Dynamic gut microbiome-metabolome in cationic bovine serum albumin induced experimental immune-complex glomerulonephritis and effect of losartan and mycophenolate mofetil on microbiota modulation.

Dynamic changes in gut dysbiosis and metabolomic dysregulation are associated with immune-complex glomerulonephritis (ICGN). However, an in-depth study on this topic is currently lacking. Herein, we report an ICGN model to address this gap. ICGN was induced via the intravenous injection of cationized bovine serum albumin (c-BSA) into Sprague-Dawley (SD) rats for two weeks, after which mycophenolate mofetil (MMF) and losartan were administered orally. Two and six weeks after ICGN establishment, fecal samples were collected and 16S ribosomal DNA (rDNA) sequencing and untargeted metabolomic were conducted. Fecal microbiota transplantation (FMT) was conducted to determine whether gut normalization caused by MMF and losartan contributed to their renal protective effects. A gradual decline in microbial diversity and richness was accompanied by a loss of renal function. Approximately 18 genera were found to have significantly different relative abundances between the early and later stages, and Marvinbryantia and Allobaculum were markedly upregulated in both stages. Untargeted metabolomics indicated that the tryptophan metabolism was enhanced in ICGN, characterized by the overproduction of indole and kynurenic acid, while the serotonin pathway was reduced. Administration of losartan and MMF ameliorated microbial dysbiosis and reduced the accumulation of indoxyl conjugates in feces. FMT using feces from animals administered MMF and losartan improved gut dysbiosis by decreasing the Firmicutes/Bacteroidetes (F/B) ratio but did not improve renal function. These findings indicate that ICGN induces serous gut dysbiosis, wherein an altered tryptophan metabolism may contribute to its progression. MMF and losartan significantly reversed the gut microbial and metabolomic dysbiosis, which partially contributed to their renoprotective effects.

miR-2940-1 is involved in the circadian regulation of oviposition in Aedes albopictus.

The vast majority of all global species have circadian rhythm cycles that allow them to adapt to natural environments. These regular rhythms are regulated by core clock genes and recent studies have also implicated roles for microRNAs in this regulation. Oviposition is an important circadian behavior in the reproductive cycle of insect vectors of diseases, and little is known about the rhythm or its regulation in mosquitoes. Aedes albopictus is a diurnal mosquito that transmits arboviruses and is the major cause of outbreaks of dengue fever in China. We analyzed the oviposition rhythm patterns of A. albopictus under different light/dark conditions and show that the mosquitoes have an oviposition peak between zeitgeber time 9 (ZT 9) and ZT 12. Furthermore, the antagomir-mediated knockdown of expression of the microRNA miR-2940-1 affected the oviposition rhythm of A. albopictus. These data support the conclusion that miR-2940-1 is involved in the regulation of oviposition rhythm in A. albopictus and provide a foundation for using oviposition rhythms as a new target for vector mosquito control.

Enhanced Sb(V) removal of sulfate-rich wastewater by anaerobic granular sludge assisted with Fe/C amendment.

Antimony (Sb) and sulfate are two common pollutants in Sb mine drainage and Sb-containing textile wastewater. In this paper, it was found that iron­carbon (Fe/C) enhanced Sb(V) removal from sulfate-rich wastewater by anaerobic granular sludge (AnGS). Sulfate inhibited Sb(V) removal (S + Sb, k = 0.101), while Fe/C alleviated the inhibition and increased Sb(V) removal rate by 2.3 times (Fe/C + S + Sb, k = 0.236). Fe/C could promote the removal of Sb(III), and Sb(III) content decreased significantly after 8 h. Meanwhile, Fe/C enhanced the removal of sulfate. The 3D-EEM spectrum of supernatant in Fe/C + S + Sb group (at 24 h) showed that Fe/C stimulated the production of soluble microbial products (SMP) in wastewater. SMP alleviated the inhibition of sulfate, promoting AnGS to reduce Sb(V). Sb(V) could be reduced to Sb(III) both by AnGS and sulfides produced from sulfate reduction. Further analysis of extracellular polymeric substances (EPS) and AnGS showed that Fe/C increased the adsorbed Sb(V) in EPS and the c-type cytochrome content in AnGS, which may be beneficial for Sb(V) removal. Sb(V) reduction in Fe/C + S + Sb group may be related to the genus Acinetobacter, while in Sb group, several bacteria may be involved in Sb(V) reduction, such as Acinetobacter, Pseudomonas and Corynebacterium. This study provided insights into Fe/C-enhanced Sb(V) removal from sulfate-rich wastewater.

AKR1C3 in carcinomas: from multifaceted roles to therapeutic strategies.

Aldo-Keto Reductase Family 1 Member C3 (AKR1C3), also known as type 5 17ß-hydroxysteroid dehydrogenase (17ß-HSD5) or prostaglandin F (PGF) synthase, functions as a pivotal enzyme in androgen biosynthesis. It catalyzes the conversion of weak androgens, estrone (a weak estrogen), and PGD2 into potent androgens (testosterone and 5α-dihydrotestosterone), 17ß-estradiol (a potent estrogen), and 11ß-PGF2α, respectively. Elevated levels of AKR1C3 activate androgen receptor (AR) signaling pathway, contributing to tumor recurrence and imparting resistance to cancer therapies. The overexpression of AKR1C3 serves as an oncogenic factor, promoting carcinoma cell proliferation, invasion, and metastasis, and is correlated with unfavorable prognosis and overall survival in carcinoma patients. Inhibiting AKR1C3 has demonstrated potent efficacy in suppressing tumor progression and overcoming treatment resistance. As a result, the development and design of AKR1C3 inhibitors have garnered increasing interest among researchers, with significant progress witnessed in recent years. Novel AKR1C3 inhibitors, including natural products and analogues of existing drugs designed based on their structures and frameworks, continue to be discovered and developed in laboratories worldwide. The AKR1C3 enzyme has emerged as a key player in carcinoma progression and therapeutic resistance, posing challenges in cancer treatment. This review aims to provide a comprehensive analysis of AKR1C3's role in carcinoma development, its implications in therapeutic resistance, and recent advancements in the development of AKR1C3 inhibitors for tumor therapies.

CPT1A mediates the succinylation of SP5 which activates transcription of PDPK1 to promote the viability and glycolysis of prostate cancer cells.

Succinylation modification involves in the progression of human cancers. The present study aimed to investigate the role of CPT1A, which is a succinyltransferase in the progression of prostate cancer (PCa). CCK-8 was used to detect the cell viability. Seahorse was performed to evaluate the cell glycolysis. Luciferase assay was used to detect the transcriptional regulation. ChIP was performed to assess the binding between transcriptional factors with the promoters. Co-IP was used to assess the binding between proteins. We found that CPT1A was highly expressed in PCa tissues and cell lines. Silencing of CPT1A inhibited the viability and glycolysis of PCa cells. Mechanistically, CPT1A promoted the succinylation of SP5, which strengthened the binding between SP5 and the promoter of PDPK1. SP5 activated PDPK1 transcription and PDPK1 activated the AKT/mTOR signal pathway. These findings might provide novel targets for the diagnosis or therapy of prostate cancer.

Design, Synthesis, and Bioevaluation of Novel Reversibly Photoswitchable PI3K Inhibitors Based on Phenylazopyridine Derivatives toward Light-Controlled Cancer Treatment.

Photopharmacology is an emerging approach for achieving light-controlled drug activity. Herein, we design and synthesize a novel series of photoswitchable PI3K inhibitors by replacing a sulfonamide moiety with an azo group in a 4-methylquinazoline-based scaffold. Through structure-activity relationship studies, compound 6g is identified to be effectively switched between its trans- and cis-configuration under irradiation with proper wavelengths. Molecular docking studies show the cis-isomer of 6g is favorable to bind to the PI3K target, supporting compound 6g in the PSS365 (cis-isomer enriched) was more potent than that in the PSSdark (trans-isomer dominated) in PI3K enzymatic assay, cell antiproliferative assay, Western blotting analysis on PI3K downstream effectors, cell cycle analysis, colony formation assay, and wound-healing assay. Relative to the cis-isomer, the trans-isomer is more metabolically stable and shows good pharmacokinetic properties in mice. Moreover, compound 6g inhibits tumor growth in nude mice and a zebrafish HGC-27 xenograft model.

Modelling the dynamic basic reproduction number of dengue based on MOI of Aedes albopictus derived from a multi-site field investigation in Guangzhou, a subtropical region.

BACKGROUND: More than half of the global population lives in areas at risk of dengue (DENV) transmission. Developing an efficient risk prediction system can help curb dengue outbreaks, but multiple variables, including mosquito-based surveillance indicators, still constrain our understanding. Mosquito or oviposition positive index (MOI) has been utilized in field surveillance to monitor the wild population density of Aedes albopictus in Guangzhou since 2005. METHODS: Based on the mosquito surveillance data using Mosq-ovitrap collection and human landing collection (HLC) launched at 12 sites in Guangzhou from 2015 to 2017, we established a MOI-based model of the basic dengue reproduction number (R0) using the classical Ross-Macdonald framework combined with a linear mixed-effects model. RESULTS: During the survey period, the mean MOI and adult mosquito density index (ADI) using HLC for Ae. albopictus were 12.96 ± 17.78 and 16.79 ± 55.92, respectively. The R0 estimated from the daily ADI (ADID) showed a significant seasonal variation. A 10-unit increase in MOI was associated with 1.08-fold (95% CI 1.05, 1.11) ADID and an increase of 0.14 (95% CI 0.05, 0.23) in the logarithmic transformation of R0. MOI-based R0 of dengue varied by month and average monthly temperature. During the active period of Ae. albopictus from April to November in Guangzhou region, a high risk of dengue outbreak was predicted by the MOI-based R0 model, especially from August to October, with the predicted R0 > 1. Meanwhile, from December to March, the estimates of MOI-based R0 were < 1. CONCLUSIONS: The present study enriched our knowledge about mosquito-based surveillance indicators and indicated that the MOI of Ae. albopictus could be valuable for application in estimating the R0 of dengue using a statistical model. The MOI-based R0 model prediction of the risk of dengue transmission varied by month and temperature in Guangzhou. Our findings lay a foundation for further development of a complex efficient dengue risk prediction system.

Discovery of Natural Ah Receptor Antagonists from Salvia miltiorrhiza Bunge and Synthesis of Analogs for Tumor Immunotherapy.

IDO/TDO/Kyn/AhR signaling plays a crucial role in regulating innate and adaptive immunity, and targeting Ah receptor (AhR) inhibition can potentially redirect immune cells toward an antitumoral phenotype. Therefore, AhR is an attractive drug target for novel small molecule cancer immunotherapies. In this study, natural products tanshinolic A-D (1-4), the first adducts composed of ortho-naphthoquinone-type tanshinone and phenolic acid featuring a unique 1,4-benzodioxan hemiacetal structure, were isolated and characterized from the roots of Salvia miltiorrhiza Bunge. Luciferase reporter gene assay revealed that these adducts exhibited significant AhR inhibitory activity. A linear strategy was developed to construct a cis-3,4-disubstituted 1,4-benzodioxan hemiacetal structure. Encouragingly, in both in vitro and in vivo experiments, (±)-13e demonstrated the ability to inhibit tumor cell proliferation, promote INF-γ secretion in CD8+ T cells, and inhibit PD-1/PD-L1 signal transduction, which could exert tumor inhibition properties by inhibiting AhR activity, positioning it as a promising candidate for tumor immunotherapy.

Re-expression of epigenetically silenced PTPRR by histone acetylation sensitizes RAS-mutant lung adenocarcinoma to SHP2 inhibition.

Silenced protein tyrosine phosphatase receptor type R (PTPRR) participates in mitogen-activated protein kinase (MAPK) signaling cascades during the genesis and development of tumors. Rat sarcoma virus (Ras) genes are frequently mutated in lung adenocarcinoma, thereby resulting in hyperactivation of downstream MAPK signaling. However, the molecular mechanism manipulating the regulation and function of PTPRR in RAS-mutant lung adenocarcinoma is not known. Patient records collected from the Cancer Genome Atlas and Gene Expression Omnibus showed that silenced PTPRR was positively correlated with the prognosis. Exogenous expression of PTPRR suppressed the proliferation and migration of lung cancer cells. PTPRR expression and Src homology 2 containing protein tyrosine phosphatase 2 (SHP2) inhibition acted synergistically to control ERK1/2 phosphorylation in RAS-driven lung cancer cells. Chromatin immunoprecipitation assay revealed that HDAC inhibition induced enriched histone acetylation in the promoter region of PTPRR and recovered PTPRR transcription. The combination of the HDAC inhibitor SAHA and SHP2 inhibitor SHP099 suppressed the progression of lung cancer markedly in vitro and in vivo. Therefore, we revealed the epigenetic silencing mechanism of PTPRR and demonstrated that combination therapy targeting HDAC and SHP2 might represent a novel strategy to treat RAS-mutant lung cancer.

Rational design and optimization of novel 4-methyl quinazoline derivatives as PI3K/HDAC dual inhibitors with benzamide as zinc binding moiety for the treatment of acute myeloid leukemia.

Simultaneous inhibition of PI3K and HDAC has shown promise for treating various cancers, leading to discovery and development of their dual inhibitors as novel anticancer agents. Herein, we disclose a new series of PI3K/HDAC dual inhibitors bearing a benzamide moiety as the pharmacophore of HDAC inhibition. Based on systematic structure-activity relationship study, compounds 36 and 51 featuring an alkyl and benzoyl linker respectively were identified with favorable potencies against both PI3K and HDAC. In cellular assays, compounds 36 and 51 showed significantly enhanced antiproliferative activities against various cancer cell lines relative to single-target inhibitors. Furthermore, western blotting analysis shows compounds 36 and 51 suppressed AKT phosphorylation and increased H3 acetylation in MV4-11 cells, while flow cytometry analysis reveals both compounds dose-dependently induced cell cycle arrest and cell apoptosis. Supported by pharmacokinetic studies, compounds 36 and 51 were subjected to the in vivo evaluation in a MV4-11 xenograft model, demonstrating significant and dose-dependent anticancer efficacies. Overall, this work provides a promising approach for the treatment of AML by simultaneously inhibiting PI3K and HDAC with a dual inhibitor.

The spatiotemporal pattern of surface ozone and its impact on agricultural productivity in China.

The slowing of agricultural productivity growth globally over the past two decades has brought a new urgency to detect its drivers and potential solutions. We show that air pollution, particularly surface ozone (O3), is strongly associated with declining agricultural total factor productivity (TFP) in China. We employ machine learning algorithms to generate estimates of high-resolution surface O3 concentrations from 2002 to 2019. Results indicate that China's O3 pollution has intensified over this 18-year period. We coupled these O3 estimates with a statistical model to show that rising O3 pollution during nonwinter seasons has reduced agricultural TFP by 18% over the 2002-2015 period. Agricultural TFP is projected to increase by 60% if surface O3 concentrations were reduced to meet the WHO air quality standards. This productivity gain has the potential to counter expected productivity losses from 2°C warming.

ACAT1 deficiency in myeloid cells promotes glioblastoma progression by enhancing the accumulation of myeloid-derived suppressor cells.

Glioblastoma (GBM) is a highly aggressive and lethal brain tumor with an immunosuppressive tumor microenvironment (TME). In this environment, myeloid cells, such as myeloid-derived suppressor cells (MDSCs), play a pivotal role in suppressing antitumor immunity. Lipometabolism is closely related to the function of myeloid cells. Here, our study reports that acetyl-CoA acetyltransferase 1 (ACAT1), the key enzyme of fatty acid oxidation (FAO) and ketogenesis, is significantly downregulated in the MDSCs infiltrated in GBM patients. To investigate the effects of ACAT1 on myeloid cells, we generated mice with myeloid-specific (LyzM-cre) depletion of ACAT1. The results show that these mice exhibited a remarkable accumulation of MDSCs and increased tumor progression both ectopically and orthotopically. The mechanism behind this effect is elevated secretion of C-X-C motif ligand 1 (CXCL1) of macrophages (Mφ). Overall, our findings demonstrate that ACAT1 could serve as a promising drug target for GBM by regulating the function of MDSCs in the TME.

First report of branch dieback caused by Neoscytalidium dimidiatum on Styphnolobium japonicum (L.) Schott in China.

Styphnolobium japonicum (L.) Schott (family Fabaceae Juss.) also called pagoda tree, is widely planted in northern China in landscape plantings, for erosion control and forestry. In recent years, symptoms of branch dieback were observed on S. japonicum in the southern part of Xinjiang province, China. From 2019 to 2022, in total ca. 1000 ha area was surveyed in Korla (41.68°N, 86.06°E), Bohu (41.95°N, 86.53°E) and Alaer (41.15°N, 80.29°E). Typical symptoms were observed in 70% of the surveyed branches. To identify the cause, we collected 50 symptomatic branches. Symptoms were initially observed on green current-year twigs, which turned grayish white in color. In the later stages of disease development, a large number of nacked black conidia formed under epidermis of perennial branches, causing visible black protrusions (pycnidia) on branch surface. The disease occurred throughout the entire growing season of S. japonicum. Symptoms also occurred on the inflorescence, fruit, and twigs. In some cases, infection resulted in tree mortality. Isolations were made from the margin between healthy and diseased tissues. Small pieces were excised, surface disinfested (75% ethanol 30 s, 1% NaClO solution 5 mins), cut into pieces (5 to 10 mm2), and incubated on PDA medium at 28℃ for 3 days. A total of 16 isolates (GH01-GH16) with similar colony morphology were obtained. The colonies were initially white, gradually turning to olive-green on the surface and black on the underside after 7 days. Microscopically, the conidia were aseptate, 1-septate, two-septate, and muriform, 2.6-4.5 × 2.9-27.6 µm (n=50). Pycnidia ranged in size from 120.2 to 135.5 × 112.4 to 118.6 µm (n=20). Those morphological characters matched the descriptions of Neoscytalidium dimidiatum (previously N. novaehollandiae) (Alizadeh et al. 2022; Pavlic et al. 2008). For molecular identification, genomic DNA of GH01-GH16 were extracted from fresh mycelia. The internal transcribed spacer (ITS), large subunit ribosomal RNA gene (LSU), and translation elongation factor 1-alpha (EF1-α) gene were amplified using the primer sets ITS1/ITS4 (White 1990), LRoR/LR5 (Vilgalys and Hester 1990) and EF1-728F/EF1-986R (Carbone and Kohn 1999). The sequences were deposited in GenBank (accession No. OP379832, OQ096643-OQ096657 for ITS, OP389048, OQ127403-OQ127417 for LSU, and OQ136617, OQ586044-OQ586058 for EF1-α). The ITS sequence had 100% identity (505/505 bp) to MT362600. Similarly, the LSU and EF1-α sequences were found to be identical to MW883823 (100%, 821/821 bp) and KX464763(99%, 256/258 bp), respectively. Pathogenicity was tested on one-year-old healthy S. japonicum seedlings. Spores of representative isolate GH01 were produced on PDA by incubating for 7-days at 28℃. Conidia were washed with sterile water. Five trees were inoculated with 1 × 106 conidia/ml conidial suspensions and five trees were sprayed with sterile water. All trees were covered with plastic bags for 24 h and kept at 25°C in a greenhouse. Signs and symptoms were similar to those observed in field collections one month after inoculation, while no symptoms occurred on the controls. The original fungus was successfully reisolated from the inoculated trees and was identified as N. dimidiatum following the methods described above. N. dimidiatum has been reported in many Asian country such as Malaysia, India, Turkey, and Iran(Akgül et al. 2019; Alizadeh et al. 2022; Khoo et al. 2023; Salunkhe et al. 2023). To our knowledge, this is the first report of N. dimidiatum associated with branch dieback of S. japonicum in China. Our findings have expanded the host range of N. dimidiatum in China and provides a theoretical basis for the diagnosis and treatment of the disease.

Hydrangea paniculata coumarins attenuate experimental membranous nephritis by bidirectional interactions with the gut microbiota.

Coumarins isolated from Hydrangea paniculata (HP) had a renal protective effect in experimental membranous nephritis (MN), but the mechanisms are not clear. Currently, we investigate whether the modulation of gut dysbiosis by HP contributes to its renal protection. Experimental MN rats were treated with HP for six weeks. Fecal 16S rDNA sequencing and metabolomics were performed. Fecal microbiota transplantation (FMT) was used for the evaluation study. The results demonstrate that deteriorated renal function and gut dysbiosis are found in MN rats, as manifested by a higher Firmicutes/Bacteroidetes ratio and reduced diversity and richness, but both changes were reversed by HP treatment. Reduced gut dysbiosis is correlated with improved colonic integrity and lower endotoxemia in HP-treated rats. HP normalized the abnormal level of fecal metabolites by increasing short-chain fatty acid production and hindering the production of uremic toxin precursors. FMT of HP-treated feces to MN animals moderately reduced endotoxemia and albuminuria. Moreover, major coumarins in HP were only biotransformed into more bioactive 7-hydroxycoumarin by gut microbiota, which strengthened the effect of HP in vivo. Depletion of the gut microbiota partially abolished its renal protective effect. In conclusion, the bidirectional interaction between HP and the gut microbiota contributes to its beneficial effect.

Discovery of Quinazoline-2,4(1H,3H)-dione Derivatives Containing a Piperizinone Moiety as Potent PARP-1/2 Inhibitors─Design, Synthesis, In Vivo Antitumor Activity, and X-ray Crystal Structure Analysis.

PARP-1/2 inhibitors have become an important therapeutic strategy for the treatment of HR-deficient tumors. However, discovery of new inhibitors with an improved and distinct pharmacological file still need enormous explorations. Herein, a series of novel highly potent PARP-1/2 inhibitors bearing an N-substituted piperazinone moiety were achieved. In particular, Cpd36 was identified as a distinct PARP inhibitor, showing remarkable enzymatic activity not only toward PARP-1 (IC50 = 0.94 nM) and PARP-2 (IC50 = 0.87 nM) but also toward PARP-7 (IC50 = 0.21 nM), as well as high selectivity over other PARP isoforms. Furthermore, Cpd36 was orally bioavailable and significantly repressed the tumor growth in both breast cancer and prostate cancer xenograft model. The crystal structures of Cpd36 within PARP-1 and PARP-2 together with the predicted binding mode within PARP-7 revealed its binding features and provided insightful information for further developing highly potent and selective PARP-1 and/or PARP-7 inhibitors.

Targeting the Subpocket Enables the Discovery of Thiadiazole-Pyridazine Derivatives as Glutaminase C Inhibitors.

As glutaminase C (GAC) has become an attractive target for cancer treatment by regulating glutaminolysis, thus, interest in GAC inhibitors has risen in recent years. Herein, a potential binding subpocket comprising basic residues was identified, and through extensive structure-activity relationship studies, promising inhibitors 11 and 39 were identified with robust GAC inhibitory activity and A549 cell antiproliferative activity. X-ray crystallography of the 11-GAC and 27-GAC complexes revealed a novel binding mode against GAC. The potency of 11 and 27 against GACK320A further highlighted the importance of the binding. Notably, compounds 11 and 39 regulated the cellular metabolite, thereby increasing reactive oxygen species by blocking glutamine metabolism. Compound 11 also exhibited excellent antiproliferative activity in the A549 cell xenograft model. We further proved that 11 is a safe GAC allosteric inhibitor. A basic subpocket is proposed that might provide new strategies for the development of novel GAC inhibitors in the future.

Biological treatment processes for saline organic wastewater and related inhibition mechanisms and facilitation techniques: A comprehensive review.

Owing to its profound pollution-inducing properties and resistance to biodegradation, saline organic wastewater (SOW) has unavoidably emerged as a predominant focal point within the wastewater treatment domain. Substantial quantities of SOW are discharged by diverse industries encompassing food processing, pharmaceuticals, leather manufacturing, petrochemicals, and textiles. Within this review, the inhibitory repercussions of elevated salinity upon biological water treatment systems are subject to methodical scrutiny spanning from sludge characteristics, microbial consortia to the physiological functionality of microorganisms have been investigated. This exposition elucidates the application of both anaerobic and aerobic biological technologies for SOW treatment, which noting that conventional bioreactors can effectually treat SOW through microbial adaptation, and elaborating that cultivation of salt-tolerant bacteria and the design of advanced bioreactors represents a promising avenue for SOW treatment. Furthermore, the mechanisms underpinning microbial acclimatization to hypersaline milieus and the methodologies aimed at amplifying the efficacy of biological SOW treatment are delved into, which point out that microorganism exhibit salt tolerance via extracellular polymeric substance accumulation or by facilitating the influx of osmolarity-regulating agents into the bacterial matrix. Finally, the projections for future inquiry are proffered, encompassing the proliferation and deployment of high salt-tolerant strains, as well as the development of techniques enhancing the salt tolerance of microflora engaged in wastewater treatment.

Unleashing the efficacy of immune checkpoint inhibitors for advanced hepatocellular carcinoma: factors, strategies, and ongoing trials.

Hepatocellular carcinoma (HCC) is a prevalent primary liver cancer, representing approximately 85% of cases. The diagnosis is often made in the middle and late stages, necessitating systemic treatment as the primary therapeutic option. Despite sorafenib being the established standard of care for advanced HCC in the past decade, the efficacy of systemic therapy remains unsatisfactory, highlighting the need for novel treatment modalities. Recent breakthroughs in immunotherapy have shown promise in HCC treatment, particularly with immune checkpoint inhibitors (ICIs). However, the response rate to ICIs is currently limited to approximately 15%-20% of HCC patients. Recently, ICIs demonstrated greater efficacy in "hot" tumors, highlighting the urgency to devise more effective approaches to transform "cold" tumors into "hot" tumors, thereby enhancing the therapeutic potential of ICIs. This review presented an updated summary of the factors influencing the effectiveness of immunotherapy in HCC treatment, identified potential combination therapies that may improve patient response rates to ICIs, and offered an overview of ongoing clinical trials focusing on ICI-based combination therapy.

The dynamics of deltamethrin resistance evolution in Aedes albopictus has an impact on fitness and dengue virus type-2 vectorial capacity.

BACKGROUND: Worldwide invasion and expansion of Aedes albopictus, an important vector of dengue, chikungunya, and Zika viruses, has become a serious concern in global public health. Chemical insecticides are the primary means currently available to control the mosquito populations. However, long-term and large-scale use of insecticides has selected for resistance in the mosquito that is accompanied by a genetic load that impacts fitness. RESULTS: A number of laboratory strains representing different resistance mechanisms were isolated and identified from laboratory-derived, deltamethrin-resistant Ae. albopictus recovered in previous work. Resistance levels and fitness costs of the strains were evaluated and compared to characterize the evolution of the resistance genotypes and phenotypes. The heterozygous F1534S mutation (1534F/S) in the voltage gated sodium channel (vgsc) gene product (VGSC), first detected in early stages of resistance evolution, not only confers high-level resistance, but also produces no significant fitness costs, leading to the rapid spread of resistance in the population. This is followed by the increase in frequency of homozygous F1534S (1534S/S) mosquitoes that have significant fitness disadvantages, prompting the emergence of an unlinked I1532T mutation with fewer side effects and a mating advantage better adapted to the selection and reproductive pressures imposed in the experiments. Metabolic resistance with no significant fitness cost and mediating a high-tolerance resistance phenotype may play a dominant role in the subsequent evolution of resistance. The different resistant strains had similar vector competence for dengue virus type-2 (DENV-2). Furthermore, a comparative analysis of vectorial capacity revealed that increased survival due to deltamethrin resistance balanced the negative fitness cost effects and contributed to the risk of dengue virus (DENV) transmission by resistant populations. The progressive evolution of resistance results in mosquitoes with both target-site insensitivity and metabolic resistance with lower fitness costs, which further leads to resistant populations with both high resistance levels and vectorial capacity. CONCLUSIONS: This study reveals a possible mechanism for the evolution of deltamethrin resistance in Aedes albopictus. These findings will help guide practical strategies for insecticide use, resistance management and the prevention and control of mosquito-borne disease.

Design, synthesis, and biological evaluation of novel bivalent PI3K inhibitors for the potential treatment of cancer.

Phosphatidylinositol 3-kinase (PI3K) signaling is among the most common alterations in cancer and has become a key target for cancer drug development. Based on a 4-methyl quinazoline scaffold, we designed and synthesized a novel series of bivalent PI3K inhibitors with different linker lengths and types. Bivalent PI3K inhibitor 27 demonstrates improved PI3K potency and antiproliferative cell activity, relative to the corresponding monovalent inhibitor 11. Compound 27 also significantly blocks the PI3K signal pathway, induces cell cycle arrest in G1 phase, and inhibits colony formation and cell migration. Furthermore, compound 27 shows dose-dependent anticancer efficacies in a HGC-27 xenograft mice model. Overall, this work provides a possible strategy to discover novel PI3K inhibitors for the treatment of cancers.