Discovery and preclinical profile of YK-2168, a differentiated selective CDK9 inhibitor in clinical development.

Emerging clinical evidence indicates that selective CDK9 inhibition may provide clinical benefits in the management of certain cancers. Many CDK9 selective inhibitors have entered clinical developments, and are being investigated. No clear winner has emerged because of unforeseen toxicity often observed in clinic with these agents. Therefore, a novel agent with differentiated profiles is still desirable. Herein, we report our design, syntheses of a novel azaindole series of selective CDK9 inhibitors. SAR studies led to a preclinical candidate YK-2168. YK2168 exhibited improved CDK9 selectivity over AZD4573 and BAY1251152; also showed differentiated intravenous PK profile and remarkable solid tumor efficacy in a mouse gastric cancer SNU16 CDX model in preclinical studies. YK-2168 is currently in clinical development in China (CTR20212900).

Relationship between maternal serum sFlt-1 level and placenta accreta spectrum disorders in the third trimester.

PURPOSE: This study aims to evaluate whether the third-trimester soluble fms-like tyrosine kinase-1 (sFlt-1) serum levels could be related to placenta accreta spectrum (PAS) disorders and the severity of postpartum blood loss. METHODS: This was a nested case-control study which compared serum sFlt-1 level between gravid women with or without PAS disorders. Spearman correlation analysis was conducted to explore the relationship between sFlt-1 level and the volume of postpartum blood loss. Confounding factors were adjusted to avoid the impact on the results. RESULTS: Sixty gravid women were enrolled: 36 women in the PAS group and 24 women in the non-PAS group. Women in the PAS group had a median sFlt-1 level of 9407.1 [2745.9-21,691.5] pg/ml, whereas women in the non-PAS group had a median sFlt-1 level of 25,779.2 [14317.1-35,626.7] pg/ml, (p < 0.001). The sFlt-1 level was negatively related to the volume of postpartum blood loss (r = - 0.358, p = 0.041). After adjusting for maternal age and gestational age at blood taking, sFlt-1 level showed no significant relationship with PAS disorders (p = 0.245) and postpartum blood loss (p = 0.526). CONCLUSION: Third-trimester sFlt-1 serum level is not independently associated with PAS disorders or postpartum blood loss after adjusting for confounding factors.

Waterborne polyurethane nanoparticles incorporating linoleic acid as a potential strategy for controlling antibiotic resistance spread in the mammalian intestine.

Plasmid-mediated conjugative transfer of antibiotic resistance genes (ARGs) within the human and animal intestine represents a substantial global health concern. linoleic acid (LA) has shown promise in inhibiting conjugation in vitro, but its in vivo effectiveness in the mammalian intestinal tract is constrained by challenges in efficiently reaching the target site. Recent advancements have led to the development of waterborne polyurethane nanoparticles for improved drug delivery. In this study, we synthesized four waterborne polyurethane nanoparticles incorporating LA (WPU@LA) using primary raw materials, including N-methyldiethanolamine, 2,2'-(piperazine-1,4-diyl) diethanol, isophorone diisocyanate, castor oil, and acetic acid. These nanoparticles, identified as WPU0.89@LA, WPU0.99@LA, WPU1.09@LA, and WPU1.19@LA, underwent assessment for their pH-responsive release property and biocompatibility. Among these, WPU0.99@LA displayed superior pH-responsive release properties and biocompatibility towards Caco-2 and IPEC-J2 cells. In a mouse model, a dosage of 10 mg/kg/day WPU0.99@LA effectively reduced the conjugation of IncX4 plasmids carrying the mobile colistin resistance gene (mcr-1) by more than 45.1-fold. In vivo toxicity assessment demonstrated that 10 mg/kg/day WPU0.99@LA maintains desirable biosafety and effectively preserves gut microbiota homeostasis. In conclusion, our study provides crucial proof-of-concept support, demonstrating that WPU0.99@LA holds significant potential in controlling the spread of antibiotic resistance within the mammalian intestine.

SGLT2 inhibitors ameliorate NAFLD in mice via downregulating PFKFB3, suppressing glycolysis and modulating macrophage polarization.

Sodium-glucose co-transporter 2 (SGLT2) inhibitor (SGLT2i) is a novel class of anti-diabetic drug, which has displayed a promising benefit for non-alcoholic fatty liver disease (NAFLD). In this study, we investigated the protective effects of SGLT2i against NAFLD and the underlying mechanisms. The db/db mice and western diet-induced NAFLD mice were treated with dapagliflozin (1 mg·kg-1·d-1, i.g.) or canagliflozin (10 mg·kg-1·d-1, i.g.) for 8 weeks. We showed that the SGLT2i significantly improved NAFLD-associated metabolic indexes, and attenuated hepatic steatosis and fibrosis. Notably, SGLT2i reduced the levels of pro-inflammatory cytokines and chemokines, downregulated M1 macrophage marker expression and upregulated M2 macrophage marker expression in liver tissues. In cultured mouse bone marrow-derived macrophages and human peripheral blood mononuclear cell-derived macrophages, the SGLT2i (10, 20 and 40 µmol/L) significantly promoted macrophage polarization from M1 to M2 phenotype. RNA sequencing, Seahorse analysis and liquid chromatography-tandem mass spectrometry analysis revealed that the SGLT2i suppressed glycolysis and triggered metabolic reprogramming in macrophages. By using genetic manipulation and pharmacological inhibition, we identified that the SGLT2i targeted PFKFB3, a key enzyme of glycolysis, to modulate the macrophage polarization of M1 to M2 phenotype. Using a co-culture of macrophages with hepatocytes, we demonstrated that the SGLT2i inhibited lipogenesis in hepatocytes via crosstalk with macrophages. In conclusion, this study highlights a potential therapeutic application for repurposing SGLT2i and identifying a potential target PFKFB3 for NAFLD treatment.

Modulating Eco-friendly Colloidal AgGaS2 Quantum Dots for Highly Efficient Photodetection and Image Sensing via Direct Growth of Ternary AgInS2 Shell.

Tailoring the optoelectronic characteristics of colloidal quantum dots (QDs) by constructing a core/shell structure offers the potential to achieve high-performing solution-processed photoelectric conversion and information processing applications. In this work, the direct growth of wurtzite ternary AgInS2 (AIS) shell on eco-friendly AgGaS2 (AGS) core QDs is realized, giving rise to broadened visible light absorption, prolonged exciton lifetime and enhanced photoluminescence quantum yield (PLQY). Ultrafast transient absorption spectroscopy demonstrats that the photoinduced carrier separation and transfer kinetics of AGS QDs are significantly optimized following the AIS shell coating. As-synthesized environmentally benign AGS/AIS core/shell QDs are employed to fabricate photodetectors (PDs), showing a remarkable responsivity of 38.4 A W-1 and a detectivity of 2.4 × 1012 Jones under visible light illumination (405 nm). Moreover, the fabricated QDs-PDs exhibit superior image-sensing capability to record complex patterns with high resolution (160 × 160 pixels) under visible light illumination at 405 and 532 nm. The findings indicate that the direct growth of multinary narrow-band shell materials on eco-friendly QDs holds great promise to implement future "green", cost-effective and high-performance optoelectronic sensing/imaging systems.

Environment-benign Colloidal Quantum Dots-modified Dual Photoelectrodes for Self-biased Photoelectrochemical Water Splitting.

Photoelectrochemical (PEC) water splitting based on colloidal quantum dots (QDs) presents a promising approach for utilizing solar energy to produce green hydrogen energy. Previous research has been mainly focused on the single-photoelectrode QDs-PEC device operated under external bias, while the investigation of dual-photoelectrode configuration for self-biased QDs-PEC system is still lacking. In this work, two types of eco-friendly Cu-AISe/ZnSe:Cu (CZAC) and Mn-AIS/ZnS@Cu (MAZC) QDs were used to respectively sensitize the semiconductor n-type TiO2 and p-type Cu2O photoelectrodes, which acted as the photoanode and photocathode to build a heavy metal-free QDs-based bias-free solar water splitting cell, yielding a maximum photocurrent density of 0.47 mA cm-2 and a solar-to-hydrogen (STH) efficiency of 0.4% under 1 sun AM 1.5G illumination (100 mW cm-2). Moreover, approximate 692 nmol of H2 and 355 nmol of O2 with molar ratio of ~2:1 was detected after two hours of continuous light illumination, demonstrating the effective overall water splitting. This work indicates a significant advancement towards the realization of a cost-effective, efficient and "green" QDs-based artificial solar-to-fuel conversion system.

Impact of Ground Granulated Blast Furnace Slag on Calcium Leaching of Low-Heat Portland Cement Paste.

Low-heat Portland cement and ground granulated blast furnace slag are widely used for the preparation of hydraulic concrete. Nevertheless, the effect and mechanism of corrosion on low-heat Portland cement paste mixed with ground granulated blast furnace slag need to be further explored. This paper investigated the impact of ground granulated blast furnace slag on the calcium leaching of low-heat Portland cement paste by evaluating its mass loss, porosity, leaching depth, compressive strength, and Vickers hardness, and comparing it with the leaching performance of ordinary Portland cement paste. Furthermore, the phase composition and morphology of low-heat Portland cement paste containing ground granulated blast furnace slag were analyzed by X-ray diffraction, mercury intrusion porosimetry, and scanning electron microscopy. The results indicate that, after 180 days of soaking in ammonium chloride solution, the mass loss rate, growth rate of porosity, leaching depth, and compressive strength loss rate of low-heat Portland cement paste were 8.0%, 43.6%, 9.1 mm, and 27.7%, respectively, while those of ordinary Portland cement paste were 7.4%, 37.8%, 8.4 mm, and 30.1%, indicating that low-heat Portland cement paste is slightly more damaging than ordinary Portland cement. The addition of ground granulated blast furnace slag could significantly improve the leaching resistance of low-heat Portland cement. For instance, after adding 20% ground granulated blast furnace slag, the above test values were 2.4%, 28.5%, 5.6 mm, and 20.8%, respectively. The reason for this is that ground granulated blast furnace slag has the potential to reduce the porosity of low-heat Portland cement paste, and it can also undergo the secondary hydration reaction with its hydration product Ca(OH)2 to enhance the paste structure. Considering the cost performance, the suitable dosage of low-heat Portland cement paste for satisfactory leaching resistance is about 20%.

The relationship between effort-reward imbalance and quality of working life among medical caregivers: mediating effects of job burnout.

Background: To determine the relationship between effort-reward imbalance (ERI) and quality of working life (QWL) among medical caregivers and the mediating role of job burnout. Methods: This was a cross-sectional survey. A total of 787 medical caregivers at seven hospitals from Sichuan and Chongqing, China, between May to September 2023 were included in this observational study. The General Information Questionnaire, Effort-Reward Imbalance Questionnaire (ERI), Maslach Burnout Inventory-General Survey (MBI-GS), and Quality of Working Life Scale (QWL7-32) were used for data collection. SPSS 26.0 and PROCESSv3.3 were used for all data analyses, including descriptive statistics. Results: A total of 820 questionnaires were distributed, of which only 787 were valid (return rate; 95.98%). The QWL score of medical caregivers was 126.94 ± 16.69. However, QWL scores were significantly different depending on age, number of children, family support status, department, years of experience, night shift status, number of night shifts per month, number of hours worked per day, monthly income, and occurrence of errors or adverse events (p < 0.05). Furthermore, job burnout and ERI were negatively correlated with QWL (p < 0.01). Job burnout mediated (95% CI = -0.365, -0.260) the relationship between ERI and QWL, accounting for 58.65% of the total effect. Conclusion: Medical caregivers have a medium level of QWL. Job burnout partially mediates the relationship between ERI and QWL. Medical caregiver managers can improve QWL by directly intervening in occupational stress and indirectly intervening in job burnout.

CRISPR-AMRtracker: A novel toolkit to monitor the antimicrobial resistance gene transfer in fecal microbiota.

The spread of antibiotic resistance genes (ARGs), particularly those carried on plasmids, poses a major risk to global health. However, the extent and frequency of ARGs transfer in microbial communities among human, animal, and environmental sectors is not well understood due to a lack of effective tracking tools. We have developed a novel fluorescent tracing tool, CRISPR-AMRtracker, to study ARG transfer. It combines CRISPR/Cas9 fluorescence tagging, fluorescence-activated cell sorting, 16S rRNA gene sequencing, and microbial community analysis. CRISPR-AMRtracker integrates a fluorescent tag immediately downstream of ARGs, enabling the tracking of ARG transfer without compromising the host cell's antibiotic susceptibility, fitness, conjugation, and transposition. Notably, our experiments demonstrate that sfGFP-tagged plasmid-borne mcr-1 can transfer across diverse bacterial species within fecal samples. This innovative approach holds the potential to illuminate the dynamics of ARG dissemination and provide valuable insights to shape effective strategies in mitigating the escalating threat of antibiotic resistance.

Recent Advances in the Biosynthesis of Mid- and Long-Chain Dicarboxylic Acids Using Terminally Oxidizing Unconventional Yeasts.

As high-performance monomers for the manufacture of polyamide materials, mid- and long-chain dicarboxylic acids (DCAi, i ≥ 6) have received extensive attention from researchers. Biosynthesis is gradually replacing chemical synthesis due to its outstanding advantages in the industrial production of mid- and long-chain dicarboxylic acids, which is mostly achieved by using the strong terminal oxidation ability of nonmodel microorganisms such as Candida tropicalis to oxidize hydrophobic substrates such as alkanes. Here, we first summarize the metabolic pathways of oxidative alkane conversion into dicarboxylic acid by terminally oxidizing unconventional yeasts and the corresponding metabolic engineering strategies. Then, we summarize the research progress on new dicarboxylic acid production processes. Finally, the future development directions in the biosynthesis of mid- and long-chain dicarboxylic acids are prospected from synthetic biology and bioprocess engineering, which can also provide a reference for the synthesis of other biobased chemicals and biomaterials.

Multi-objective optimization and life cycle assessment of mass-integrated combined heat and power system.

As the effects of climate change become more widely recognized, technical innovation and green energy will promote the growth of combined heat and power systems. This study proposes a novel mass-integrated combined heat and power system and conducts energy analysis, exergy analysis, and techno-economic analysis for the system. The optimization strategy integrated polynomial regression and non-dominated sorting genetic algorithm III is established, with system thermal efficiency, exergy efficiency, and return on investment (ROI) as objective functions. The system's environmental consequences are then assessed throughout its life cycle using life cycle assessment (LCA) under ideal operating circumstances. The findings reveal that the waste heat recovery heat exchanger has the highest exergy destruction in the system, with a value of 674.61 kW. Furthermore, the intermediate heat exchanger 1 and intermediate heat exchanger 2 (IHX2) with lesser exergy efficiency have an exergy destruction of less than 32.00 kW. The IHX2 is the most expensive equipment in the system, costing $90,931.19, but it also provides the most potential for system improvement. The multi-objective optimization findings suggest that the thermal efficiency, exergy efficiency, and ROI for the system are 0.17, 0.97, and 0.30, respectively. The LCA demonstrates that the system has a negligible influence on global warming and ozone generation with corresponding LCA findings of less than 4.20. The construction and operation phases of the investigation system have the most significant environmental consequences. The correlation between the raw materials necessary for the construction of the equipment in the system and the reaction temperatures, conditions, and waste composition during the preparation of the working fluids is large, so it is necessary to take corresponding environmental protection measures during production and processing to reduce the system's environmental emissions from the source and promote ecologically sustainable development.

Progress on the Anti-Inflammatory Activity and Structure-Efficacy Relationship of Polysaccharides from Medical and Edible Homologous Traditional Chinese Medicines.

Medicinal food varieties developed according to the theory of medical and edible homologues are effective at preventing and treating chronic diseases and in health care. As of 2022, 110 types of traditional Chinese medicines from the same source of medicine and food have been published by the National Health Commission. Inflammation is the immune system's first response to injury, infection, and stress. Chronic inflammation is closely related to many diseases such as atherosclerosis and cancer. Therefore, timely intervention for inflammation is the mainstay treatment for other complex diseases. However, some traditional anti-inflammatory drugs on the market are commonly associated with a number of adverse effects, which seriously affect the health and safety of patients. Therefore, the in-depth development of new safe, harmless, and effective anti-inflammatory drugs has become a hot topic of research and an urgent clinical need. Polysaccharides, one of the main active ingredients of medical and edible homologous traditional Chinese medicines (MEHTCMs), have been confirmed by a large number of studies to exert anti-inflammatory effects through multiple targets and are considered potential natural anti-inflammatory drugs. In addition, the structure of medical and edible homologous traditional Chinese medicines' polysaccharides (MEHTCMPs) may be the key factor determining their anti-inflammatory activity, which makes the underlying the anti-inflammatory effects of polysaccharides and their structure-efficacy relationship hot topics of domestic and international research. However, due to the limitations of the current analytical techniques and tools, the structures have not been fully elucidated and the structure-efficacy relationship is relatively ambiguous, which are some of the difficulties in the process of developing and utilizing MEHTCMPs as novel anti-inflammatory drugs in the future. For this reason, this paper summarizes the potential anti-inflammatory mechanisms of MEHTCMPs, such as the regulation of the Toll-like receptor-related signaling pathway, MAPK signaling pathway, JAK-STAT signaling pathway, NLRP3 signaling pathway, PI3K-AKT signaling pathway, PPAR-γ signaling pathway, Nrf2-HO-1 signaling pathway, and the regulation of intestinal flora, and it systematically analyzes and evaluates the relationships between the anti-inflammatory activity of MEHTCMPs and their structures.

[Proximal femoral nail antirotation combined with locking plate in the treatment of femoral intertrochanteric fractures with lateral wall fractures].

OBJECTIVE: To investigate the effect of locking plate internal fixation for the treatment of proximal lateral femoral wall fracture. METHODS: From January 2021 to June 2022, 31 patients with intertrochanteric fractures and lateral wall fractures were treated. Among them, 15 patients were treated with proximal femoral nail antirotation (PFNA) fixation including 3 males and 12 females with an average age of (75.87±7.46) years old;the other 16 patients were treated with 3.5 mm pre-curved screw locking plate fixtion for lateral wall fracture including 4 males and 12 females with an average age of (76.15±9.47) years old. After surgery, the surgical index, tip-apical distance(TAD), postoperative standing weight-bearing time, and fracture reduction were compared between two groups. Postoperative hip function was evaluated according to Harris hip score. RESULTS: All patients were followed up for an average of (12±5) months ranging from 7 to 17 months. The immediate postoperative neck angle ranged from 111° to 132°(119.3±8.3)°. Fracture reduction results were excellent in 11 cases, fair in 2, worse in 1 in PFNA group;excellent in 12, fair in 3, worse in 1 in PFNA+locking plate group. One case of the PFNA group had a spiral blade cut out through the femoral head. There were significant differences in the time of operation, the amount of blood loss during the operation, the length of incision between two groups(P<0.05). There was no significant difference in TAD and postoperative standing weight-bearing time between two groups(P>0.05). There were significant differences in Harris scores at 6 months after surgery between two groups(P<0.05). CONCLUSION: The application of PFNA-assisted locking plate in the treatment of femoral intertrochanteric fractures with lateral wall fractures is effective, and can restore the integrity of lateral wall, improve the stability of PFNA internal fixation, and reduce postoperative complications.

GATIS score for predicting the prognosis of rectal neuroendocrine neoplasms: A Chinese multicenter study of 12-year experience.

BACKGROUND: There is currently a shortage of accurate, efficient, and precise predictive instruments for rectal neuroendocrine neoplasms (NENs). AIM: To develop a predictive model for individuals with rectal NENs (R-NENs) using data from a large cohort. METHODS: Data from patients with primary R-NENs were retrospectively collected from 17 large-scale referral medical centers in China. Random forest and Cox proportional hazard models were used to identify the risk factors for overall survival and progression-free survival, and two nomograms were constructed. RESULTS: A total of 1408 patients with R-NENs were included. Tumor grade, T stage, tumor size, age, and a prognostic nutritional index were important risk factors for prognosis. The GATIS score was calculated based on these five indicators. For overall survival prediction, the respective C-indexes in the training set were 0.915 (95% confidence interval: 0.866-0.964) for overall survival prediction and 0.908 (95% confidence interval: 0.872-0.944) for progression-free survival prediction. According to decision curve analysis, net benefit of the GATIS score was higher than that of a single factor. The time-dependent area under the receiver operating characteristic curve showed that the predictive power of the GATIS score was higher than that of the TNM stage and pathological grade at all time periods. CONCLUSION: The GATIS score had a good predictive effect on the prognosis of patients with R-NENs, with efficacy superior to that of the World Health Organization grade and TNM stage.

Diagnostic Accuracy of Combined 3.0T Magnetic Resonance Imaging and Molybdenum Target X-Ray in Triple-Negative Breast Cancer: Correlation with Prognosis in Patients Undergoing Sentinel Lymph Node Biopsy.

Objective: This study assessed the diagnostic efficacy of combining 3.0T MRI and molybdenum target X-ray in triple-negative breast carcinoma (TNBC) and its association with the prognosis of sentinel lymph node biopsy (SLNB). Methods: The retrospective analysis included 128 patients suspected of having TNBC, who underwent 3.0T MRI and molybdenum target X-ray. Sensitivity and specificity were calculated for each imaging technique, and their combined diagnosis was evaluated using the four-table method. Consistency between the imaging techniques and pathological examination was assessed using the consistency checking method. Additionally, changes in imaging indicators were compared among patients with different prognostic indicators. Results: Among the 128 patients, 86 were diagnosed with TNBC through pathological examination. The sensitivity and specificity of 3.0T MRI for TNBC were 82.56% and 76.19%, respectively. Molybdenum target X-ray exhibited a sensitivity of 77.91% and specificity of 78.57%. The combined diagnosis of the two techniques showed a sensitivity of 90.70% and specificity of 86.36%. There was good agreement between both imaging techniques and pathological examination results. Significant differences were observed in imaging indicators based on tumor diameter, histological grade, and lymph node metastasis. Conclusion: Both 3.0T MRI and molybdenum target X-ray are valuable in diagnosing TNBC. Additionally, these imaging techniques provide prognostic information and can aid in treatment decision-making. The findings highlight the importance of 3.0T MRI and molybdenum target X-ray in improving the outcomes of patients with TNBC.

Understanding the global subnational migration patterns driven by hydrological intrusion exposure.

Amid the escalating global climatic challenges, hydrological risks significantly influence human settlement patterns, underscoring the imperative for an in-depth comprehension of hydrological change's ramifications on human migration. However, predominant research has been circumscribed to the national level. The study delves into the nonlinear effects of hydrological risks on migration dynamics in 46,776 global subnational units. Meanwhile, leveraging remote sensing, we procured globally consistent metrics of hydrological intrusion exposure, offering a holistic risk assessment encompassing hazard, exposure, and vulnerability dimensions, thus complementing previous work. Here, we show that exposure is the primary migration driver, surpassing socioeconomic factors. Surrounding disparities further intensified exposure's impact. Vulnerable groups, especially the economically disadvantaged and elderly, tend to remain in high-risk areas, with the former predominantly migrating within proximate vicinities. The nonlinear analysis delineates an S-shaped trajectory for hydrological exposure, transitioning from resistance to migration and culminating in entrapment, revealing dependence on settlement resilience and adaptability.

Innovative Delivery System Combining CRISPR-Cas12f for Combatting Antimicrobial Resistance in Gram-Negative Bacteria.

Antimicrobial resistance poses a significant global challenge, demanding innovative approaches, such as the CRISPR-Cas-mediated resistance plasmid or gene-curing system, to effectively combat this urgent crisis. To enable successful curing of antimicrobial genes or plasmids through CRISPR-Cas technology, the development of an efficient broad-host-range delivery system is paramount. In this study, we have successfully designed and constructed a novel functional gene delivery plasmid, pQ-mini, utilizing the backbone of a broad-host-range Inc.Q plasmid. Moreover, we have integrated the CRISPR-Cas12f system into the pQ-mini plasmid to enable gene-curing in broad-host of bacteria. Our findings demonstrate that pQ-mini facilitates the highly efficient transfer of genetic elements to diverse bacteria, particularly in various species in the order of Enterobacterales, exhibiting a broader host range and superior conjugation efficiency compared to the commonly used pMB1-like plasmid. Notably, pQ-mini effectively delivers the CRISPR-Cas12f system to antimicrobial-resistant strains, resulting in remarkable curing efficiencies for plasmid-borne mcr-1 or blaKPC genes that are comparable to those achieved by the previously reported pCasCure system. In conclusion, our study successfully establishes and optimizes pQ-mini as a broad-host-range functional gene delivery vector. Furthermore, in combination with the CRISPR-Cas system, pQ-mini demonstrates its potential for broad-host delivery, highlighting its promising role as a novel antimicrobial tool against the growing threat of antimicrobial resistance.

Microbial Degradation of Tetracycline Antibiotics: Mechanisms and Environmental Implications.

The escalating global consumption of tetracyclines (TCs) as broad-spectrum antibiotics necessitates innovative approaches to mitigate their pervasive environmental persistence and associated risks. While initiatives such as China's antimicrobial reduction efforts highlight the urgency of responsible TC usage, the need for efficient degradation methods remains paramount. Microbial degradation emerges as a promising solution, offering novel insights into degradation pathways and mechanisms. Despite challenges, including the optimization of microbial activity conditions and the risk of antibiotic resistance development, microbial degradation showcases significant innovation in its cost-effectiveness, environmental friendliness, and simplicity of implementation compared to traditional degradation methods. While the published reviews have summarized some aspects of biodegradation of TCs, a systematic and comprehensive summary of all the TC biodegradation pathways, reactions, intermediates, and final products including ring-opening products involved with enzymes and mechanisms of each bacterium and fungus reported is necessary. This review aims to fill the current gap in the literature by offering a thorough and systematic overview of the structure, bioactivity mechanism, detection methods, microbial degradation pathways, and molecular mechanisms of all tetracycline antibiotics in various microorganisms. It comprehensively collects and analyzes data on the microbial degradation pathways, including bacteria and fungi, intermediate and final products, ring-opening products, product toxicity, and the degradation mechanisms for all tetracyclines. Additionally, it points out future directions for the discovery of degradation-related genes/enzymes and microbial resources that can effectively degrade tetracyclines. This review is expected to contribute to advancing knowledge in this field and promoting the development of sustainable remediation strategies for contaminated environments.

Dual drug-loaded metal-phenolic networks for targeted magnetic resonance imaging and synergistic chemo-chemodynamic therapy of breast cancer.

The development of nanomedicines with simplified compositions and synergistic theranostic functionalities remains a great challenge. Herein, we develop a simple method to integrate both atovaquone (ATO, a mitochondrial inhibitor) and cisplatin within tannic acid (TA)-iron (Fe) networks coated with hyaluronic acid (HA) for targeted magnetic resonance (MR) imaging-guided chemo-chemodynamic synergistic therapy. The formed TFP@ATO-HA displayed good colloidal stability with a mean size of 95.5 nm, which could accumulate at tumor sites after circulation and be specifically taken up by metastatic 4T1 cells overexpressing CD44 receptors. In the tumor microenvironment, TFP@ATO-HA could release ATO/cisplatin and Fe3+ in a pH-responsive manner, deplete glutathione, and generate reactive oxygen species with endogenous H2O2 for chemodynamic therapy (CDT). Additionally, ATO could enhance chemotherapeutic efficacy by inhibiting mitochondrial respiration, relieving hypoxia, and amplifying the CDT effect by decreasing intracellular pH and elevating Fenton reaction efficiency. In vivo experiments demonstrated that TFP@ATO-HA could effectively inhibit tumor growth and suppress lung metastases without obvious systemic toxicity. Furthermore, TFP@ATO-HA exhibited a r1 relaxivity of 2.6 mM-1 s-1 and targeted MR imaging of 4T1 tumors. Dual drug-loaded metal-phenolic networks can be easily prepared and act as effective theranostic nanoplatforms for targeted MR imaging and synergistic chemo-chemodynamic therapy.