes and analyzed the effects of exogenous microbial agents and citric acid addition on the remediation effect of Cd contamination by S. nigrum L. The results showed that relative to that of the CK treatment, the root, stem, and leaf biomass of the GM treatment significantly increased by 35.67%, 41.35%, and 65.38%, and the root and stem biomass of the GM+BM+CA treatment significantly increased by 73.38% and 75.38%. The GM+BM+CA treatment significantly increased Cd accumulation in leaves by 226.84%. The GM+BM+CA treatment significantly increased the Cd transport factor from stem to leaves by 52.47%. The GM+BM+CA treatment significantly increased the leaf bioconcentration factor by 120.53%. In addition, the combined restoration also had an impact on the rhizosphere microbial community structure, especially in inducing the relative abundance of some key microbial groups such as Proteobacteria, Actinobacteria, Glomeromycota, and Olpidiomycota to increase by 2.00%-5.77%, 0.76%-9.96%, 2.11%-3.63%, and 0.54%-2.98%, respectively. According to the RDA analysis, Proteobacteria and Actinobacteria were negatively correlated with soil total Cd, whereas Glomeromycota and Olpidiomycota were negatively correlated with soil total Cd. The changes in key microorganisms enhanced the ability of S. nigrum L. to absorb rhizosphere nutrients and resist Cd stress, increased the Cd accumulation ability of S. nigrum L., and effectively reduced the total Cd content in soil. In conclusion, G. mosseae, citric acid, and B. megaterium activated insoluble Cd in the soil by co-inoculation, which contributed to more Cd accumulation by S. nigrum L. and also produced co-remediation with G. mosseae. The enrichment plant-microorganism combined remediation Cd-contaminated soil has good application potential.

Pneumocystis jirovecii pneumonia associated with immune checkpoint inhibitors: A systematic literature review of published case reports and disproportionality analysis based on the FAERS database.

Background: Pneumocystis jirovecii pneumonia (PJP) has been reported with ICIs but limited to case reports. The clinical features of PJP with ICIs remain mostly unknown. This study aims to investigate the association of PJP with ICIs and describe clinical features. Methods: Reports of PJP recorded in FAERS (January 2004-December 2022) were identified through the preferred term "Pneumocystis jirovecii pneumonia". Demographic and clinical features were described, and disproportionality signals were assessed through the Reporting Odds Ratio (ROR) and Information Component (IC), using traditional chemotherapy and targeted therapy as comparators, and adjusting signals by excluding contaminant immunosuppressive drugs and pre-existing diseases. A systematic literature review was conducted to describe clinical features of published PJP reports with ICIs. Bradford Hill criteria was adopted for global assessment of the evidence. Results: We identified 677 reports of PJP associated with ICIs, in which 300 (44.3%) PJP cases with fatal outcome. Nivolumab (IC025 2.05), pembrolizumab (IC025 1.88), ipilimumab (IC025 1.43), atezolizumab (IC025 0.36), durvalumab (IC025 1.65), nivolumab plus ipilimumab (IC025 1.59) have significant signals compared to other drugs in FAERS database. After excluding pre-existing diseases and immunosuppressive agents which may increase susceptibility of PJP, the signals for PJP associated with nivolumab, pembrolizumab, durvalumab, nivolumab plus ipilimumab remained robust (IC025 > 0). When compared to other anticancer regimens, although all ICIs showed a lower disproportionate signal for PJP than chemotherapy, nivolumab (IC025 0.33, p < 0.001), pembrolizumab (IC025 0.16, p < 0.001), both PD-1 inhibitors, presented a higher signal for PJP than targeted therapy. Male gender (IC025 0.26, p < 0.001) and age >65 years (IC025 0.38, p < 0.001) were predominant in PJP cases associated with across all ICIs. In literature, 15 PJP cases associated with ICIs were reported in 10 published case reports. 12 of 15 (80.0%) of cases received PD-1 inhibitors before PJP was diagnosed. Conclusion: By the combined analysis of post-marketing data from FAERS and published case reports, we identified ICIs may be associated with PJP, especially in males aged >65years. After accounting for confounders, PD-1 inhibitors emerged with a robust disproportionality signal when compared to PD-L1/CTLA-4 inhibitors as well as targeted therapy. Further research is warranted to validate our findings.

Do antibody-drug conjugates increase the risk of sepsis in cancer patients? A pharmacovigilance study.

Introduction: Antibody-drug conjugates (ADCs) produce unparalleled efficacy in refractory neoplasms but can also lead to serious toxicities. Although ADC-related sepsis has been reported, the clinical features are not well characterized in real-world studies. Objective: The aim of this study was to identify the association between ADCs and sepsis using FAERS data and uncover the clinical characteristics of ADC-related sepsis. Methods: We performed disproportionality analysis using FAERS data and compared rates of sepsis in cancer patients receiving ADCs vs. other regimens. Associations between ADCs and sepsis were assessed using reporting odds ratios (RORs) and information component (IC). For each treatment group, we detected drug interaction signals, and conducted subgroup analyses (age, gender, and regimens) and sensitivity analyses. Results: A total of 24,618 cases were reported with ADCs between Q1, 2004 and Q3, 2021. Sepsis, septic shock, multiple organ dysfunction syndrome, and other sepsis-related toxicities were significantly associated with ADCs than other drugs in this database. Sepsis and multiple organ dysfunction syndrome have the highest safety concerns with ADCs compared with other anticancer monotherapies. Gemtuzumab ozogamicin and inotuzumab ozogamicin showed increased safety risks than other ADCs. For the top nine ADC-related sepsis, males showed higher sepsis safety concern than females (p <0.001); however, age did not exert influence on the risk of sepsis. We identified that 973 of 2,441 (39.9%) cases had acute myeloid leukemia (AML), and 766 of 2613 (29.3%) cases on ADCs died during therapy. Time-to-onset analysis indicated ADC-related sepsis is prone to occur within a month after administration. Co-administration of ADCs with colony-stimulating factors, proton pump inhibitors, H2-receptor antagonists, or CYP3A4/5 inhibitors showed to synergistically increase the risk of sepsis-related toxicities. Conclusion: Antibody-drug conjugates may increase the risk of sepsis in cancer patients, leading to high mortality. Further studies are warranted to characterize the underlying mechanisms and design preventive measures for ADC-related sepsis.

Metabolic Activation of the Toxic Natural Products From Herbal and Dietary Supplements Leading to Toxicities.

Currently, herbal and dietary supplements have been widely applied to prevent and treat various diseases. However, the potential toxicities and adverse reactions of herbal and dietary supplements have been increasingly reported, and have gradually attracted widespread attention from clinical pharmacists and physicians. Metabolic activation of specific natural products from herbal and dietary supplements is mediated by hepatic cytochrome P450 or intestinal bacteria, and generates chemical reactive/toxic metabolites that bind to cellular reduced glutathione or macromolecules, and form reactive metabolites-glutathione/protein/DNA adducts, and these protein/DNA adducts can result in toxicities. The present review focuses on the relation between metabolic activation and toxicities of natural products, and provides updated, comprehensive and critical comment on the toxic mechanisms of reactive metabolites. The key inductive role of metabolic activation in toxicity is highlighted, and frequently toxic functional groups of toxic natural products were summarized. The biotransformation of drug cytochrome P450 or intestinal bacteria involved in metabolic activation were clarified, the reactive metabolites-protein adducts were selected as biomarkers for predicting toxicity. And finally, further perspectives between metabolic activation and toxicities of natural products from herbal and dietary supplements are discussed, to provide a reference for the reasonable and safe usage of herbal and dietary supplements.

Discovery of quality markers in Rubus Chingii Hu using UPLC-ESI-QTOF-MS.

Raspberry, the fruit of Rubus Chingii Hu, has been used as a traditional Chinese medicine (TCM) to nourish kidney and strengthen Yang-qi. In order to determine the quality of raspberry, the quality markers (Q-markers) of raspberry that can improve renal function were investigated using UPLC-ESI-QTOF-MS in this study. The results of serum pharmacochemistry indicated that six components rutin, ellagic acid, kaempferol-3-rutinoside, astragalin, tiliroside, and goshonoside F5 in raspberry were absorbed into rat blood. The HEK293 cells treated with cisplatin were used to evaluate the kidney-protecting activity of these absorbed components. All these components could markedly inhibit cell damage induced by cisplatin and restore the levels of malondialdehyde (MDA) and catalase (CAT) in the cells, suggesting that these components may be the Q-markers of raspberry. More importantly, except for ellagic acid, other five Q-markers in raspberries from Dexing of Jiangxi province were higher than those from most of other areas. It is well known that Dexing raspberry is the Dao-di herbs raspberry used in the clinic of Chinese Medicine, demonstrating that these components could be used as Q-markers of raspberry. This study provides a reliable and valuable method for quality evaluation of raspberry.