Peptide-Mediated Small Molecule Lysosome-Targeting Chimeras for Targeted Degradation of Membrane and Intracellular Proteins.

Targeted protein degradation through the lysosomal pathway has attracted increasing attention and expanded the scope of degradable proteins. However, the endogenous lysosomal degradation strategies are mainly based on antibodies or nanobodies. Effective small molecule lysosomal degraders are still rather rare. Herein, a new lysosomal degradation approach, termed peptide-mediated small molecule lysosome-targeting chimeras (PSMLTACs), was developed by the incorporation of small molecule ligands with a lysosome-sorting NPGY motif containing the cell-penetrating peptide. PSMLTACs were successfully applied to degrade both membrane and intracellular targets. In particular, the PSMLTAC strategy demonstrated higher degradation efficiency on membrane target PD-L1 and intracellular target PDEδ than corresponding PROTAC degraders. Taken together, this proof-of-concept provides a convenient and effective strategy for targeted protein degradation.

CaCO3-Encapsulated polydopamine with an adsorbed TLR7 agonist for improved tumor photothermal immunotherapy.

Because of the tumor's recurrence and significant metastasis, the standard single-therapy paradigm has failed to meet clinical requirements. Recently, researchers have focused their emphasis on phototherapy and immunogenic cell death (ICD) techniques. In response to the current problems of immunotherapy, a multifunctional drug delivery nanosystem (PDA-IMQ@CaCO3-blinatumomab, PICB) was constructed by using high physiological compatibility of polydopamine (PDA) and calcium carbonate (CaCO3). Toll-like receptor 7 (TLR7) agonist imiquimod (IMQ) and bispecific antibody (BsAb) blinatumomab were loaded onto PDA-CaCO3 nanoparticles (NPs). The findings revealed that the system exhibited the advantages of good dispersion, high stability, excellent physiological compatibility, low toxicity, and high drug loading rate. Compared to the control group, it resulted in a 2.4-fold decrease in FOXP3+ regulatory T-cells within the tumor and a 5.0-fold increase in CD4+ effector T-cells, and promoted the production of damage-related molecular patterns to reinvigorate the ICD effect. PICB had a strong inhibitory effect on tumor growth in 4T1 tumor-bearing mice, and has no toxicity to other organs. Therefore, the multifunctional drug delivery nanosystem constructed in this study could effectively exert the properties of various components in vivo, fully demonstrate the synergistic effect between immunotherapy and photothermal therapy, thus significantly improving the tumor therapeutic efficacy, and has a promising clinical application.

Construction and synergistic anti-tumor study of a tumor microenvironment-based multifunctional nano-drug delivery system.

To solve the problems existing in the clinical application of hypericin (Hyp) and tirapazamine (TPZ), a nano-drug delivery system with synergistic anti-tumor functions was constructed using mesoporous silica nanoparticles (MSN) and sodium alginate (SA). The system exhibited excellent stability, physiological compatibility and targeted drug release performance in tumor tissues. In the in vitro and in vivo experiments, Hyp released from MSN killed tumor cells through photodynamic therapy (PDT). The degree of hypoxia in the tumor tissue site was exacerbated, enabling TPZ to fully exert its anti-tumor activity. Our studies suggested that the synergistic effects between the components of the nano-drug delivery system significantly improve the anti-tumor properties of Hyp and TPZ.

PTEN inhibition enhances sensitivity of ovarian cancer cells to the poly (ADP-ribose) polymerase inhibitor by suppressing the MRE11-RAD50-NBN complex.

BACKGROUND: Poly (ADP-ribose) polymerase inhibitors (PARPis) can effectively treat ovarian cancer patients with defective homologous recombination (HR). Loss or dysfunction of PTEN, a typical tumour suppressor, impairs double-strand break (DSB) repair. Hence, we explored the possibility of inhibiting PTEN to induce HR deficiency (HRD) for PARPi application. METHODS: Functional studies using PTEN inhibitor VO-OHpic and PARPi olaparib were performed to explore the molecular mechanisms in vitro and in vivo. RESULTS: In this study, the combination of VO-OHpic with olaparib exhibited synergistic inhibitory effects on ovarian cancer cells was demonstrated. Furthermore, VO-OHpic was shown to enhance DSBs by reducing nuclear expression of PTEN and inhibiting HR repair through the modulation of MRE11-RAD50-NBN (MRN) complex, critical for DSB repair. TCGA and GTEx analysis revealed a strong correlation between PTEN and MRN in ovarian cancer. Mechanistic studies indicated that VO-OHpic reduced expression of MRN, likely by decreasing PTEN/E2F1-mediated transcription. Moreover, PTEN-knockdown inhibited expression of MRN, increased sensitivities to olaparib, and induced DSBs. In vivo experiments showed that the combination of VO-OHpic with olaparib exhibited enhanced inhibitory effects on tumour growth. CONCLUSIONS: Collectively, this study highlights the potential of PTEN inhibitors in combination therapy with PARPis to create HRD for HRD-negative ovarian cancers.

The Protective Role of Transcript-Induced in Spermiogenesis 40 in Cerebral Ischemia-Reperfusion Injury.

Prompt reperfusion after cerebral ischemia is important to maintain neuronal survival and reduce permanent disability and death. However, the resupply of blood can induce oxidative stress, inflammatory response and apoptosis, further leading to tissue damage. Here, we report the versatile biological roles of transcript-induced in spermiogenesis 40 (Tisp40) in ischemic stroke. We found that the expression of Tisp40 was upregulated in ischemia/reperfusion-induced brain tissues and oxygen glucose deprivation/returned -stimulated neurons. Tisp40 deficiency increased the infarct size and neurological deficit score, and promoted inflammation and apoptosis. Tisp40 overexpression played the opposite role. In vitro, the oxygen glucose deprivation/returned model was established in Tisp40 knockdown and overexpression primary cultured cortical neurons. Tisp40 knockdown can aggravate the process of inflammation and apoptosis, and Tisp40 overexpression ameliorated the aforementioned processes. Mechanistically, Tisp40 protected against ischemic stroke via activating the AKT signaling pathway. Tisp40 may be a new therapeutic target in brain ischemia/reperfusion injury.

A multi-functional drug delivery nanosystem release of TLR-7 immunostimulant and OKT3 induced efficient cancer immunotherapy.

Immunotherapy has some shortcomings such as off-target toxicity, treatment time and poor immunogenicity, which limit its therapeutic effect. Nanomaterials are particularly attractive in immunotherapy due to their drug delivery capabilities. Nano drug delivery system loaded with Toll-like receptor (TLR) agonist imiquimod (IMQ) and CD3 immune antibody OKT3 is constructed by using polydopamine (PDA) and CaCO3. While PDA-IMQ@CaCO3-OKT3 (PICO NPs) drug delivery system has the advantages of high biocompatibility, low toxicity, degradability. Antitumor studies in vitro and in vivo have shown that the system can effectively inhibit the proliferation of mouse breast cancer cells and the activity of Regulatory T Cells (Tregs), activate immunogenic cell death (ICD), and enhance the activity of antigen-presenting cells (APCs). Effectively eliminate tumor immunosuppression and fully activate immune function.

TBC1D25 alleviates nonalcoholic steatohepatitis by inhibiting abnormal lipid accumulation and inflammation.

Nonalcoholic fatty liver disease (NAFLD) is a strong stimulant of cardiovascular diseases, affecting one-quarter of the world's population. TBC1 domain family member 25 (TBC1D25) regulates the development of myocardial hypertrophy and cerebral ischemia-reperfusion injury; however, its effect on NAFLD/nonalcoholic steatohepatitis (NASH) has not been reported. In this study, we demonstrated that TBC1D25 expression is upregulated in NASH. TBC1D25 deficiency aggravated hepatic steatosis, inflammation, and fibrosis in NASH. In vitro tests revealed that TBC1D25 overexpression restrained NASH responses. Subsequent mechanistic validation experiments demonstrated that TBC1D25 interfered with NASH progression by inhibiting abnormal lipid accumulation and inflammation. TBC1D25 deficiency significantly promoted NASH occurrence and development. Therefore, TBC1D25 may potentially be used as a clinical therapeutic target for NASH treatment.

The rising death burden of atrial fibrillation and flutter in low-income regions and younger populations.

Objective: The aim of the study was to depict the global death burden of atrial fibrillation and/or flutter (AFF) between 1990 and 2019 and predict this burden in the next decade. Methods: We retrieved annual death data on cases and rates of AFF between 1990 and 2019 from the Global Burden of Disease (GBD) Study 2019 and projected the trends for 2020-2029 by developing the Bayesian age-period-cohort model. Results: The global number of deaths from AFF increased from 117,038.00 in 1990 to 315,336.80 in 2019. This number is projected to reach 404,593.40 by 2029. The age-standardized mortality rates (ASMRs) of AFF have increased significantly in low- to middle-sociodemographic index (SDI) regions, which will surpass that in high SDI regions and reach above 4.60 per 100,000 by 2029. Globally, women have a higher ASMR than men, which is largely attributed to disproportionately higher mortality in women than men in lower SDI regions. Notably, AFF-related premature mortality continues to worsen worldwide. A pandemic of high systolic blood pressure and high body mass index (BMI) largely contributes to AFF-associated death. In particular, low- to middle-SDI regions and younger populations are increasingly affected by the rapidly growing current and future risk of high BMI. Conclusion: The global death burden of AFF in low-income countries and younger generations have not been sufficiently controlled in the past and will continue growing in the future, which is largely attributed to metabolic risks, particularly for high BMI. There is an urgent need to implement effective measures to control AFF-related mortality.

Energy substrate metabolism and oxidative stress in metabolic cardiomyopathy.

Metabolic cardiomyopathy is an emerging cause of heart failure in patients with obesity, insulin resistance, and diabetes. It is characterized by impaired myocardial metabolic flexibility, intramyocardial triglyceride accumulation, and lipotoxic damage in association with structural and functional alterations of the heart, unrelated to hypertension, coronary artery disease, and other cardiovascular diseases. Oxidative stress plays an important role in the development and progression of metabolic cardiomyopathy. Mitochondria are the most significant sources of reactive oxygen species (ROS) in cardiomyocytes. Disturbances in myocardial substrate metabolism induce mitochondrial adaptation and dysfunction, manifested as a mismatch between mitochondrial fatty acid oxidation and the electron transport chain (ETC) activity, which facilitates ROS production within the ETC components. In addition, non-ETC sources of mitochondrial ROS, such as ß-oxidation of fatty acids, may also produce a considerable quantity of ROS in metabolic cardiomyopathy. Augmented ROS production in cardiomyocytes can induce a variety of effects, including the programming of myocardial energy substrate metabolism, modulation of metabolic inflammation, redox modification of ion channels and transporters, and cardiomyocyte apoptosis, ultimately leading to the structural and functional alterations of the heart. Based on the above mechanistic views, the present review summarizes the current understanding of the mechanisms underlying metabolic cardiomyopathy, focusing on the role of oxidative stress.

Canalized gene expression during development mediates caste differentiation in ants.

Ant colonies are higher-level organisms consisting of specialized reproductive and non-reproductive individuals that differentiate early in development, similar to germ-soma segregation in bilateral Metazoa. Analogous to diverging cell lines, developmental differentiation of individual ants has often been considered in epigenetic terms but the sets of genes that determine caste phenotypes throughout larval and pupal development remain unknown. Here, we reconstruct the individual developmental trajectories of two ant species, Monomorium pharaonis and Acromyrmex echinatior, after obtaining >1,400 whole-genome transcriptomes. Using a new backward prediction algorithm, we show that caste phenotypes can be accurately predicted by genome-wide transcriptome profiling. We find that caste differentiation is increasingly canalized from early development onwards, particularly in germline individuals (gynes/queens) and that the juvenile hormone signalling pathway plays a key role in this process by regulating body mass divergence between castes. We quantified gene-specific canalization levels and found that canalized genes with gyne/queen-biased expression were enriched for ovary and wing functions while canalized genes with worker-biased expression were enriched in brain and behavioural functions. Suppression in gyne larvae of Freja, a highly canalized gyne-biased ovary gene, disturbed pupal development by inducing non-adaptive intermediate phenotypes between gynes and workers. Our results are consistent with natural selection actively maintaining canalized caste phenotypes while securing robustness in the life cycle ontogeny of ant colonies.

The method for termination of mid-trimester pregnancy with placenta previa: A case study.

BACKGROUND: Prenatal bleeding is very dangerous for pregnant women with placenta previa during termination of pregnancy in the mid-trimester. Traditionally, cesarean section or hysterectomy is used to stop bleeding. This study aims to investigate the method for termination of mid-trimester pregnancy with placenta previa, especially emergency uterine artery embolization (UAE) combined with cervical double balloon (CDB). METHODS: A retrospective study was conducted based on 261 cases of mid-pregnancy termination in our hospital, where 34 cases with placenta previa were set as the observation group, and the remaining 227 cases were set as control group. At first, the termination method of Mifepristone combined with Misoprostol/Ethacridine Lactate was adopted. If the volume of prenatal bleeding was up to 400 mL, emergency uterine artery embolization (UAE) was implemented to stop bleeding, then cervical double balloon (CDB) was used to promote cervical ripening. Receiver operating characteristic (ROC) curves analysis was performed to assess the accuracy in predicting the length of placental edge crossed the cervical os for prenatal bleeding. RESULTS: The number of gravidity/parities, the rate of cesarean section, the medical cost, the rate of previous cesarean section were all higher in the observation group than in the control group (P < .05). The volume of prenatal hemorrhage, postpartum hemorrhage, the rate of puerperal morbidity, emergency UAE rate and ICU rate were higher in the observation group than in the control group (P < .05). There were 4 cases showing prenatal hemorrhage up to 400 mL and undergoing emergency UAE + CDB in the observation group, while there were no such cases in the control group (P < .05). An optimal cut-off value of 1.7cm for the length of placental edge crossed the cervical os in diagnosing prenatal hemorrhage demonstrated sensitivity and specificity of 75.0% and 86.7%, respectively (area under the ROC curve, 0.858). CONCLUSION: The combined therapy of mifepristone and Misoprostol/Ethacridine Lactate was useful for termination of mid-trimester pregnancy with placenta previa, and attention needs to be attached to prenatal hemorrhage during labor induction. Emergency UAE + CDB is a good combination method to treat prenatal hemorrhage and promote cervical ripening during the induction.

A Dual Functional Drug Delivery System that Combines Photothermal Therapy and Immunotherapy to Treat Tumors.

Cancer is one of the main diseases threatening human health. Immunotherapy, in which cancer is treated by activating immune cells and inducing the body's immune response, has rapidly developed. Photothermal therapy (PTT), a new treatment method that ablates tumors by light irradiation, has attracted great attention for its good therapeutic effect and low toxic side effects. In the present study, we combined photothermal and immunotherapy to design a novel nanoparticle delivery system by loading indoleamine 2,3-dioxygenase (IDO) inhibitors and toll-like receptor (TLR) agonists into polydopamine (PDA) nanoparticles coated with polyethylene imine (PEI). This delivery system has the advantages of high homogeneity, good stability, excellent biocompatibility, and low toxicity. In vitro antitumor studies showed that the system effectively inhibited the proliferation of mouse breast carcinoma cells and induced cell apoptosis. From the in vivo studies, we found that the system inhibited the growth of mouse breast carcinoma, facilitated the maturation of antigen-presenting cells, promoted T lymphocyte differentiation, and induced the body's immune response. The present study developed a dual functional drug delivery system combining photothermal therapy and immunotherapy to efficiently improve antitumor therapy with potential clinical application.

Electrochemical oxidation of copper-clad laminate for manufacturing printed circuit boards via bioleaching by the fungus Phanerochaete chrysosporium.

The leaching and electrochemical oxidation of the copper-clad laminate for manufacturing printed circuit boards were investigated in systems with and without the fungus P. chrysosporium, which yielded the copper-leaching efficiencies of 54% and 7.0%, respectively. In particular, the formation of a biofilm on the electrode surface reduced the open-circuit potential and increased the corrosion level, and the degree of increase and the rate of change of the current density in the fungal leaching system were higher than those of the sterile system. In addition, the cyclic voltammetry curves showed oxidation peaks that correspond to the oxidation of Cu to Cu2+. Further, for the fungal leaching system, the peak potential was highly negative and the curve area and peak current density were relatively high. Moreover, the electrochemical polarization parameters and the impedance characteristics were affected by the fungus, and the leaching systems were controlled by charge transfer and diffusion. In summary, P. chrysosporium can accelerate the leaching of copper as a result of the formation of extracellular electron transfer-induced microbiologically influenced corrosion (EET-MIC) and metabolite-induced microbiologically influenced corrosion (M-MIC). The enzymes and organic acids, which act as fungal metabolites, participate in the leaching of copper.

Spot 42 RNA regulates putrescine catabolism in Escherichia coli by controlling the expression of puuE at the post-transcription level.

Putrescine, a typical polyamine compound important for cell growth and stress resistance, can be utilized as an energy source. However, the regulation of its catabolism is unclear. Here the small RNA (sRNA) Spot 42, an essential regulator of carbon catabolite repression (CCR), was confirmed to participate in the post-transcriptional regulation of putrescine catabolism in Escherichia coli. Its encoding gene spf exclusively exists in the γ-proteobacteria and contains specific binding sites to the 5'-untranslated regions of the puuE gene, which encodes transaminase in the glutamylated putrescine pathway of putrescine catabolism converting γ-aminobutyrate (GABA) into succinate semialdehyde (SSA). The transcription of the spf gene was induced by glucose, inhibited by putrescine, and unaffected by PuuR, the repressor of puu genes. Excess Spot 42 repressed the expression of PuuE significantly in an antisense mechanism through the direct and specific base-pairing between the 51`-57 nt of Spot 42 and the 5'-UTR of puuE. Interestingly, Spot 42 mainly influenced the stability of the puuCBE transcript. This work revealed the regulatory role of Spot 42 in putrescine catabolism, in the switch between favorable and non-favorable carbon source utilization, and in the balance of metabolism of carbon and nitrogen sources.

Trends in cesarean delivery rates in primipara and the associated factors.

BACKGROUND: Few studies have focused on cesarean delivery (CD) trends among primipara under the one-child and the two-child policies. This study aimed to explore the trends in CD rates among primipara during 1995-2019 and the associated factors with CD risk. METHODS: This study obtained clinical data on primiparous mothers and newborns from 1995 to 2019 at a large tertiary hospital in Wuhan, China. Trends in CD rates were calculated using the joinpoint regression analysis. The Chi-square tests and log-binomial regression analyses were used to evaluate the associations between primary variables and CD risk. RESULTS: CD rates showed a significant upward trend with an average annual percentage change (APC) of 2.2% (95% CI: 0.6, 3.8%) during the study period. In 1995-2006, the CD rates continued to increase with an APC of 7.8% (95% CI: 4.8, 10.9%). After 2006, the CD rates started to decline by an APC of - 4.1% (95% CI: - 5.5, - 2.6%). The CD rates non-significantly increased from 36.2% in 2016 to 43.2% in 2019. Moreover, the highest CD rate during 2015-2019 was observed on August 30 (59.2%) and the lowest on September 1 (29.7%). Primipara of older age and those with >3pregnancies had higher risks of CD. Furthermore, primipara who gave birth to newborns with low birth weight and macrosomia had higher risks of CD. CONCLUSIONS: Maternal and fetal as well as social and cultural factors may contribute to the rising trend of CD rates. Effective measures should be taken to control CD under the two-child policy, especially for primipara.

Acute fatty liver of pregnancy cases in a maternal and child health hospital of China: Three case reports.

RATIONALE: Acute fatty liver of pregnancy (AFLP) is extremely hazardous to pregnant woman in the 3rd trimester of pregnancy. AFLP has an insidious onset and nonspecific experimental indicators, which therefore is difficult to be diagnosed. PATIENT CONCERNS: Case 1 was transferred to our hospital for hypertensive disorders complicating pregnancy at gestation of 38 weeks + 3 days. Case 2 was transferred to our hospital for suspicious fetal heart monitoring response at gestation of 36 weeks + 4 days. Case 3 was transferred to our hospital for prelabor rupture of membranes at gestation of 37 weeks + 1 days. DIAGNOSIS: The diagnosis of AFLP was based on the Swansea criteria. INTERVENTIONS: All 3 cases were delivered by cesarean section, and they were all transferred to intensive care unit for further treatment. Cases 2 and 3 were subjected to plasma exchange and continuous renal replacement therapy. OUTCOMES: In this study, all 3 patients were initially diagnosed as gastritis. In addition, case 1 was diagnosed as preeclampsia and her AFLP was misdiagnosed with postpartum hemorrhage after cesarean delivery. Case 2 was admitted to the hospital for intrahepatic cholestasis of pregnancy and fetal distress, but we considered it as AFLP before delivery. Case 3 was treated according to severe intrahepatic cholestasis of pregnancy, but we rediagnosed it as postpartum hemorrhage and disseminated intravascular coagulation after cesarean delivery. Neonatal asphyxia and complications were not found. All of the 3 cases were fully recovered and discharged from our hospital. LESSONS: If there are multiple risk factors including vomiting, abdominal pain, and fetal distress, AFLP should be highly suspected. Early diagnosis, especially before termination of pregnancy, is the key to successful treatment of AFLP.

Perinatal Depression of Exposed Maternal Women in the COVID-19 Pandemic in Wuhan, China.

Objective: This study aims to investigate perinatal depression in women who gave birth during the COVID-19 pandemic in Wuhan, and to evaluate the effect of the pandemic on perinatal depression prevalence. Methods: A cross-sectional investigation was conducted into women hospitalized for delivery in Hubei Maternity and Child Healthcare Hospital from December 31, 2019 to March 22, 2020, a period which encompasses the entire time frame of the COVID-19 pandemic in Wuhan. The Edinburgh Postnatal Depression Scale (EPDS) was adopted to evaluate perinatal depression status. A Chi-square test and logistic regression model were utilized for data analysis. Results: A total of 2,883 participants were included, 33.71% of whom were found to suffer from depressive symptoms. In detail, 27.02%, 5.24%, and 1.46% were designated as having mild, moderate, and severe depressive symptoms, respectively. The perinatal depression prevalence increased as the COVID-19 pandemic worsened. Compared to the period from December 31, 2019 to January 12, 2020, perinatal depression risk significantly decreased within the 3 weeks of March 2-22, 2020 (1st week: OR = 0.39, 95% CI: 0.20, 0.78; 2nd week: OR = 0.35, 95% CI: 0.17, 0.73; and 3rd week: OR = 0.48, 95% CI: 0.25, 0.94); and the postnatal depression risk significantly rose within the four weeks of January 27-February 23, 2020 (1st week: OR = 1.78, 95% CI: 1.18, 2.68; 2nd week: OR = 2.03, 95% CI: 1.35, 3.04; 3rd week: OR = 1.48, 95% CI: 1.02, 2.14; and 4th week: OR = 1.73, 95% CI: 1.20, 2.48). Conclusion: The dynamic change of perinatal depression was associated with the progression of the COVID-19 pandemic among new mothers who were exposed to the pandemic. An elevated risk of postnatal depression was also observed during the COVID-19 pandemic.

One-pot synthesis and characterization of ovalbumin-conjugated gold nanoparticles: A comparative study of adjuvanticity against the physical mixture of ovalbumin and gold nanoparticles.

Only few adjuvants are licensed for use in humans and there is a need to develop safe and improved vaccine adjuvants. In this study, we report the one-pot synthesis of antigen ovalbumin (OVA)-conjugated gold nanoparticles (OVA@GNPs). A systematical study was performed by comparing OVA@GNPs with the simple mixture of OVA and gold nanoparticles (OVA+GNPs), including their physiochemical properties through spectrometric and electrophoretic analysis, in vitro stability, cytotoxicity and cellular uptake, and in vivo humoral immune responses following subcutaneous and transcutaneous immunization in mice. The results demonstrate a much stronger interaction between protein and GNPs in OVA@GNPs than OVA+GNPs, which makes OVA@GNPs more stable under in vitro conditions than OVA+GNPs with the ability to induce 4 times higher OVA-specific serum IgG titers following subcutaneous immunization. We also show the dose sparing of OVA@GNPs, as the dosage for aluminum adjuvant required to reach to an equivalent OVA-specific antibody titer was almost five times higher than OVA@GNPs. However, we found that the co-administration of small-sized GNPs had a limited ability for the transcutaneous delivery of OVA. These results demonstrate the potential application of one-pot synthesis approach for producing antigen protein-conjugated gold nanoparticles for vaccine delivery.

NOD-like receptor signaling in inflammation-associated cancers: From functions to targeted therapies.

BACKGROUND: Recently, many studies have reported that some botanicals and natural products were able to regulate NOD-like receptor signaling. NOD-like receptors (NLRs) have been established as crucial regulators in inflammation-associated tumorigenesis, angiogenesis, cancer cell stemness and chemoresistance. NLRs specifically sense pathogen-associated molecular patterns and respond by activating other signaling regulators, including Rip2 kinase, NF-κB, MAPK and ASC/caspase-1, leading to the secretion of various cytokines. PURPOSE: The aim of this article is to review the molecular mechanisms of NOD-like receptor signaling in inflammation-associated cancers and the NLRs-targeted botanicals and synthetic small molecules in cancer intervention. RESULTS: Aberrant activation of NLRs occurs in various cancers, orchestrating the tissue microenvironment and potentiating neoplastic risk. Blocking NLR inflammasome activation by botanicals or synthetic small molecules may be a valuable way to prevent cancer progression. Moreover, due to the roles of NLRs in regulating cytokine production, NLR signaling may be correlated with senescence-associated secretory phenotype. CONCLUSION: In this review, we discuss how NLR signaling is involved in inflammation-associated cancers, and highlight the NLR-targeted botanicals and synthetic small molecules in cancer intervention.

Poly (ADP-ribose) polymerase inhibitors combined with other small-molecular compounds for the treatment of ovarian cancer.

Ovarian cancer is a heterogeneous disease with complex molecular and genetic hallmarks. Benefitting from profound understanding of molecular mechanisms in ovarian cancer pathogenesis, novel targeted drugs have been actively explored in preclinical studies and clinical trials. Considered as one of the most potent and effective targeted therapies for the treatment of ovarian cancer, poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) take advantages of synthetic lethality mechanisms to prevent DNA damage repair in cancer cells and cause their death, especially in cancers with BRCA mutations. Mounting evidence has indicated that the combination of PARPis with cytotoxic drugs or other targeted drugs has shown favorable synergistic effects. Excitingly, the antitumor activity of combination therapy of PARPis has been actively tested in multiple clinical trials and in-vitro or in-vivo experiments. In this review, we will briefly discuss the molecular mechanisms of PARPis combined with other therapeutic small-molecular compounds for the treatment of ovarian cancer.