Role of Nanomedicine-Based Therapeutics in the Treatment of CNS Disorders.

Central nervous system disorders, especially neurodegenerative diseases, are a public health priority and demand a strong scientific response. Various therapy procedures have been used in the past, but their therapeutic value has been insufficient. The blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier is two of the barriers that protect the central nervous system (CNS), but are the main barriers to medicine delivery into the CNS for treating CNS disorders, such as brain tumors, Parkinson's disease, Alzheimer's disease, and Huntington's disease. Nanotechnology-based medicinal approaches deliver valuable cargos targeting molecular and cellular processes with greater safety, efficacy, and specificity than traditional approaches. CNS diseases include a wide range of brain ailments connected to short- and long-term disability. They affect millions of people worldwide and are anticipated to become more common in the coming years. Nanotechnology-based brain therapy could solve the BBB problem. This review analyzes nanomedicine's role in medication delivery; immunotherapy, chemotherapy, and gene therapy are combined with nanomedicines to treat CNS disorders. We also evaluated nanotechnology-based approaches for CNS disease amelioration, with the intention of stimulating the immune system by delivering medications across the BBB.

Pathogenesis and Therapeutic Strategies Related to Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD), one of the most common types of chronic liver disease, is strongly correlated with obesity, insulin resistance, metabolic syndrome, and genetic components. The pathological progression of NAFLD, consisting of non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), and liver cirrhosis, is characterized by a broad spectrum of clinical phenotypes. Although patients with mild NAFL are considered to show no obvious clinical symptoms, patients with long-term NAFL may culminate in NASH and further liver fibrosis. Even though various drugs are able to improve NAFLD, there are no FDA-approved medications that directly treat NAFLD. In this paper, the pathogenesis of NAFLD, the potential therapeutic targets, and their underlying mechanisms of action were reviewed.

Hydrogen Sulfide and Its Donors: Keys to Unlock the Chains of Nonalcoholic Fatty Liver Disease.

Hydrogen sulfide (H2S) has emerged as the third "gasotransmitters" and has a crucial function in the diversity of physiological functions in mammals. In particular, H2S is considered indispensable in preventing the development of liver inflammation in the case of excessive caloric ingestion. Note that the concentration of endogenous H2S was usually low, making it difficult to discern the precise biological functions. Therefore, exogenous delivery of H2S is conducive to probe the physiological and pathological roles of this gas in cellular and animal studies. In this review, the production and metabolic pathways of H2S in vivo, the types of donors currently used for H2S release, and study evidence of H2S improvement effects on nonalcoholic fatty liver disease are systematically introduced.

Pharmacologic characterization of fluzoparib, a novel poly(ADP-ribose) polymerase inhibitor undergoing clinical trials.

Poly(ADP-ribose) polymerase (PARP) enzymes play an important role in repairing DNA damage and maintaining genomic stability. Olaparib, the first-in-class PARP inhibitor, has shown remarkable clinical benefits in the treatment of BRCA-mutated ovarian or breast cancer. However, the undesirable hematological toxicity and pharmacokinetic properties of olaparib limit its clinical application. Here, we report the first preclinical characterization of fluzoparib (code name: SHR-3162), a novel, potent, and orally available inhibitor of PARP. Fluzoparib potently inhibited PARP1 enzyme activity and induced DNA double-strand breaks, G2 /M arrest, and apoptosis in homologous recombination repair (HR)-deficient cells. Fluzoparib preferentially inhibited the proliferation of HR-deficient cells and sensitized both HR-deficient and HR-proficient cells to cytotoxic drugs. Notably, fluzoparib showed good pharmacokinetic properties, favorable toxicity profile, and superior antitumor activity in HR-deficient xenografts models. Furthermore, fluzoparib in combination with apatinib or with apatinib plus paclitaxel elicited significantly improved antitumor responses without extra toxicity. Based on these findings, studies to evaluate the efficacy and safety of fluzoparib (phase II) and those two combinations (phase I) have been initiated. Taken together, our results implicate fluzoparib as a novel attractive PARP inhibitor.

SHR-A1403, a novel c-Met antibody-drug conjugate, exerts encouraging anti-tumor activity in c-Met-overexpressing models.

Emerging evidence demonstrates that a c-Met antibody-drug conjugate (ADC) has superior efficacy and safety profiles compared with those of currently available small molecules or antibody inhibitors for the treatment of c-Met-overexpressing cancers. Here we described both the in vitro and in vivo efficacies of SHR-A1403, a novel c-Met ADC composed of a humanized IgG2 monoclonal antibody against c-Met conjugated to a novel cytotoxic microtubule inhibitor. SHR-A1403 showed high affinity to c-Met proteins derived from human or monkey and potent inhibitory effects in cancer cell lines with high c-Met protein expression. In mice bearing tumors derived from cancer cell lines or patient HCC tissues with confirmed c-Met overexpression, SHR-A1403 showed excellent anti-tumor efficacy. Antibody binding with c-Met contributed to SHR-A1403 endocytosis; the subsequent translocation to lysosomes and cytotoxicity of the released toxin are speculated to be predominant mechanisms underlying the anti-tumor activity of SHR-A1403. In conclusion, SHR-A1403 showed significant anti-tumor activity in cancer cell lines, xenograft mouse models and an HCC PDX model, which all have high c-Met levels. These data provide references for SHR-A1403 as a potential therapy for the treatment of cancers with c-Met overexpression.

Preclinical pharmacokinetics of a novel anti-c-Met antibody-drug conjugate, SHR-A1403, in rodents and non-human primates.

1. The in vivo pharmacokinetics (PK) profiles of a novel c-Met antibody-drug conjugate (ADC), SHR-A1403, were investigated and characterized in mice, rats and monkeys. 2. Serum concentrations of ADC and total antibody were detected using validated ELISA methods. The results showed low systemic clearance of both ADC and total antibody in all three species as reflected by gradual decrease in serum concentrations. Half-life (t1/2) of ADC ranged from 4.6 to 11.3 days in the three species. 3. Tissue distribution study in tumor-bearing mice showed high accumulation of 125I-SHR-A1403 in tumor tissues over the other organs/tissues, indicating the favorable safety of SHR-A1403 and characteristics of an ADC drug. 4. Relatively low grade of anti-drug antibody (ADA) in monkeys had no impact on PK profile of the ADC. 5. During discovery stage, undesirable exposure and/or ADA incidence were observed for SHR-A1403 with high or low drug-antibody ratio (DAR), which was DAR = 5 to 6 and DAR = 1, respectively, and therefore prompted selection of an appropriate DAR value (DAR = 2) for SHR-A1403 used in preclinical development and clinical trials. 6. In conclusion, our work demonstrated favorable PK characterization of SHR-A1403, and supported for investigational new drug application (IND) and the ongoing first-in-human trial in the US.

Preclinical Development of SHR-1819, a Potent Humanized IL-4Rα Antibody for Treating Type 2 Inflammatory Diseases.

Background: Interleukin (IL)-4 and IL-13 are critical pathogenic factors for type 2 inflammation-related allergic diseases, sharing the mutual receptor subunit IL-4Rα. However, it was ineffective for certain type 2 inflammation diseases by targeting IL-4, IL-13 ligand alone or both in clinical studies. The work presented herein aimed to evaluate the preclinical efficacy and pharmacokinetics profile of a novel monoclonal antibody against IL-4Rα, SHR-1819, as a promising therapy for type 2 inflammation diseases. Methods: SHR-1819 was generated through immunization by C57BL/6 mice with recombinant hIL-4Rα protein, followed by humanization and affinity maturation. Then, its binding properties with IL-4Rα were determined using surface plasmon resonance (SPR) and ELISA. In vitro inhibitory effects of SHR-1819 were assessed on hIL-4-/hIL-13-induced cell proliferation and signal transducer and activator of transcription 6 (STAT6) signaling activation. In vivo efficacy of SHR-1819 was evaluated in several type 2 inflammatory diseases models, including asthma, atopic dermatitis (AD), and allergic rhinitis (AR) by using hIL-4/hIL-4Rα transgenic mice. Furthermore, the pharmacokinetic (PK) profiles of SHR-1819 were characterized. Results: SHR-1819 showed high binding affinity to human IL-4Rα and effectively blocked IL-4Rα at sub-nanomolar concentration. In vitro assays indicated that SHR-1819 significantly inhibited TF-1 cell proliferation and STAT6 activation induced by hIL-4/hIL-13. In the asthma model, SHR-1819 could reduce airway hyperresponsiveness, decrease serum IgE levels, and alleviated inflammatory lung cell infiltration. In the AD model, SHR-1819 could significantly alleviate inflammatory and skin symptoms. In the AR model, it could remarkably decrease the frequencies of nasal rubbing and sneezing, and inflammatory cell infiltration in nasal tissues. These in vivo efficacy studies demonstrated the therapeutic potential of SHR-1819 in preclinical disease models. Moreover, subcutaneous administration of SHR-1819 exhibited favorable bioavailability in mice. Conclusion: The results supported SHR-1819 as a promising preclinical candidate for the treatment of type 2 inflammatory diseases, including asthma, AD and AR.

Inequalities in Resource Distribution and Healthcare Service Utilization of Long-Term Care in China.

BACKGROUND: Long-term care (LTC) services help the elderly maintain their functional ability and live with dignity. In China, the establishment of an equitable LTC system is a primary focus of the current public health reform. This paper assesses levels of equality in resources for and utilization of LTC services between urban and rural areas and economic regions in China. METHODS: We use social services data from the China Civil Affairs Statistical Yearbooks. Gini coefficients against elderly population size are calculated for the number of institutions, beds, and workers, and the concentration index (CI) against per capita disposable income is calculated for the number of disabled residents per 1000 elderly people and the number of rehabilitation and nursing services per resident. RESULTS: The Gini coefficients against the elderly population in urban areas indicate relatively good equality. In rural areas, the Gini coefficients have increased rapidly from relatively low values since 2015. The CI values in both urban and rural areas are positive, indicating that utilization is concentrated in the richer population. In rural areas, the CI values for rehabilitation and nursing have remained above 0.50 for the last three years, implying high levels of income-related inequality. The negative CI values for rehabilitation and nursing services in urban areas in the Central economic region and rural areas in the Western region imply a concentration of resource utilization toward poorer groups. The Eastern region shows relatively high internal inequality. CONCLUSION: Inequalities exist between urban and rural areas in the utilization of LTC services, despite similar numbers of institution and bed resources. Resource distribution and healthcare service utilization are more equal in urban areas, creating a low level of equilibrium. This urban-rural split is a source of risk for both formal and informal LTC. The Eastern region has the largest number of resources, the highest level of utilization, and the greatest internal variation. In the future, the Chinese government should enhance support for the utilization of services for the elderly with LTC needs.

Genetic Engineering and Biosynthesis Technology: Keys to Unlocking the Chains of Phage Therapy.

Phages possess the ability to selectively eliminate pathogenic bacteria by recognizing bacterial surface receptors. Since their discovery, phages have been recognized for their potent bactericidal properties, making them a promising alternative to antibiotics in the context of rising antibiotic resistance. However, the rapid emergence of phage-resistant strains (generally involving temperature phage) and the limited host range of most phage strains have hindered their antibacterial efficacy, impeding their full potential. In recent years, advancements in genetic engineering and biosynthesis technology have facilitated the precise engineering of phages, thereby unleashing their potential as a novel source of antibacterial agents. In this review, we present a comprehensive overview of the diverse strategies employed for phage genetic engineering, as well as discuss their benefits and drawbacks in terms of bactericidal effect.

Investigation of hub ferroptosis-related genes and the immune landscape in recurrent pregnancy loss and unexplained infertility using bioinformatics analysis.

Background: Recurrent pregnancy loss (RPL) and unexplained infertility (UI) are common pregnancy disorders that affect women's physical and mental health and lack effective treatment. Endometrial factors are one factor that leads to RPL. The latest research indicates that ferroptosis and immunity are closely related to the normal physiological function of the endometrium and may play a role in the pathogenesis of RPL and UI. Therefore, the present study analyzed the relationship between ferroptosis genes and immune infiltration in RPL and UI. Methods: We downloaded the GSE165004 dataset and analyzed differences in ferroptosis-related genes (FRGs) between RPL and UI patients and healthy controls. Hub differentially expressed ferroptosis-related genes (DE-FRGs) were screened using the LASSO algorithm, the SVM-RFE algorithm and the protein-protein interaction (PPI) network. Differences in immune infiltration between healthy endometrium and RPL and UI endometrium was analyzed, and the relationship between hub DE-FRGs and immune cell infiltration was examined. Results: We extracted 409 FRGs and identified 36 up-regulated and 32 down-regulated DE-FRGs in RPL and UI. Twenty-one genes were screened using the LASSO regression algorithm, and 17 genes were screened using the SVM-RFE algorithm. We intersected the LASSO genes, SVM-RFE genes and PPI network proteins to obtain 5 hub DE-FRGs. Gene set enrichment analysis (GSEA) functional enrichment analysis results indicated that the cytokine-cytokine receptor interaction signaling pathway was the common pathway for hub DE-FRGs. T follicular helper cells were highly infiltrated in RPL and UI, and M1 and M2 macrophages were highly infiltrated. The expression levels of MAPK1 and RELA positively correlated with T follicular helper cells. Conclusions: Ferroptosis-related genes may disrupt endometrial functions and signaling pathways and lead to the occurrence of RPL and UI.

Recent advances in the role of endogenous hydrogen sulphide in cancer cells.

Hydrogen sulphide (H2 S) is a gaseous neurotransmitter that can be self-synthesized by living organisms. With the deepening of research, the pathophysiological mechanisms of endogenous H2 S in cancer have been increasingly elucidated: (1) promote angiogenesis, (2) stimulate cell bioenergetics, (3) promote migration and proliferation thereby invasion, (4) inhibit apoptosis and (5) activate abnormal cell cycle. However, the increasing H2 S levels via exogenous sources show the opposite trend. This phenomenon can be explained by the bell-shaped pharmacological model of H2 S, that is, the production of endogenous (low concentration) H2 S promotes tumour growth while the exogenous (high concentration) H2 S inhibits tumour growth. Here, we review the impact of endogenous H2 S synthesis and metabolism on tumour progression, summarize the mechanism of action of H2 S in tumour growth, and discuss the possibility of H2 S as a potential target for tumour treatment.

BJTJ-1837, a novel FXI activation-blocking antibody.

Background: Factor (F)XI contributes to thrombosis development while it plays a limited role in normal hemostasis. FXI targeting has the potential for preventing and treating thrombosis with little bleeding risk. Objectives: The aim of this study was to develop novel antibody therapeutics against FXI for the treatment of thrombosis-related diseases. Methods: Mouse hybridoma technology was applied to screen for anti-FXI antibodies. Surface plasma resonance, enzyme inhibition, activated partial thromboplastin time, and prothrombin time assays were conducted to characterize the binding affinity and activity of antibodies. A cynomolgus monkey arterial venous shunt model was applied to validate the antithrombotic activities. Results: A humanized antibody, BJTJ-1837, reported here bound to the protease domain of FXI and activated FXI with high affinity. BJTJ-1837 fully inhibited the activation of FXI by activated FXII and thrombin. BJTJ-1837 also demonstrated strong anticoagulant activity in human and cynomolgus monkey plasma as measured by activated partial thromboplastin time. Moreover, BJTJ-1837 showed favorable antithrombotic activity with a dose-dependent protection in an arterial venous shunt thrombosis model in cynomolgus monkeys without the bleeding adverse effect. Furthermore, BJTJ-1837 displayed favorable pharmacokinetic and pharmacodynamic properties and good developability. Conclusion: As a potential antithrombotic therapeutic agent with a safe profile, BJTJ-1837 is a very promising FXI activation-blocking antibody candidate.

Urgent aortic valve replacement in octogenarians: does an 'urgent' status increase morbidity and mortality?

BACKGROUND AND AIM OF THE STUDY: The study aim was to investigate the influence of 'urgent' status on short and long-term mortality and morbidity in a consecutive series of octogenarian patients who underwent aortic valve replacement (AVR). METHODS: Between January 2005 and March 2009, data were extracted for 141 consecutive patients aged over 80 years who underwent AVR either urgently (n = 49) or electively (n = 92). Early outcomes (in-hospital mortality, postoperative morbidities) and long-term outcomes were compared during a 39-month follow up period. The outcomes were compared after adjustment for differences in baseline risk factors. RESULTS: Patients of the 'urgent' group were older and had more comorbidities than those in the 'elective' group. There was a non-significant trend towards a higher in-hospital mortality in the 'urgent' group (10.2% versus 4.3%, p = 0.18). The 39-month survival rate was 81% in elective patients, and 71% in urgent patients (p = 0.166). CONCLUSION: AVR can be performed in the elderly population with acceptable early and mid-term results, despite their urgent status. A large clinical trial is warranted to confirm the influence of an urgent status in octogenarian patients treated with surgical AVR.

The impact of pulmonary hypertension on outcomes of patients with low left ventricular ejection fraction: a propensity analysis.

BACKGROUND AND AIM OF THE STUDY: Pulmonary hypertension (PH) is commonly described as a risk factor in cardiac surgery; however, the effect of a low left ventricular ejection fraction (LVEF) on PH has not been assessed. Hence, the study aim was to determine whether PH increases operative mortality and survival outcome in patients with a low LVEF. METHODS: Between January 2001 and September 2009, a total of 845 consecutive patients with LVEF < 40% was enrolled into the study. Among these patients, 444 had a pulmonary pressure < 40 mmHg (NPH group), while in 401 patients the pulmonary pressure was > or = 40 mmHg. RESULTS: Preoperatively, the PH patients were older (p < 0.001), had a lower LVEF (p = 0.001), and had a higher logistic EuroSCORE (p < 0.001) and serum creatinine level (p < 0.026) when compared to NPH patients. The PH patients showed a greater tendency to develop postoperative complications (p < 0.001). After adjusting by propensity score, the in-hospital mortality was significantly higher among PH patients (p < 0.001), while multivariate logistic regressions revealed PH as an independent predictor for in-hospital mortality (p = 0.036). The 12-, 36-, and 60-month follow up mortality rates were significantly higher in the PH group. By using a Cox logistic regression model, PH was shown to be an independent predictor for follow up mortality (p = 0.035). CONCLUSION: Pulmonary hypertension increased the morbidity and mortality in patients with a low LVEF who were undergoing cardiac surgery. Future studies may identify subgroups that may benefit from a preoperative optimization of PH and/or intra- and postoperative therapies directed at minimizing the effects of the condition.

Assessment of Attitudes and Intentions towards COVID-19 Vaccines and Associated Factors among General Populations of Pakistan: A Cross-Sectional Study.

OBJECTIVE: The goal of public health in combatting COVID-19 is to increase herd immunity. However, vaccine reluctance makes attaining herd immunity a worldwide challenge. This investigation aimed to identify negative and positive attitudes and intentions about COVID-19 vaccinations. METHODS: A cross-sectional online survey was conducted once free COVID-19 vaccines became available in Pakistan in 2021. 4392 Pakistanis aged 18 and older were surveyed from seven administrative units between 1 July and 30 August 2021. Online structured questionnaires were utilized to collect data using a simple sampling procedure. The questionnaires were divided into three major sections: sociodemographic, health factors, and attitudes toward COVID-19. RESULTS: The survey link was shared with approximately 4500 participants. 97.6%(4392) completed the survey once begun. Frequency, percentage and Chi-square tests were used to analyze statistical data. Most of the participants in the research were men (2703 (61.54%)), 3277 (74.61%) were aged 18-29 years, and 1824 (41.53%) were residents of the Khyber Pakhtunkhwa province. (18.69%) Respondents expressed COVID-19 vaccine hesitancy, whereas 36.66% of participants liked getting the Sinopharm and Sinovac vaccines and (35.84%) of participants preferred the Pfizer vaccine. A significant number of participants (38.05%) were concerned about the vaccine's unexpected side effects Thus, it is essential to realize that many participants were concerned about the vaccine's unexpected side effects. CONCLUSIONS: The overall high level of concern about the unforeseen side effects of COVID-19 vaccines, as well as widespread vaccine hesitancy among Pakistani populations and its predictors, should be taken into account if public health intervention campaigns in Pakistan are changing negative attitudes and improving compliance with regard to COVID-19 vaccines.

[Experimental studies of therapeutic effect of Rheum officinale on acute pancreatitis].

OBJECTIVE: To investigate the therapeutic effect of Rheum officinale on acute pancreatitis. METHODS: Buffered sodium taurocholate (3% m/V) was injected into the pancreatico-biliary duct to induce acute pancreatitis. Death rate,coefficient of pancreas, serum amylyse (AMY), hemocuprein (SOD), TNF-alpha and IL-1beta level were examined at 6, 12 and 24 hours after operations. Pathology analysis were also obtained. RESULTS: Compared with corresponding pancreatitis groups,death rate, coefficient of pancreas, serum TNF-alpha and IL-1beta level of drug groups decreased remarkably (P < 0.05), while serum SOD level significantly increased (P < 0.01). Serum AMY level of drug groups increased at 6 h (P < 0.01), decreased at 12 h (P < 0.01) and had no statistics disparity at 24 h (P > 0.05) compared with respective pancreatitis group. Although score points of all drug groups were lower than corresponding pancreatitis groups, the growth tendency of both were similar. CONCLUSION: Rheum officinale Baill has the effect of prevention to pancreas pathological changes in the animal pattern, but not able to reverse the tendency.

Liquid chromatography-mass spectrometry method for the quantification of an anti-sclerostin monoclonal antibody in cynomolgus monkey serum.

Liquid chromatography tandem mass spectrometry (LC-MS/MS) has gradually become a promising alternative to ligand binding assay for the bioanalysis of biotherapeutic molecules, due to its rapid method development and high accuracy. In this study, we established a new LC-MS/MS method for the determination of the anti-sclerostin monoclonal antibody (SHR-1222) in cynomolgus monkey serum, and compared it to a previous electrochemiluminescence method. The antibody was quantified by detecting the surrogate peptide obtained by trypsin digestion. The surrogate peptide was carefully selected by investigating its uniqueness, stability and MS response. The quantitative range of the proposed method was 2.00-500 µg/mL, and this verified method was successfully applied to the toxicokinetic assessment of SHR-1222 in cynomolgus monkey serum. It was found that the concentrations of SHR-1222 in cynomolgus monkeys displayed an excellent agreement between the LC-MS/MS and electrochemiluminescence methods (ratios of drug exposure, 0.8-1.0). Notably, two monkeys in the 60 mg/kg dose group had abnormal profiles with a low detection value of SHR-1222 in their individual sample. Combining the high-level anti-drug antibodies (ADAs) in these samples and the consistent quantitative results of the two methods, we found that the decreased concentration of SHR-1222 was due to the accelerated clearance mediated by ADAs rather than the interference of ADAs to the detection platform. Taken together, we successfully developed an accurate, efficient and cost-effective LC-MS/MS method for the quantification of SHR-1222 in serum samples, which could serve as a powerful tool to improve the preclinical development of antibody drugs.

[In vitro study on two kind of recombinant adeno-associated virus-mediated transfection efficiency with enhanced green fluorescent protein into rats osteoblasts].

OBJECTIVE: To compare the transfection efficiency of two kind of recombinant adeno-associated virus-mediated transfection to rats osteoblasts with enhanced green fluorescent protein and assess the feasibility of it as a vector for gene therapy of osteoblast lesions. METHODS: The osteoblasts of rats were isolated, cultured and identified with type I collagen staged digestion method. According to different multiplicity of infection (MOI) (MOI = 1 x 10(3), 1 x 10(4), 1 X 10(4), 5 x 10(5)), rAAV-EGFP was transfected into osteoblasts with rAAV only and rAAV-ADV co-transfection respectively. The expression of EGFP along with the transfection time was observed under inverted fluorescence microscope. The transfection efficiency and fluorescence intensity was evaluated by flow cytometry. The best MOI value was analysed and the cell growth curves were obtained according to the best MOI value to evaluate the toxic effects of rAAV-EGFP. RESULTS: The cultured cells possessed the biological behaviors of osteoblasts. The transfection efficiency of the rAAV was increased with the increasing of MOI. The EGFP expression reached the maximum on day 5 in ADV(-) group, the transfection efficiency of rAAV2/6-EGFP and rAAV2/9-EGFP was 90.2% and 66.1% respectively when MOI was 1 x 10(5) and no significant increase was observed when MOI was 5 x 10(5). In ADV(+) group, EGFP expression reached its maximum on day 3, the transfection efficiency of rAAV2/6-EGFP and rAAV2/9-EGFP was 47.6% and 30.5% respectively when MOI was 5 x 10(5). And no significant biologic effects on the cyto-activity was observed. CONCLUSION: The transfection efficiency of two kind of virus vectors was both very high and rAAV2/6's is higher than that of rAAV2/9. This suggested the potential of rAAV-EGFP as a safe and efficient vector for gene therapy.

Discovery of Clinical Candidate (5-(3-(4-Chlorophenoxy)prop-1-yn-1-yl)-3-hydroxypicolinoyl)glycine, an Orally Bioavailable Prolyl Hydroxylase Inhibitor for the Treatment of Anemia.

The design and discovery of a new series of (5-alkynyl-3-hydroxypicolinoyl)glycine inhibitors of prolyl hydroxylase (PHD) are described. These compounds showed potent in vitro inhibitory activity toward PHD2 in a fluorescence polarization-based assay. Remarkably, oral administration of 17, with an IC50 of 64.2 nM toward PHD2, was found to stabilize HIF-α, elevate erythropoietin (EPO), and alleviate anemia in a cisplatin-induced anemia mouse model with an oral dose of 25 mg/kg. Rat and dog studies showed that 17 has good pharmacokinetic properties, with oral bioavailabilities of 55.7 and 54.0%, respectively, and shows excellent safety profiles even at a high dose of 200 mg/kg in these animals. Based on these results, 17 is currently being evaluated in a phase I clinical trial for anemia.

Fluzoparib increases radiation sensitivity of non-small cell lung cancer (NSCLC) cells without BRCA1/2 mutation, a novel PARP1 inhibitor undergoing clinical trials.

PROPOSE: Poly (ADP-ribose) polymerase 1 inhibitors were originally investigated as anti-cancer therapeutics with BRCA1/2 genes mutation. Here, we investigate the effectiveness of a novel PARP1 inhibitor fluzoparib, for enhancing the radiation sensitivity of NSCLC cells lacking BRCA1/2 mutation. METHODS: We used MTS assays, western blotting, colony formation assays, immunofluorescence staining, and flow cytometry to evaluate the radiosensitization of NSCLC cells to fluzoparib and explore the underlying mechanisms in vitro. Through BRCA1 and RAD50 genes knockdown, we established dysfunctional homologous recombination (HR) DNA repair pathway models in NSCLC cells. We next investigated the radiosensitization effect of fluzoparib in vivo using human NSCLC xenograft models in mice. The expression of PARP1 and BRCA1 in human NSCLC tumor samples was measured by immunohistochemistry. Furthermore, we sequenced HR-related gene mutations and analyzed their frequencies in advanced NSCLC. RESULTS: In vitro experiments in NSCLC cell lines along with in vivo experiments using an NSCLC xenograft mouse model demonstrated the radiosensitization effect of fluzoparib. The underlying mechanisms involved increased apoptosis, cell-cycle arrest, enhanced irradiation-induced DNA damage, and delayed DNA-damage repair. Immunohistochemical staining showed no correlation between the expression of PARP1 and BRCA1. Moreover, our sequencing results revealed high mutation frequencies for the BRCA1/2, CHEK2, ATR, and RAD50 genes. CONCLUSION: The potential therapeutic value of fluzoparib for increasing the radiation sensitivity of NSCLC is well confirmed. Moreover, our findings of high mutation frequencies among HR genes suggest that PARP1 inhibition may be an effective treatment strategy for advanced non-small cell lung cancer patients.