Novel application potential of cinaciguat in the treatment of mixed hyperlipidemia through targeting PTL/NPC1L1 and alleviating intestinal microbiota dysbiosis and metabolic disorders.

Mixed hyperlipidemia, characterized by high levels of triglycerides and cholesterol, is a key risk factor leading to atherosclerosis and other cardiovascular diseases. Existing clinical drugs usually only work on a single indicator, decreasing either triglyceride or cholesterol levels. Developing dual-acting agents that reduce both triglycerides and cholesterol remains a great challenge. Pancreatic triglyceride lipase (PTL) and Niemann-Pick C1-like 1 (NPC1L1) have been identified as crucial proteins in the transport of triglycerides and cholesterol. Here, cinaciguat, a known agent used in the treatment of acute decompensated heart failure, was identified as a potent dual inhibitor targeting PTL and NPC1L1. We presented in vitro evidence from surface plasmon resonance analysis that cinaciguat interacted with PTL and NPC1L1. Furthermore, cinaciguat exhibited potent PTL-inhibition activity. Fluorescence-labeled cholesterol uptake analysis and confocal imaging showed that cinaciguat effectively inhibited cholesterol uptake. In vivo evaluation showed that cinaciguat significantly reduced the plasma levels of triglycerides and cholesterol, and effectively alleviated high-fat diet-induced intestinal microbiota dysbiosis and metabolic disorders. These results collectively suggest that cinaciguat has the potential to be further developed for the therapy of mixed hyperlipidemia.

Multifunctional small-molecule theranostic agents for tumor-specific imaging and targeted chemotherapy.

Cancer is one of the leading causes of death worldwide. Although great progress has been achieved in cancer diagnosis and treatment, novel therapies are still urgently needed to increase the efficacy and reduce the side effects of conventional therapies. Personalized medicine involves administering patients drugs that are specific to the characteristics of their tumors, and has significantly reduced side effects and increased overall survival rates. Multifunctional theranostic drugs are designed to combine diagnostic and therapeutic functions into a single molecule, which reduces the number of drugs administered to patients and increases patient compliance, and have shown great potential in propelling personalized medicine. This review focuses on multifunctional small-molecule theranostic agents for tumor-specific imaging and targeted chemotherapy, with a particular emphasis placed on highlighting design strategies and application in vitro or in vivo. The challenges and future perspectives of multifunctional small molecules are also discussed.

Photosensitizer-based small molecule theranostic agents for tumor-targeted monitoring and phototherapy.

Small molecule theranostic agents for tumor treatment exhibited triadic properties in tumor targeting, imaging, and therapy, which have attracted increasing attention as a potential complement for, or improved to, classical small molecule antitumor drugs. Photosensitizer have dual functions of imaging and phototherapy, and have been widely used in the construction of small molecule theranostic agents over the last decade. In this review, we summarized representative agents that have been studied in the field of small molecule theranostic agents based on photosensitizer in the last decade, and highlighted their characteristics and application in tumor-targeted monitoring and phototherapy. The challenges and future perspectives of photosensitizers in building small molecule theranostic agents for diagnosis and therapy of tumors were also discussed.

Risk factors of immune checkpoint inhibitor-associated acute kidney injury: evidence from clinical studies and FDA pharmacovigilance database.

BACKGROUND: Several risk factors of immune checkpoint inhibitors (ICIs)-associated acute kidney injury (AKI) have been reported sporadically. To identify the risk factors of ICIs-associated AKI in a large-scale population, therefore we conducted a systematic review and a real-world retrospective study. METHODS: We search literature concerning risk factors of ICIs-associated AKI in ClinicalTrials.gov and electronic databases (PubMed, Cochrane Library, Embase) up to January 2022. Meta-analysis was performed by using odds ratios (ORs) with 95%CIs. In a separate retrospective pharmacovigilance study by extracting data from US FDA Adverse Event Reporting System (FAERS) database, disproportionality was analyzed using the reporting odds ratio (ROR). RESULTS: A total of 9 studies (5927 patients) were included in the meta-analysis. The following factors were associated with increased risk of ICIs-associated AKI, including proton pump inhibitors(PPIs) (OR = 2.07, 95%CI 1.78-2.42), angiotensin-converting enzyme inhibitors (ACEIs)/ angiotensin receptor blockers (ARBs) (OR = 1.56, 95%CI 1.24-1.95), nonsteroidal anti-inflammatory drugs (NSAIDs) (OR = 1.29, 95%CI 1.01-1.65), diuretics (OR = 2.00, 95%CI 1.38-2.89), diabetes mellitus (OR = 1.28, 95%CI 1.04-1.57), genitourinary cancer (OR = 1.46, 95%CI 1.15-1.85), combination therapy of ICIs (OR = 1.93, 95%CI 1.25-2.97) and extrarenal immune-related adverse events(irAEs) (OR = 2.51, 95%CI 1.96-3.20). Furthermore, analysis from FAERS database verified that concurrent exposures of PPIs (ROR = 2.10, 95%CI 1.91-2.31), ACEIs/ARBs (ROR = 3.25, 95%CI 2.95-3.57), NSAIDs (ROR = 3.06, 95%CI 2.81-3.32) or diuretics (ROR = 2.82, 95%CI 2.50-3.19) were observed significant signals associated with AKI in ICIs-treated patients. CONCLUSIONS: Concurrent exposures of PPIs, ACEIs/ARBs, NSAIDs or diuretics, diabetes mellitus, genitourinary cancer, combination therapy, and extrarenal irAEs seem to increase the risk of AKI in ICIs-treated patients.

Optical Microfiber with a Gold Nanorods-Black Phosphorous Nanointerface: An Ultrasensitive Biosensor and Nanotherapy Platform.

The detection and therapy of cancers in the early stage significantly alleviate the associated dangers. Optical devices offer new opportunities for these early measures. However, the clinical translation of the existing methods is severely hindered by their relatively low sensitivity or unclear physiological metabolism. Here, an optical microfiber sensor with a drug loading gold nanorod-black phosphorous nanointerface, as an ultrasensitive biosensor and nanotherapy platform, is developed to meet the early-stage requirement. With interface sensitization and functionalization of the hybrid nanointerface, the microfiber sensor presents an ultrahigh sensing performance, achieving the selective detection of the HER2 biomarker with limits of detection of 0.66 aM in buffer solution and 0.77 aM in 10% serum. It can also distinguish breast cancer cells from other cells in the early stage. Additionally, enabled by the interface, the optical microfiber is able to realize cellular nanotherapy, including photothermal/chemotherapy with pump laser coupling after diagnosis, and evaluate therapy results in real time. The immobilization of the interface on the optical microfiber surface prevents the damage to normal cells induced by nanomaterial enrichment, making the device more efficient and intelligent. This study opens up a new avenue for the development of smart optical platforms for sensitive biosensing and precision therapy.

Phenethoxy Derivatives with Anti-inflammatory Activities from the Betelnut Endophytic Trichoderma asperellum G10.

Eight new phenethoxy derivatives, trichoasperellins A-H (1-8), were isolated from the endophytic fungus Trichoderma asperellum G10 isolated from the medicinal plant Areca catechu L. The structures of these compounds were elucidated from spectroscopic data, J-based configurational analysis, and Mosher's methods. Compounds 1-4 and 6-8 bear one or two multioxidized C7 moieties with the same carbon skeleton. The carbon skeletons of compounds 6-8 are new, all containing three moieties connected via two acetal carbons similar to those of disaccharide glycosides. Compound 4 inhibited nitric oxide production with an IC50 value of 48.3 µM, comparable to that of the positive control indomethacin (IC50, 42.3 µM).

3D nanointerface enhanced optical microfiber for real-time detection and sizing of single nanoparticles.

Portable devices, which can detect and characterize the individual nanoparticles in real time, are of insignificant interest for early diagnosis, homeland security, semiconductor manufacturing and environmental monitoring. Optical microfibers present a good potential in this field, however, are restricted by the sensitivity limit. This study reports the development of a 3D plasmonic nanointerface, which is made of a Cu-BTC framework supporting Cu3-xP nanocrystals, enhancing the optical microfiber for real-time detection and sizing of single nanoparticles. The Cu3-xP nanocrystals are successfully embedded in the 3D Cu-BTC framework. The localized-surface plasmon resonance is tuned to coincide with the evanescent field of the optical microfiber. The 3D Cu-BTC framework, as the scaffold of nanocrystals, confines the local resonance field on the microfiber with three dimensions, at which the binding of target nanoparticles occurs. Based on the evanescent field confinement and surface enhancement by the nanointerface, the optical microfiber sensor overcomes its sensitivity limit, and enables the detection and sizing of the individual nanoparticles. The compact size and low optical power supply of the sensor confirm its suitability as a portable device for the real-time single-nanoparticle characterization, especially for the convenient evaluation of the ultrafine particles in the environment. This work opens up an approach to overcome the sensitivity limit of the optical microfibers, as long with stimulating the portable real-time single-nanoparticle detection and sizing.

Radical Dehydroxymethylative Fluorination of Carbohydrates and Divergent Transformations of the Resulting Reverse Glycosyl Fluorides.

A mild and convenient method for the synthesis of reverse glycosyl fluorides (RGFs) has been developed that is based on the silver-promoted radical dehydroxymethylative fluorination of carbohydrates. A salient feature of the reaction is that furanoid and pyranoid carbohydrates furnish structurally diverse RGFs bearing a wide variety of functional groups in good to excellent yields. Intramolecular hydrogen atom transfer experiments revealed that the reaction involves an underexploited radical fluorination that proceeds via ß-fragmentation of sugar-derived primary alkoxyl radicals. Structurally divergent RGFs were obtained by catalytic C-F bond activation, and our method thus offers a concise and efficient strategy for the synthesis of reverse glycosides by late-stage diversification of RGFs. The potential of this method is showcased by the preparation and diversification of sotagliflozin, leading to the discovery of a promising SGLT2 inhibitor candidate.

Transition-Metal-Free Synthesis of C-Glycosylated Phenanthridines via K2S2O8-Mediated Oxidative Radical Decarboxylation of Uronic Acids.

We have developed an efficient protocol for the synthesis of C-glycosylated phenanthridines. Tetrafuranos-4-yl and pentapyranos-5-yl radicals, generated from K2S2O8-mediated oxidative decarboxylation of furan- and pyranuronic acids, undergo attack to 2-isocyanodiphenyls and ensuing homolytic aromatic substitution to provide diverse C-glycosylated phenanthridines in satisfactory yields without resort to transition metals. This reaction tolerates various functional groups, and enables ready synthesis of complex oligosaccharide-based phenanthridines. The C-glycosylated phenanthridine derived from ß-cyclodextrin has been prepared, which might be potential in medicinal and biological chemistry due to its flexible conformation.

Helvolic Acid Derivatives with Antibacterial Activities against Streptococcus agalactiae from the Marine-Derived Fungus Aspergillus fumigatus HNMF0047.

Streptococcus agalactiae is a hazardous pathogen that can cause great harm to humans and fish. In the present study, the known fungal metabolite helvolic acid (10), seven new helvolic acid derivatives named 16- O-deacetylhelvolic acid 21,16-lactone (2), 6- O-propionyl-6,16- O-dideacetylhelvolic acid 21,16-lactone (3), 1,2-dihydro-6,16- O-dideacetylhelvolic acid 21,16-lactone (4), 1,2-dihydro-16- O-deacetylhelvolic acid 21,16-lactone (5), 16- O-propionyl-16- O-deacetylhelvolic acid (6), 6- O-propionyl-6- O-deacetylhelvolic acid (7), and 24- epi-6ß,16ß-diacetoxy-25-hydroxy-3,7-dioxo-29-nordammara-1,17(20)-diene-21,24-lactone (9), and two known ones (1 and 8) were isolated from the marine-derived fungus Aspergillus fumigatus HNMF0047 obtained from an unidentified sponge from Wenchang Beach, Hainan Province, China. The structures and the absolute configurations of the new compounds were unambiguously elucidated by spectroscopic data and electronic circular dichroism (ECD) spectroscopic analyses along with quantum ECD calculations. In addition, the spectroscopic data of compound 1 are reported here for the first time, the configuration of C-24 of known compound 8 was revised based on comparison of its ROESY data with its C-24 epimer 9, and the absolute configuration of 8 was also determined for the first time. Compounds 6, 7, and 10 showed stronger antibacterial activity than a tobramycin control against S. agalactiae with MIC values of 16, 2, and 8 µg/mL, respectively.

Two New Succinimide Derivatives Cladosporitins A and B from the Mangrove-derived Fungus Cladosporium sp. HNWSW-1.

Two new succinimide-containing derivatives, cladosporitins A (1) and B (2), were isolated from the fermentation cultures of the mangrove-derived fungus Cladosporium sp. HNWSW-1, along with a new pyrone, clapone (3), as well as the previously reported talaroconvolutin A (4) and anthraquinone (5). The structures of the isolated compounds were elucidated by 1D, 2D NMR, and HRMS spectral analysis. Compound 2 showed cytotoxicity against BEL-7042, K562 and SGC-7901 cell lines with IC50 values of 29.4 ± 0.35 µM, 25.6 ± 0.47 µM, and 41.7 ± 0.71 µM, respectively, whereas compound 4 exhibited cytotoxicity against Hela and BEL-7042 cell lines with IC50 values of 14.9 ± 0.21 µM and 26.7 ± 1.1 µM, respectively. In addition, compounds 4 and 5 displayed inhibitory activity against α-glycosidase, with IC50 values of 78.2 ± 2.1 µM and 49.3 ± 10.6 µM, respectively.

Knowledge Maps and Emerging Trends in Cell-Cultured Meat since the 21st Century Research: Based on Different National Perspectives of Spatial-Temporal Analysis.

Cell-cultured meat holds significant environmental value as an alternative protein source. Throughout the 21st century, cell-cultured meat has progressively penetrated commercial markets. However, a systematic review encompassing the entire field needs improvement. Employing Citespace, Vosviewer, and R-Bibliometrix software, a bibliometric analysis was used to present the research progress and general development trends of 484 articles on cell-cultured meat from 2000 to 2022 based on countries, authors, institutions, and keywords. This analysis provides ideas for the future development of cell-cultured meat in different countries or regions worldwide. Research on cell-cultured meat from 2000 to 2022 has undergone two phases: fluctuating growth (2000-2013) and rapid growth (2013-2022). Noteworthy contributions to cell-cultured meat studies emerge from author groups in the United States of America, the United Kingdom, and China, with influential institutions like the University of Bath significantly impacting pertinent research. Furthermore, over the past two decades, research has leaned towards exploring topics such as "biomaterials", "cultured", "land use", "public opinion", "animal welfare", and "food safety". Furthermore, this study reveals differences in nomenclature between regions and institutions. "Cultured meat" is more popular in some countries than in other forms. Institutions in Asia use "cultured meat" more frequently; however, institutions in the Americas adopt "cultivated meat" and rarely adopt "in vitro meat", and institutions in the European region have no particularly prominent tendency towards a specific nomenclature. Future research should emphasize aligning the labeling of cell-cultured meat with effective management strategies and referencing regulatory policies across various countries. For the first time, we use three different bibliometric methods to analyze temporal and spatial variation in research on cellular meat. The results of this study have a multiplier effect. We provide a theoretical basis and a practical reference for the identification of alternatives in the dual context of "food crisis and food security" and "climate crisis". At the same time, we also provide a reference for the sustainable development of the food system.

Development and validation of a nomogram for predicting the occurrence of renal dysfunction after treatment of immune checkpoint inhibitor: a retrospective case-control study.

PURPOSE: The administration of immune checkpoint inhibitors (ICIs) may lead to renal adverse events, notably including renal dysfunction. To early predict the probability of renal dysfunction after ICIs therapy, a retrospective case-control study was conducted. METHODS: Clinical information on ICIs-treated patients was collected. Multivariable logistic regression was applied to identify risk factors for renal dysfunction after ICIs treatment. Moreover, a nomogram model was developed and validated internally. RESULTS: A total of 442 patients were included, among which 35 (7.9%) experienced renal dysfunction after ICIs treatment. Lower baseline estimated glomerular filtration rate (eGFR) (OR 0.941; 95% CI 0.917 to 0.966; p<0.001), concurrent exposure of platinum(OR 4.014; 95% CI 1.557 to 10.346; p=0.004), comorbidities of hypertension (OR 3.478; 95% CI 1.600 to 7.562; p=0.002) and infection (OR 5.402; 95% CI 1.544 to 18.904; p=0.008) were found to be independent associated with renal dysfunction after ICIs treatment. To develop a predictive nomogram for the occurrence of renal dysfunction after ICIs treatment, the included cases were divided into training and validation groups in a ratio of 7:3 randomly. The above four independent risk factors were included in the model. The area under the receiver operating characteristic curves of the predictiive model were 0.822 (0.723-0.922) and 0.815 (0.699-0.930) in the training and validation groups, respectively. CONCLUSIONS: Lower baseline eGFR, platinum exposure, comorbidities of hypertension and infection were predictors of renal dysfunction in ICIs-treated patients with cancer. A nomogram was developed to predict the probability of renal dysfunction after ICIs treatment, which might be operable and valuable in clinical practice.

Operando Decoding of Surface Chemical and Thermal Events in Photoelectrocatalysis via a Lab-Around-Microfiber Sensor.

Operando decoding of the key parameters of photo-electric catalysis provides reliable information for catalytic effect evaluation and catalytic mechanism exploration. However, to capture the details of surface-localized and rapid chemical and thermal events at the nanoscale in real-time is highly challenging. A promising approach based on a lab-around-microfiber sensor capable of simulating photo-electric catalytic reactions on the surface of optical fibers as well as monitoring reactant concentration changes and catalytic heat generation processes is demonstrated. Due to the penetration depth of submicron size and the fast response ability of the evanescent field, the lab-around-microfiber sensor overcame the difficulty of reading instantaneous surface parameters in the submicron range. This sensor operando dismantled the changes in reactant concentration and temperature on the catalyst surface induced by light and voltage, respectively. It also decoded the impact of catalyst composition on the adsorption efficiency and catalytic efficiency across various wavelengths and determined the synchronized occurrence of pollutant degradation and catalytic thermal effects. Stable correlations between the real-time parameters and catalytic activities are obtained, helping to provide a basic understanding of the catalytic process and mechanism. This approach fills an important gap in the current monitoring methods of catalytic processes and heat production.

Multimodal phototherapy agents target lipid droplets for near-infrared imaging-guided type I photodynamic/photothermal therapy.

The construction and optimization of a single phototherapeutic agent with photoluminescence, type I photodynamic therapy (PDT), and photothermal therapy (PTT) functions remain challenging. In this study, we aimed to design and synthesize four donor-acceptor (D-A) type aggregation-induced emission molecules: PSI, TPSI, PSSI, and TPSSI. We employed phenothiazine as an electron donor and 1,3-bis(dicyanomethylidene)indan as a strong electron acceptor in the synthesis process. Among them, TPSSI exhibited efficient type I reactive oxygen species generation, high photothermal conversion efficiency (45.44 %), and near-infrared emission. These observations can be attributed to the introduction of a triphenylamine electron donor group and a thiophene unit, which resulted in increased D-A strengths, a reduced singlet-triplet energy gap, and increased free intramolecular motion. TPSSI was loaded into bovine serum albumin to prepare biocompatible TPSSI nanoparticles (NPs). Our results have indicated that TPSSI NPs can target lipid droplets with negligible dark toxicity and can efficiently generate O2•- in hypoxic tumor environments. Moreover, TPSSI NPs selectively targeted 4T1 tumor tissues and exhibited a good PDT-PTT synergistic effect in vitro and in vivo. We believe that the successful preparation of multifunctional phototherapeutic agents will promote the development of efficient tumor diagnosis and treatment technologies. STATEMENT OF SIGNIFICANCE: The construction of a single phototherapeutic agent with photoluminescence, type I photodynamic therapy, and photothermal therapy functions, and its optimization remain challenging. In this study, we construct four donor-acceptor aggregation-induced emission molecules using phenothiazine as an electron donor and 1,3-Bis(dicyanomethylidene)indan as a strong electron acceptor. By optimizing the molecular structure, an integrated phototherapy agent with fluorescence imaging ability and high photodynamic / photothermal therapy performance was prepared. We believe that the successful preparation of multifunctional phototherapeutic agents will promote the development of efficient tumor diagnosis and treatment technology.

Comparison of Dosage of Glucocorticoid in Idiopathic Membranous Nephropathy: A Systematic Review and Network Meta-Analysis.

PURPOSE: Idiopathic membranous nephropathy (IMN) with moderate risk or above was recommended to receive immunosuppressive therapy. We attempted to evaluate the optimal dose of glucocorticoid when combined with evidence-proven effective immunosuppressants by network meta-analysis. METHODS: A systematic review of the literature was conducted in PubMed, Embase, Cochrane Library, and ClinicalTrials.gov from inception until January 2022. Randomized controlled trials (RCTs) in IMN limited to supportive care, glucocorticoids, cyclophosphamide, chlorambucil, calcineurin inhibitors (CNIs), and rituximab were screened. RESULTS: Twenty-eight RCTs of 1,830 patients were included. Therapeutic regimens were divided as follows: moderate- to high-dose glucocorticoids plus CNIs (HMSCn), moderate- to high-dose glucocorticoids plus cyclophosphamide (HMSCt), moderate- to high-dose glucocorticoids plus chlorambucil (HMSCh), zero- to low-dose glucocorticoids plus CNIs (LNSCn), zero- to low-dose glucocorticoids plus cyclophosphamide (LNSCt), rituximab alone (R), glucocorticoids alone (SE), and supportive care alone (SP). Compared with SP, HMSCh (risk ratio [RR]: 1.77, 95% confidence interval [CI]: 1, 3.18), HMSCn (RR: 2.5, 95%CI: 1.25, 5.11), HMSCt (RR: 2.15, 95%CI: 1.29, 3.64), LNSCn (RR: 2.16, 95%CI: 1.25, 3.95), and R (RR: 2.07, 95%CI: 1, 4.39) had a higher probability of total remission rate, while HMSCn represented the highest probability depending on the surface under the cumulative ranking area (SUCRA) ranking values. Regarding infection, no significant difference was found between different doses of glucocorticoids plus the same immunosuppressant. HMSCn and HMSCt showed superiority in reducing 24-hour urine total protein compared with HMSCh, LNSCn, SE, and SP, while HMSCn seemed to be the most effective regimen through the ranking of SUCRA value. CONCLUSION: Moderate- to high-dose glucocorticoids showed superiority in proteinuria remission when combined with CNIs in IMN, with no increasing risk of infection.

Marriage of a Dual-Plasmonic Interface and Optical Microfiber for NIR-II Cancer Theranostics.

The use of light as a powerful tool for disease treatment has introduced a new era in tumor treatment and provided abundant opportunities for light-based tumor theranostics. This work reports a photothermal theranostic fiber integrating cancer detection and therapeutic functions. Its self-heating effect can be tuned at ultralow powers and used for self-heating detection and tumor ablation. The fiber, consisting of a dual-plasmonic nanointerface and an optical microfiber, can be used to distinguish cancer cells from normal cells, quantify cancer cells, perform hyperthermal ablation of cancer cells, and evaluate the ablation efficacy. Its cancer cell ablation rate reaches 89% in a single treatment. In vitro and in vivo studies reveal quick, deep-tissue photonic hyperthermia in the NIR-II window, which can markedly ablate tumors. The marriage of a dual-plasmonic nanointerface and an optical microfiber presents a novel paradigm in photothermal therapy, offering the potential to surmount the challenges posed by limited light penetration depth, nonspecific accumulation in normal tissues, and inadvertent damage in current methods. This work thus provides insight for the exploration of an integrated theranostic platform with simultaneous functions in cancer diagnostics, therapeutics, and postoperative monitoring for future practical applications.

Quantitative Assessment of Fungal Biomarkers in Clinical Samples via an Interface-Modulated Optical Fiber Biosensor.

Invasive fungal infections pose a significant public health threat. The lack of precise and timely diagnosis is a primary factor contributing to the significant increase in patient mortality rates. Here, an interface-modulated biosensor utilizing an optical fiber for quantitative analysis of fungal biomarkers at the early stage of point-of-care testing (POCT), is reported. By integrating surface refractive index (RI) modulation and plasmon enhancement, the sensor to achieve high sensitivity in a directional response to the target analytes, is successfully optimized. As a result, a compact fiber-optic sensor with rapid response time, cost-effectiveness, exceptional sensitivity, stability, and specificity, is developed. This sensor can successfully identify the biomarkers of specific pathogens from blood or other tissue specimens in animal models. It quantifies clinical blood samples with precision and effectively discriminates between negative and positive cases, thereby providing timely alerts to potential patients. It significantly reduces the detection time of fungal infection to only 30 min. Additionally, this approach exhibits remarkable stability and achieves a limit of detection (LOD) three orders of magnitude lower than existing methods. It overcomes the limitations of existing detection methods, including a high rate of misdiagnosis, prolonged detection time, elevated costs, and the requirement for stringent laboratory conditions.

Molecular evolution and characterization of type III polyketide synthase gene family in Aquilaria sinensis.

2-(2-Phenylethyl) chromone (PEC) and its derivatives are markers of agarwood formation and are also related to agarwood quality. However, the biosynthetic and regulatory mechanisms of PECs still remain mysterious. Several studies suggested that type III polyketide synthases (PKSs) contribute to PEC biosynthesis in Aquilaria sinensis. Furthermore, systematic studies on the evolution of PKSs in A. sinensis have rarely been reported. Herein, we comprehensively analyzed PKS genes from 12 plant genomes and characterized the AsPKSs in detail. A unique branch contained only AsPKS members was identified through evolutionary analysis, including AsPKS01 that was previously indicated to participate in PEC biosynthesis. AsPKS07 and AsPKS08, two tandem-duplicated genes of AsPKS01 and lacking orthologous genes in evolutionary models, were selected for their transient expression in the leaves of Nicotiana benthamiana. Subsequently, PECs were detected in the extracts of N. benthamiana leaves, suggesting that AsPKS07 and AsPKS08 promote PEC biosynthesis. The interaction between the promoters of AsPKS07, AsPKS08 and five basic leucine zippers (bZIPs) from the S subfamily indicated that their transcripts could be regulated by these transcription factors (TFs) and might further contribute to PECs biosynthesis in A. sinensis. Our findings provide valuable insights into the molecular evolution of the PKS gene family in A. sinensis and serve as a foundation for advancing PEC production through the bioengineering of gene clusters. Ultimately, this contribution is expected to shed light on the mechanism underlying agarwood formation.

Doxorubicin prodrug-based nanomedicines for the treatment of cancer.

The chemotherapeutic drug of doxorubicin (DOX) has witnessed widespread applications for treating various cancers. DOX-treated dying cells bear cellular modifications which allow enhanced presentation of tumor antigen and neighboring dendritic cell activation. Furthermore, DOX also facilitate the immune-mediated clearance of tumor cells. However, disadvantages such as severe off-target toxicity, and prominent hydrophobicity have resulted in unsatisfactory clinical therapeutic outcomes. The effective delivery of DOX drug molecules is still challenging despite the rapid advances in nanotechnology and biomaterials. Huge progress has been witnessed in DOX nanoprodrugs owing to their brilliant benefits such as tumor stimuli-responsive drug release capacity, high drug loading efficiency and so on. This review summarized recent progresses of DOX prodrug-based nanomedicines to provide deep insights into future development and inspire researchers to explore DOX nanoprodrugs with real clinical applications.