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Cisplatin is a chemotherapeutic agent widely employed in the treatment of various solid tumors. However, its use is often restricted by acute kidney injury (AKI) which is the dose-limiting adverse effect of cisplatin. While numerous studies aiming to alleviate the AKI have been conducted, there are no effective remedies in clinical practice. In this paper, a targeted metabolomics study was performed to reveal the potential relationship between tryptophan metabolism and cisplatin-induced AKI. A chemical derivatization integrated liquid chromatography coupled tandem mass spectrometry (LC-MS/MS) approach was utilized to quantify 29 metabolites in the tryptophan pathway in rat kidney medulla and cortex after cisplatin administration. Results showed that tryptophan metabolism was remarkably disturbed both in the medulla and cortex after cisplatin administration. We also found that the tryptophan pathway in the medulla was more sensitive to cisplatin exposure compared with the cortex. Among these metabolites, indoxyl sulfate was focused for further study because it accumulated most significantly in the kidney cortex and medulla in a dose-dependent manner. A function verification study proved that chlormethiazole, a widely used CYP2E1 inhibitor, could reduce the production of indoxyl sulfate in the liver and attenuate cisplatin-induced AKI in rats. In conclusion, our study depicted the tryptophan pathway in cisplatin-induced AKI for the first time and demonstrated tryptophan metabolism is closely associated with the renal toxicity caused by cisplatin, which can be of great use for the discovery of renal toxicity attenuating remedies.

Intestinal toxicity induced by chemotherapeutics has become an important reason for the interruption of therapy and withdrawal of approved agents. In this study, we demonstrated that chemotherapeutics-induced intestinal damage were commonly characterized by the sharp upregulation of tryptophan (Trp)−kynurenine (KYN)−kynurenic acid (KA) axis metabolism. Mechanistically, chemotherapy-induced intestinal damage triggered the formation of an interleukin-6 (IL-6)−indoleamine 2,3-dioxygenase 1 (IDO1)−aryl hydrocarbon receptor (AHR) positive feedback loop, which accelerated kynurenine pathway metabolism in gut. Besides, AHR and G protein-coupled receptor 35 (GPR35) negative feedback regulates intestinal damage and inflammation to maintain intestinal integrity and homeostasis through gradually sensing kynurenic acid level in gut and macrophage, respectively. Moreover, based on virtual screening and biological verification, vardenafil and linagliptin as GPR35 and AHR agonists respectively were discovered from 2388 approved drugs. Importantly, the results that vardenafil and linagliptin significantly alleviated chemotherapy-induced intestinal toxicity in vivo suggests that chemotherapeutics combined with the two could be a promising therapeutic strategy for cancer patients in clinic. This work highlights GPR35 and AHR as the guardian of kynurenine pathway metabolism and core component of defense responses against intestinal damage., Graphical abstract AHR and GPR35 constitute a rationale of defense responses against chemotherapy-induced intestinal damage through gradually sensing Trp–KYN–KA axis metabolism. The formation of IL-6–IDO1–AHR positive feedback loop is driven by AHR through sensing Trp–KYN–KA axis metabolism. AHR and GPR35 sense KA level in a gradient-dependent manner to maintain intestinal integrity and homeostasis.Image 1

Background: As phases of COVID-19 vaccination are quickly rolling out, how to evaluate the vaccination effects and then make safe reopening plans has become a prime concern for local governments and school officials.Methods: We develop a contact network agent-based model (CN-ABM) to simulate on-campus disease transmission scenarios at the micro-scale. The CN-ABM establishes a contact network for each agent based on their daily activity pattern, evaluates the agent's health status change in different activity environments, and then simulates the epidemic curve on campus. Based on the developed model, we identify how different community risk levels, teaching modalities, and vaccination rates would shape the epidemic curve. Results: The results show that in scenarios where vaccination is not available, restricting on-campus students to under 50% can largely flatten the epi curve (peak value < 2%); and the best result (peak value < 1%) can be achieved by limiting on-campus students to less than 25%. In scenarios where vaccination is available, it is suggested to maintain a maximum of 75% on-campus students and a vaccination rate of at least 45% to suppress the curve (peak value < 2%); and the best result (peak value < 1%) can be achieved at a vaccination rate of 65%. The study also derives the transmission chain of infectious agents, which can be used to identify high-risk activity environments. Conclusions: The developed CN-ABM model can be employed to evaluate the health outcome of COVID-19 outbreaks on campus based on different disease transmission scenarios. It can assist local government and school officials with developing proactive intervention strategies to safely reopen schools.

Irinotecan (CPT-11) in combination with 5-fluorouracil and leucovorin is a first-line chemotherapy regimen for the treatment of colorectal cancer; however, its clinical application is limited by the dose-limiting gastrointestinal toxicity of colitis. In our previous studies, several bile acids (BAs) were found significantly elevated in the colon of the CPT-11-induced rat colitis model. On the other hand, NLRP3 inflammasome has been reported to play important roles in mediating colitis. Interestingly, BA was stated to activate the NLRP3 inflammasome in some studies, while in some other reports, it showed an inhibitory effect. We assumed that the inflammatory status in different circumstances might have contributed to the controversial findings. In this study, we first discovered, under non-inflammatory conditions, that supplementing BA could activate the NLRP3 inflammasome in THP-1-differentiated macrophages and promote inflammation. In lipopolysaccharide (LPS)-induced inflammatory macrophages, however, BA inhibited the NLRP3 inflammasome and reduced inflammation. Further experiments demonstrated that Takeda G protein-coupled receptor 5 (TGR5) is essential in mediating the inhibitory effect of BA, while phospho-SP1 (p-SP1) is key to the activation. Furthermore, we applied the above findings to ameliorate CPT-11-caused colitis in rats by inhibiting SP1 with mithramycin A (MitA) or activating TGR5 using oleanolic acid (OA). Our findings may shed light on the discovery of effective interventions for reducing dose-limiting chemotherapy-induced colitis.

The emergence of different virus variants, the rapidly changing epidemic, and demands for economic recovery all require continual adjustment and optimization of COVID-19 intervention policies. For the purpose, it is both important and necessary to evaluate the effectiveness of different policies already in-place, which is the basis for optimization. Although some scholars have used epidemiological models, such as susceptible-exposed-infected-removed (SEIR), to perform evaluation, they might be inaccurate because those models often ignore the time-varying nature of transmission rate. This study proposes a new scheme to evaluate the efficiency of dynamic COVID-19 interventions using a new model named as iLSEIR-DRAM. First, we improved the traditional LSEIR model by adopting a five-parameter logistic function β(t) to depict the key parameter of transmission rate. Then, we estimated the parameters by using an adaptive Markov Chain Monte Carlo (MCMC) algorithm, which combines delayed rejection and adaptive metropolis samplers (DRAM). Finally, we developed a new quantitative indicator to evaluate the efficiency of COVID-19 interventions, which is based on parameters in β(t) and considers both the decreasing degree of the transmission rate and the emerging time of the epidemic inflection point. This scheme was applied to seven cities in Guangdong Province. We found that the iLSEIR-DRAM model can retrace the COVID-19 transmission quite well, with the simulation accuracy being over 95% in all cities. The proposed indicator succeeds in evaluating the historical intervention efficiency and makes the efficiency comparable among different cities. The comparison results showed that the intervention policies implemented in Guangzhou is the most efficient, which is consistent with public awareness. The proposed scheme for efficiency evaluation in this study is easy to implement and may promote precise prevention and control of the COVID-19 epidemic.