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A hyperactive immune response can be observed in patients with bacterial or viral infection, which may lead to the overproduction of proinflammatory cytokines, or “cytokine storm”, and a poor clinical outcome. Extensive research efforts have been devoted to the discovery of effective immune modulators, yet the therapeutic options are still very limited. Here, we focused on the clinically indicated anti-inflammatory natural product Calculus bovis and its related patent drug Babaodan to investigate the major active molecules in the medicinal mixture. Combined with high-resolution mass spectrometry, transgenic zebrafish-based phenotypic screening, and mouse macrophage models, taurochiolic acid (TCA) and glycoholic acid (GCA) were identified as two naturally derived anti-inflammatory agents with high efficacy and safety. Both bile acids significantly inhibited the lipopolysaccharide-induced macrophage recruitment and the secretion of proinflammatory cytokines/chemokines in in vivo and in vitro models. Further studies identified strongly increased expression of the farnesoid X receptor at both the mRNA and protein levels upon the administration of TCA or GCA, which may be essential for mediating the anti-inflammatory effects of the two bile acids. In conclusion, we identified TCA and GCA as two major anti-inflammatory compounds in Calculus bovis and Babaodan, which could be important quality markers for the future development of Calculus bovis, as well as promising lead compounds in the treatment of overactive immune responses.

The dung beetle primarily feeds on the feces of herbivorous animals and play a crucial role in ecological processes like material cycles and soil improvement. This study aims to explore the diversity and composition of the gut microbiota of Catharsius molossus (a renowned dung beetle originating from China and introduced to multiple countries for its ecological value) and exploring whether these gut microbes are transmitted vertically across generations. Using 16S rRNA and ITS rRNA gene sequencing techniques, we described the diversity and composition of gut microbes in C . molossus from different localities and different developmental stages (Egg, young larvae and old larvae). We discovered that the diversity of gut microbiota of dung beetles varied obviously among different geographical localities and different developmental stages, and we also discussed the potential influencing factors. Interestingly, the microbial community structure within the brood balls is more similar to male dung beetle than to that of females, which is consistent with the observation that the brood ball is constructed by the male dung beetle, with the female laying egg in it at the final step. This unique breeding method facilitates offspring in inheriting microbial communities from both the mother and the father. Initially, the larvae’s gut microbiota closely mirrors that of the parental gift in these brood balls. As larvae grow, significant changes occur in their gut microbiota, including an increase in symbiotic bacteria like Lactococcus and Enterococcus . Analysis of the gut bacteria of adult dung beetles across various localities and different developmental stages identified nine core genera in adults, contributing to 67.80% of the total microbial abundance, and 11 core genera in beetles at different developmental stages, accounting for 49.13% of the total. Notably, seven genera were common between these two core groups. Our results suggest that Parental gifts can play a role in the vertical transmission of microbes, and the abundance of probiotics increases with larval development, supporting the hypothesis that \"larval feeding behavior occurs in two stages: larvae first feed on parental gifts to acquire necessary microbes, then enrich symbiotic microbiota through consuming their own feces.\"

The cytochrome P450 enzyme 3A4 (CYP3A4) mediates numerous drug-drug interactions (DDIs) by inducing the metabolism of co-administered drugs, which can result in reduced therapeutic efficacy or increased toxicity. This study developed and validated a Physiologically Based Pharmacokinetic (PBPK) model to predict CYP3A4 induction-mediated DDIs, focusing on the early stages of clinical drug development. The PBPK model for rifampicin, a potent CYP3A4 inducer, was developed and validated using human pharmacokinetic data. Subsequently, PBPK models for 'victim' drugs were constructed and validated. The PBPK-DDI model's predictive performance was assessed by comparing predicted area under the curve (AUC) and maximum concentration (C ) ratioswith empirical data, using both the 0.5 to 2-fold criterion and theGuest criteria. The rifampicin PBPK model accurately simulated human pharmacokinetic profiles. The PBPK-DDI model demonstrated high predictive accuracy for AUC ratios, with 89% of predictions within the 0.5 to 2-fold criterion and 79% meeting the Guest criteria. For Cmax ratios, an impressive 93% of predictions were within the acceptable range. The model significantly outperformed the static model, particularly in estimating DDI risks associated with CYP3A4 induction. The PBPK-DDI model is a reliable tool for predicting CYP3A4 induction-mediated DDIs. Its high predictive accuracy, confirmed by adherence to evaluation standards, affirms its reliability for drug development and clinical pharmacology. Future refinements may further enhance its predictive value.

Aim: The 20(S)-ginsenoside Rh2 (Rh2) is being developed as a new antitumor drug. However, to date, little is known about the kinetics of its deglycosylation metabolite (protopanoxadiol) (PPD) following Rh2 administration. The aim of this work was to 1) simultaneously characterise the pharmacokinetics of Rh2 and PPD following intravenous and oral Rh2 administration, 2) develop and validate a mechanism-based pharmacokinetic model to describe the deglycosylation kinetics and 3) predict the percentage of Rh2 entering the systemic circulation in PPD form. Methods: Plasma samples were collected from rats after the I.V. or P.O. administration of Rh2. The plasma Rh2 and PPD concentrations were determined using HPLC-MS. The transformation from Rh2 to PPD, its absorption, and elimination were integrated into the mechanism based pharmacokinetic model to describe the pharmacokinetics of Rh2 and PPD simultaneously at 10 mg/kg. The concentration data collected following a 20 mg/kg dose of Rh2 was used for model validation. Results: Following Rh2 administration, PPD exhibited high exposure and atypical double peaks. The model described the abnormal kinetics well and was further validated using external data. A total of 11% of the administered Rh2 was predicted to be transformed into PPD and enter the systemic circulation after I.V. administration, and a total of 20% of Rh2 was predicted to be absorbed into the systemic circulation in PPD form after P.O. administration of Rh2. Conclusion: The developed model provides a useful tool to quantitatively study the deglycosylation kinetics of Rh2 and thus, provides a valuable resource for future pharmacokinetic studies of glycosides with similar deglycosylation metabolism.

Enhanced P53 signaling may lead to hematopoietic disorders, yet an effective therapeutic strategy is still lacking. Our study, along with previous research, suggests that P53 overactivation and hematopoietic defects are major consequences of zinc deficiency. However, the relationship between these two pathological processes remains unclear. In this study, we observed a severe reduction in the number of hematopoietic stem cells (HSCs) and multi‐lineage progenitor cells in zebrafish treated with the zinc chelator N , N , N ′, N ′‐tetrakis(2‐pyridylmethyl)ethylenediamine and showed the indispensable role of P53 signaling in the process. Next, we took advantage of HSCs‐labeled transgenic zebrafish and conducted a highly efficient phenotypic screening for small molecules against P53‐dependent hematopoietic disorders. Hydroxysafflor yellow A (HSYA), a natural chalcone glycoside, exhibited potent protection against hematopoietic failure in zinc‐deficient zebrafish and strongly inhibited the P53 pathway. We confirmed the protective effect of HSYA in zinc‐deficient mice bone marrow nucleated cells, which showed a significant suppression of P53 signaling and oxidative stress. Furthermore, the hematopoietic‐protective activity of HSYA was validated using a mice model of myelotoxicity induced by 5‐FU. In summary, our work provides an effective phenotypic screening strategy for identifying hematopoietic‐protective agents and reveals the novel role of HSYA as a promising lead compound in rescuing hematopoietic disorders associated with P53 overactivation.

The dung beetle primarily feeds on the feces of herbivorous animals and play a crucial role in ecological processes like material cycles and soil improvement. This study aims to explore the diversity and composition of the gut microbiota of Catharsius molossus (a renowned dung beetle originating from China and introduced to multiple countries for its ecological value) and exploring whether these gut microbes are transmitted vertically across generations. Using 16S rRNA and ITS rRNA gene sequencing techniques, we described the diversity and composition of gut microbes in C. molossus from different localities and different developmental stages (Egg, young larvae and old larvae). We discovered that the diversity of gut microbiota of dung beetles varied obviously among different geographical localities and different developmental stages, and we also discussed the potential influencing factors. Interestingly, the microbial community structure within the brood balls is more similar to male dung beetle than to that of females, which is consistent with the observation that the brood ball is constructed by the male dung beetle, with the female laying egg in it at the final step. This unique breeding method facilitates offspring in inheriting microbial communities from both the mother and the father. Initially, the larvae's gut microbiota closely mirrors that of the parental gift in these brood balls. As larvae grow, significant changes occur in their gut microbiota, including an increase in symbiotic bacteria like Lactococcus and Enterococcus. Analysis of the gut bacteria of adult dung beetles across various localities and different developmental stages identified nine core genera in adults, contributing to 67.80% of the total microbial abundance, and 11 core genera in beetles at different developmental stages, accounting for 49.13% of the total. Notably, seven genera were common between these two core groups. Our results suggest that Parental gifts can play a role in the vertical transmission of microbes, and the abundance of probiotics increases with larval development, supporting the hypothesis that \"larval feeding behavior occurs in two stages: larvae first feed on parental gifts to acquire necessary microbes, then enrich symbiotic microbiota through consuming their own feces.\"

In this study, the maximum tolerated dose (MTD) of lobaplatin (LBP) when it was combined with docetaxel (TXT) for the treatment of solid tumours that had progressed following chemotherapy was determined, and toxicities to this regimen were evaluated. A modified Fibonacci method was used for the dose escalation of LBP. The patients received TXT (at a fixed dose of 60 mg/m2) on day one (d1) and LBP (at an initial tested dose of 30 mg/m2) on day two (d2) of a treatment cycle that was repeated every 21 days. Each dose group consisted of at least three cases. In the absence of dose-limiting toxicity (DLT), we proceeded to the next dose group, with a dose increment of 5 mg/m2 between groups, until DLT occurred. The dose immediately below the dose that produced DLT was regarded as the MTD. The 17 patients examined in this study completed a total of 58 cycles of chemotherapy, and a total of three dose-escalation groups (30 mg/m2 LBP, 35 mg/m2 LBP, and 40 mg/m2 LBP) were established. The main adverse event that was observed was myelosuppression. DLT occurred in four patients, including three patients in the 40 mg/m2 LBP group and one patient in the 35 mg/m2 LBP group. In total, three out of the four patients in the 40 mg/m2 LBP group exhibited DLT. We determined that the treatment administered to the 35 mg/m2 LBP group represented the MTD. Thus, our phase I trial revealed that the MTD for the tested LBP combination regimen was 35 mg/m2 LBP and 60 mg/m2 TXT. This regimen resulted in mild adverse reactions and favourable patient tolerance. Therefore, we recommend the use of these dosages in phase II clinical trials.

Gastric cancer is the fourth most common type of cancer globally and accounts for the second highest cancer-associated mortality rate in the world. Current treatment strategies for gastric cancer include surgery, radiotherapy, chemotherapy and targeted therapy. Intraperitoneal (IP) chemotherapy may increase the IP concentrations of chemotherapy drugs and reduce the systemic toxicity. At present, IP chemotherapy is used to treat patients with advanced gastric cancer, which has a high rate of peritoneal recurrence. The present study evaluated the feasibility of using docetaxel, cisplatin and fluorouracil (DCF) in an IP and intravenous (IV) dual chemotherapy regimen for the treatment of advanced gastric cancer. The treatment-associated adverse reactions and preliminary efficacy were reported. The first dose level utilized the full dose of DCF: Docetaxel, day one, 45 mg/m2 (IP) and day eight, 30 mg/m2 (IV); cisplatin (DDP), day one, 75 mg/m2 (IP); and fluorouracil (FU), days one to five, 750 mg/m2 (continuous IV). A total of six patients were treated at this level and two patients withdrew due to serious adverse reactions. Taking into account that the the tolerated doses used in combination regimens for Eastern populations are lower than that of the corresponding doses for Western populations, the dosages of the three drugs were all reduced by 20% in the application of the second dose level: Docetaxel, day one, 30 mg/m2 (IP) and day eight, 30 mg/m2 (IV); DDP, day two, 60 mg/m2 (IP); and FU, days one to five, 600 mg/m2 (continuous IV). A total of 26 patients were treated at this level. The main adverse reaction was bone marrow suppression, with grade III/IV neutropenia, leukopenia and febrile neutropenia accounting for 61.5, 53.8 and 19.2% of reactions, respectively, and grade III/IV anemia and thrombocytopenia accounting for 19.2 and 15.4% of reactions, respectively. Gastrointestinal adverse reactions primarily consisted of abdominal pain, with grade III/IV abdominal pain accounting for 30.8% of reactions. Only 7.7% of the patients withdrew from the treatment. The median time to progression (TTP) was five months [95% confidence interval (CI), 1.0-9.0 months], and the median overall survival (OS) was nine months (95% CI, 7.4-10.6 months). It was concluded that the DCF regimen with reduced dosage should be applied. IP and IV dual chemotherapy for the treatment of unresectable advanced gastric cancer is tolerated and demonstrated a good initial efficacy. Strategies for mitigating and reducing the adverse gastrointestinal reactions, particularly abdominal pain, may be the focus of future studies.

With accumulating evidence suggesting that amyloid-β （Aβ） deposition is a good diagnostic biomarker for Alzheimer＇s disease （AD）, the discovery of active Aβ probes has become an active area of research. Among the existing imaging methods, optical imaging targeting Aβ aggregates （fibrils or oligomers）, especially using near-infrared （NIR） fluorescent probes, is increasingly recognized as a promising approach for the early diagnosis of AD due to its real time detection, low cost, lack of radioactive exposure and high-resolution. In the past decade, a variety of fluorescent probes have been developed and tested for efficiency in vitro, and several probes have shown efficacy in AD transgenic mice. This review classifies these representative probes based on their chemical structures and functional modes （dominant solvent-dependent mode and a novel solvent-independent mode）. Moreover, the pharmaceutical characteristics of these representative probes are summarized and discussed. This review provides important perspectives for the future development of novel NIR Aβ diagnostic probes.