Durvalumab Consolidation After Chemoradiotherapy in Elderly Patients With Unresectable Stage III NSCLC: A Real-World Multicenter Study.

BACKGROUND: The PACIFIC trial demonstrated survival benefit of durvalumab after concurrent chemoradiotherapy (CCRT) in unresectable stage III non-small-cell lung cancer. Data on the effectiveness and safety of durvalumab in elderly patients is lacking. METHODS: This retrospective study was conducted between September 2017 and September 2022. Progression-free survival (PFS), overall survival (OS), recurrence patterns, first subsequent treatment after recurrence, factors associated with survival outcomes, and adverse events (AEs) were compared. RESULTS: Of the 286 patients, 120 (42.0%) were ≥ 70 years and 166 (58.0%) were < 70 years. The median PFS (17.7 vs. 19.4 months; P = .43) and median OS (35.7 months vs. not reached; P = .13) were similar between 2 groups. Proportion of patients who completed durvalumab was lower in elderly patients (27.5% vs. 39.2%; P = .040). In elderly patients, ECOG PS 0 or 1 was associated with better PFS, and being male and having received a cisplatin-based regimen during CCRT were factors associated with better and worse OS, respectively. In patients aged < 70 years, a PD-L1 ≥ 50% was associated with improved PFS and OS. Elderly patients experienced more treatment-related AEs, grade 3/4 AEs, permanent discontinuation of durvalumab, and treatment-related deaths. Among the AEs leading to permanent discontinuation or death, pulmonary AE was significantly more common in elderly patients. CONCLUSION: Durvalumab demonstrated similar outcomes in elderly compared to younger patients. However, AEs were more common in elderly patients. Thus, judicious selection of patients and chemotherapy regimens, coupled with careful AE monitoring, are important factors for ensuring optimal durvalumab treatment.

Development of the Korean Association for Lung Cancer Clinical Practice Guidelines: Recommendations on Radial Probe Endobronchial Ultrasound for Diagnosing Lung Cancer - An Updated Meta-Analysis.

PURPOSE: Radial probe endobronchial ultrasound (RP-EBUS) accurately locates peripheral lung lesions (PLLs) during transbronchial biopsy (TBB). We performed an updated meta-analysis of the diagnostic yield of TBB for PLLs using RP-EBUS to generate recommendations for the development of the Korean Association of Lung Cancer guidelines. MATERIALS AND METHODS: We systematically searched MEDLINE and EMBASE (from January 2013 to December 2022), and performed a meta-analysis using R software. The diagnostic yield was evaluated by dividing the number of successful diagnoses by the total lesion number. Subgroup analysis was performed to identify related factors. RESULTS: Forty-one studies with a total of 13,133 PLLs were included. The pooled diagnostic yield of RP-EBUS was 0.72 (95% confidence interval [CI], 0.70 to 0.75). Significant heterogeneity was observed among studies (χ2=292.38, p < 0.01, I2=86.4%). In a subgroup analysis, there was a significant difference in diagnostic yield based on RP-EBUS findings (within, adjacent to, invisible), with a risk ratio of 1.45 (95% CI, 1.23 to 1.72) between within and adjacent to, 4.20 (95% CI, 1.89 to 9.32) between within and invisible, and 2.59 (95% CI, 1.32 to 5.01) between adjacent to and invisible. There was a significant difference in diagnostic yield based on lesion size, histologic diagnosis, computed tomography (CT) bronchus sign, lesion character, and location from the hilum. The overall complication rate of TBB with RP-EBUS was 6.8% (bleeding, 4.5%; pneumothorax, 1.4%). CONCLUSION: Our study showed that TBB with RP-EBUS is an accurate diagnostic tool for PLLs with good safety profiles, especially for PLLs with within orientation on RP-EBUS or positive CT bronchus sign.

Neuroprotective Effects of Black Pepper and Its Bioactive Compounds in Age-Related Neurological Disorders.

Age-related neurological disorders (ANDs), including neurodegenerative diseases, are multifactorial disorders whose risk increases with age. The main pathological hallmarks of ANDs include behavioral changes, excessive oxidative stress, progressive functional declines, impaired mitochondrial function, protein misfolding, neuroinflammation, and neuronal cell death. Recently, efforts have been made to overcome ANDs because of their increased age-dependent prevalence. Black pepper, the fruit of Piper nigrum L. in the family Piperaceae, is an important food spice that has long been used in traditional medicine to treat various human diseases. Consumption of black pepper and black pepper-enriched products is associated with numerous health benefits due to its antioxidant, antidiabetic, anti-obesity, antihypertensive, anti-inflammatory, anticancer, hepatoprotective, and neuroprotective properties. This review shows that black pepper's major bioactive neuroprotective compounds, such as piperine, effectively prevent AND symptoms and pathological conditions by modulating cell survival signaling and death. Relevant molecular mechanisms are also discussed. In addition, we highlight how recently developed novel nanodelivery systems are vital for improving the efficacy, solubility, bioavailability, and neuroprotective properties of black pepper (and thus piperine) in different experimental AND models, including clinical trials. This extensive review shows that black pepper and its active ingredients have therapeutic potential for ANDs.

Favorable Conditions for the Detection of EGFR T790M Mutation Using Plasma Sample in Patients with Non-Small-Cell Lung Cancer.

BACKGROUND: Detection of the epidermal growth factor receptor (EGFR) T790M mutation using plasma samples has been considered simple and non-invasive, but the relatively high false negative results lead to additional tissue sampling in some patients. Until now, the characteristics of patients who prefer liquid biopsy have not yet been established. METHODS: To evaluate the favorable conditions for the detection of T790M mutations using plasma samples, a multicenter retrospective study was performed between May 2018 and December 2021. Patients whose T790M mutation was detected in a plasma sample were classified as the plasma positive group. Study subjects with a T790M mutation not detected in a plasma sample but only in a tissue sample were grouped as the plasma false negative group. RESULTS: Plasma positive and plasma false negative groups were found in 74 and 32 patients, respectively. As a result, 40% of patients with one or two metastatic organs at the time of re-biopsy had false negative plasma sample results, and 69% of patients with three or more metastatic organs at the time of re-biopsy had positive plasma results. In multivariate analysis, three or more metastatic organs at initial diagnosis were independently associated with the detection of a T790M mutation using plasma samples. CONCLUSION: Our results demonstrated that the detection rate of a T790M mutation using plasma samples was related to the tumor burden, particularly to the number of metastatic organs.

Acute Eosinophilic Pneumonia after Combined Use of Conventional and Heat-Not-Burn Cigarettes: A Case Report.

Background: Acute eosinophilic pneumonia (AEP) is a rare acute respiratory disease accompanied by fever, shortness of breath, and cough. Although the pathogenesis of the disease is not yet established, the patient's condition improves with a rapid therapeutic response to systemic corticosteroids. Conventional cigarettes or heat-not-burn cigarettes are the most common cause of AEP among young people. Case Presentation: A 22-year-old woman with dyspnea, cough, and fever did not improve after visiting the local medical center and was admitted to the emergency room. The patient denied having any recent travel history or insect bites. She was treated with appropriate antibiotics according to the community acquired pneumonia, but there was no improvement. Chest radiography showed bilateral patches of pulmonary infiltration, and chest computed tomography revealed bilateral multifocal patchy consolidations with multiple small nodular ground-glass opacities and interlobular septal thickening. The bronchoalveolar lavage result was dominantly eosinophilic. The patient's condition improved rapidly after the use of intravenous methylprednisolone and then a change to oral methylprednisolone. Finally, the patient was hospitalized for 9 days, and the duration of use of methylprednisolone including outpatient visits was 14 days. Results: The early treatment of AEP yields a good prognosis, but since the symptoms of AEP are similar to those of infectious diseases such as community-acquired pneumonia, physicians should be meticulous in differentiating AEP from other diseases. Conclusions: Since AEP shows a good response to steroids, early detection using an appropriate diagnostic method is recommended. In addition, there should be strong education against smoking in any form.

α-Synuclein upregulates bim-mediated apoptosis by negatively regulating endogenous GCN5.

α-synuclein (αS) is a ß-sheet intracellular protein that has been implicated as a major pathological hallmark of Parkinson's disease (PD). Several studies have shown that overexpression of αS causes dopaminergic cell loss; however, the role of αS in apoptosis remains not fully known. Therefore, this study aims to address the mechanisms of the αS overexpression model in apoptosis and to its correlation with PD pathogenesis. Here, we used a human αS (hαS) plasmid to characterize the role of ectopic αS in neuronal apoptosis in sporadic PD in vitro. We found that overexpression of αS transcriptionally upregulated Bim-mediated apoptosis in neuronal SH-SY5Y cells. Interestingly, αS overexpression inhibited general control non-depressible 5 (GCN5), a histone acetyltransferase (HAT), and promoted transcriptional upregulation of Bim. Consequently, co-overexpression of GCN5 in the αS overexpressed model showed a reversal of αS toxicity in neuronal cells. These in vitro findings support the hypothesis of αS-mediated histone deacetylation and dopaminergic neuronal loss in PD. Moreover, our study indicates that therapeutic activation/homeostasis of GCN5 may benefit PD and other α-synucleinopathies.

A Life-Threatening Infection after Endobronchial Ultrasound Transbronchial Lung Biopsy with Guide Sheath: A Case Report.

BACKGROUND AND OBJECTIVES: Endobronchial ultrasound transbronchial lung biopsy with guide sheath (EBUS-GS-TBLB) has been regarded as a reasonable diagnostic method with an acceptable diagnostic yield. In addition, EBUS-GS-TBLB is considered safer and less invasive compared to percutaneous needle biopsy and thoracoscopic surgery. However, we encountered a case of life-threatening procedure-related fatal infection, which was successfully managed. CASE PRESENTATION: A 61-year-old man with a 30 pack-year smoking history was referred to our clinic with a necrotic lung mass in the right middle lobe on a chest computed tomography scan. EBUS-GS-TBLB was performed for a pathological diagnosis without immediate complications. Eight days after the procedure, the patient visited the hospital with sudden hemoptysis and severe dyspnea with fever. A chest computed tomography revealed a ruptured lung abscess and pneumonia, developed after EBUS-GS-TBLB. Extracorporeal membrane oxygenation (ECMO) and mechanical ventilation were initiated to manage refractory hypoxia. While maintaining ECMO, video-assisted thoracoscopic surgery was performed at the patient's bedside in the intensive care unit. After surgery, the patient's vital signs gradually improved, and a chest computed tomography revealed a reduction in the extent of the lung abscess. RESULTS: Although EBUS-GS-TBLB is minimally invasive and relatively safe when used for the diagnosis of peripheral lung lesions, pulmonary physicians should be aware of this rare but critical complication. CONCLUSIONS: We suggest that the careful prescription of prophylactic antibiotics before EBUS-GS-TBLB would be wise if the mass featured a necrotic, cavitary, or cystic lesion.

Dioscin-Mediated Autophagy Alleviates MPP+-Induced Neuronal Degeneration: An In Vitro Parkinson's Disease Model.

Autophagy is a cellular homeostatic process by which cells degrade and recycle their malfunctioned contents, and impairment in this process could lead to Parkinson's disease (PD) pathogenesis. Dioscin, a steroidal saponin, has induced autophagy in several cell lines and animal models. The role of dioscin-mediated autophagy in PD remains to be investigated. Therefore, this study aims to investigate the hypothesis that dioscin-regulated autophagy and autophagy-related (ATG) proteins could protect neuronal cells in PD via reducing apoptosis and enhancing neurogenesis. In this study, the 1-methyl-4-phenylpyridinium ion (MPP+) was used to induce neurotoxicity and impair autophagic flux in a human neuroblastoma cell line (SH-SY5Y). The result showed that dioscin pre-treatment counters MPP+-mediated autophagic flux impairment and alleviates MPP+-induced apoptosis by downregulating activated caspase-3 and BCL2 associated X, apoptosis regulator (Bax) expression while increasing B-cell lymphoma 2 (Bcl-2) expression. In addition, dioscin pre-treatment was found to increase neurotrophic factors and tyrosine hydroxylase expression, suggesting that dioscin could ameliorate MPP+-induced degeneration in dopaminergic neurons and benefit the PD model. To conclude, we showed dioscin's neuroprotective activity in neuronal SH-SY5Y cells might be partly related to its autophagy induction and suppression of the mitochondrial apoptosis pathway.

Immunostimulatory Effect of Heat-Killed Probiotics on RAW264.7 Macrophages.

Probiotics modulate the gut microbiota, which in turn regulate immune responses to maintain balanced immune homeostasis in the host. However, it is unclear how probiotic bacteria regulate immune responses. In this study we investigated the immunomodulatory effects of heat-killed probiotics, including Lactiplantibacillus plantarum KC3 (LP3), Lactiplantibacillus plantarum CKDB008 (LP8), and Limosilactobacillus fermentum SRK414 (LF4), via phagocytosis, nitric oxide (NO), and pro-inflammatory cytokine production in macrophages. We thus found that heat-killed LP8 could promote the clearance of foreign pathogens by enhancing the phagocytosis of macrophages. Treatment with heat-killed LP8 induced the production of NO and pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1ß. In addition, heat-killed LP8 suppressed the production of NO and cytokines in LPS-induced RAW264.7 cells, suggesting that heat-killed LP8 exerts immunomodulatory effects depending on the host condition. In sum, these results indicate that heat-killed LP8 possesses the potential for immune modulation while providing a molecular basis for the development of functional probiotics prepared from inactivated bacterial cells.

Molecular Mechanisms and Therapeutic Potential of α- and ß-Asarone in the Treatment of Neurological Disorders.

Neurological disorders are important causes of morbidity and mortality around the world. The increasing prevalence of neurological disorders, associated with an aging population, has intensified the societal burden associated with these diseases, for which no effective treatment strategies currently exist. Therefore, the identification and development of novel therapeutic approaches, able to halt or reverse neuronal loss by targeting the underlying causal factors that lead to neurodegeneration and neuronal cell death, are urgently necessary. Plants and other natural products have been explored as sources of safe, naturally occurring secondary metabolites with potential neuroprotective properties. The secondary metabolites α- and ß-asarone can be found in high levels in the rhizomes of the medicinal plant Acorus calamus (L.). α- and ß-asarone exhibit multiple pharmacological properties including antioxidant, anti-inflammatory, antiapoptotic, anticancer, and neuroprotective effects. This paper aims to provide an overview of the current research on the therapeutic potential of α- and ß-asarone in the treatment of neurological disorders, particularly neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), as well as cerebral ischemic disease, and epilepsy. Current research indicates that α- and ß-asarone exert neuroprotective effects by mitigating oxidative stress, abnormal protein accumulation, neuroinflammation, neurotrophic factor deficit, and promoting neuronal cell survival, as well as activating various neuroprotective signalling pathways. Although the beneficial effects exerted by α- and ß-asarone have been demonstrated through in vitro and in vivo animal studies, additional research is required to translate laboratory results into safe and effective therapies for patients with AD, PD, and other neurological and neurodegenerative diseases.

Piperine and Its Metabolite's Pharmacology in Neurodegenerative and Neurological Diseases.

Piperine (PIP) is an active alkaloid of black and long peppers. An increasing amount of evidence is suggesting that PIP and its metabolite's could be a potential therapeutic to intervene different disease conditions including chronic inflammation, cardiac and hepatic diseases, neurodegenerative diseases, and cancer. In addition, the omnipresence of PIP in food and beverages made this compound an important investigational material. It has now become essential to understand PIP pharmacology and toxicology to determine its merits and demerits, especially its effect on the central nervous system (CNS). Although several earlier reports documented that PIP has poor pharmacokinetic properties, such as absorption, bioavailability, and blood-brain barrier permeability. However, its interaction with metabolic enzyme cytochrome P450 superfamily and competitive hydrophobic interaction at Monoamine oxide B (MAO-B) active site have made PIP both a xenobiotics bioenhancer and a potential MAO-B inhibitor. Moreover, recent advancements in pharmaceutical technology have overcome several of PIP's limitations, including bioavailability and blood-brain barrier permeability, even at low doses. Contrarily, the structure activity relationship (SAR) study of PIP suggesting that its several metabolites are reactive and plausibly responsible for acute toxicity or have pharmacological potentiality. Considering the importance of PIP and its metabolites as an emerging drug target, this study aims to combine the current knowledge of PIP pharmacology and biochemistry with neurodegenerative and neurological disease therapy.

Lab-on-a-Disc for Point-of-Care Infection Diagnostics.

Reliable, inexpensive, and rapid diagnostic tools are essential to control and prevent the spread of infectious diseases. Many commercial kits for coronavirus disease 2019 (COVID-19) diagnostics have played a crucial role in the fight against the COVID-19 pandemic. Most current standard in vitro diagnostic (IVD) protocols for infectious diseases are sensitive but time-consuming and require sophisticated laboratory equipment and specially trained personnel. Recent advances in biosensor technology suggest the potential to deliver point-of-care (POC) diagnostics that are affordable and provide accurate results in a short time. The ideal "sample-in-answer-out" type fully integrated POC infection diagnostic platforms are expected to be autonomous or easy-to-operate, equipment-free or infrastructure-independent, and high-throughput or easy to upscale. In this Account, we detail the recent progress made by our group and others in the development of centrifugal microfluidic devices or lab-on-a-disc (LOAD) systems. Unlike conventional pump-based fluid actuation, the centrifugal force generated by spinning the disc induces liquid pumping and no external fluidic interconnects are required. This allows a total fluidic network required for multiple steps of biological assays to be integrated on a disc, enabling fully automated POC diagnostics. Various applications have been demonstrated, including liquid biopsy for personalized cancer management, food applications, and environmental monitoring; here, we focus on IVD for infectious disease. First, we introduce various on-disc unit operation technologies, including reagent storage, sedimentation, filtration, valving, decanting, aliquoting, mixing, separation, serial dilution, washing, and calibration. Such centrifugal microfluidic technologies have already proved promising for micro-total-analysis systems for automated IVD ranging from molecular detection of pathogens to multiplexed enzyme-linked immunosorbent assays (ELISAs) that use raw samples such as whole blood or saliva. Some recent examples of LOAD systems for molecular diagnostics in which some or all steps of the assays are integrated on a disc, including pathogen enrichment, nucleic acid extraction, amplification, and detection, are discussed in detail. We then introduce fully automated ELISA systems with enhanced sensitivity. Furthermore, we demonstrate a toy-inspired fidget spinner that enables electricity-free and rapid analysis of pathogens from undiluted urine samples of patients with urinary tract infection symptoms and a phenotypic antimicrobial susceptibility test for an extreme POC diagnostics application. Considering the urgent need for cost-effective and reliable POC infection diagnostic tools, especially in the current pandemic crisis, the current limitations and future directions of fast and broad adaptation in real-world settings are also discussed. With proper attention to key challenges and leverage with recent advances in bio-sensing technologies, molecular biology, nanomaterials, analytical chemistry, miniaturization, system integration, and data management, LOAD systems hold the potential to deliver POC infection diagnostic tools with unprecedented performance regarding time, accuracy, and cost. We hope the new insight and promise of LOAD systems for POC infection diagnostics presented in this Account can spark new ideas and inspire further research and development to create better healthcare systems for current and future pandemics.

Clinical course of asymptomatic malignant pleural effusion in non-small cell lung cancer patients: A multicenter retrospective study.

ABSTRACT: The British Thoracic Society guidelines recommend observation for patients with asymptomatic malignant pleural effusion (MPE). However, asymptomatic MPE can become symptomatic. This study examined the clinical course of asymptomatic MPE in patients with non-small cell lung cancer (NSCLC), including the incidence and timing of symptom development of asymptomatic MPE and the associated factors.Retrospective data of 4822 NSCLC patients between January 2012 and December 2017 were reviewed. Symptom development of asymptomatic MPE was defined as the development of symptoms requiring additional treatment, such as insertion of a chest tube, within 1 year in patients who lacked MPE symptoms at the time of diagnosis. Clinical information, pathological parameters, and radiological characteristics were reviewed. Patient data up to 1 year from the initial diagnosis were reviewed.Of 113 patients with asymptomatic MPE, 46 (41%) became symptomatic within 1 year despite appropriate anticancer treatment. The median time to symptom development was 4 months, and 38 patients (83%) developed symptoms within 6 months. Multivariate logistic regression showed that female sex (odds ratio [OR], 0.256; 95% confidence interval [CI], 0.101-0.649; P = .004) and the depth of pleural effusion on initial computed tomography (CT) (OR, 0.957; 95% CI, 0.932-0.982; P = .001) were independently associated with symptom development of asymptomatic MPE.A fraction of 41% of patients with asymptomatic MPE became symptomatic within 1 year. Female sex and larger MPE on initial CT were independently associated with symptom development of asymptomatic MPE.

The Neuroprotective Effects of GPR4 Inhibition through the Attenuation of Caspase Mediated Apoptotic Cell Death in an MPTP Induced Mouse Model of Parkinson's Disease.

The proton-activated G protein-coupled receptor (GPCR) 4 (GPR4) is constitutively active at physiological pH, and GPR4 knockout protected dopaminergic neurons from caspase-dependent mitochondria-associated apoptosis. This study explored the role of GPR4 in a 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-treated mouse model of Parkinson's disease (PD). In mice, subchronic MPTP administration causes oxidative stress-induced apoptosis in the dopaminergic neurons of the substantia nigra pars compacta (SNpc), resulting in motor deficits. NE52-QQ57, a selective GPR4 antagonist, reduced dopaminergic neuronal loss in MPTP-treated mice, improving motor and memory functions. MPTP and NE52-QQ57 co-treatment in mice significantly decreased pro-apoptotic marker Bax protein levels and increased anti-apoptotic marker Bcl-2 protein levels in the SNpc and striatum. MPTP-induced caspase 3 activation and poly (ADP-ribose) polymerase (PARP) cleavage significantly decreased in the SNpc and striatum of mice co-treated with NE52-QQ57. MPTP and NE52-QQ57 co-treatment significantly increased tyrosine hydroxylase (TH)-positive cell numbers in the SNpc and striatum compared with MPTP alone. NE52-QQ57 and MPTP co-treatment improved rotarod and pole test-assessed motor performance and improved Y-maze test-assessed spatial memory. Our findings suggest GPR4 may represent a potential therapeutic target for PD, and GPR4 activation is involved in caspase-mediated neuronal apoptosis in the SNpc and striatum of MPTP-treated mice.

Unexpected exposure to Mycobacterium tuberculosis during bronchoscopy using radial probe endobronchial ultrasound.

BACKGROUND: Bronchoscopy using radial probe endobronchial ultrasound (EBUS) is performed when a peripheral lung lesion (PLL) is suspected to be malignant. However, pulmonary tuberculosis is diagnosed in some patients, and healthcare workers could therefore be exposed to tuberculosis if sufficient precautions are not taken. In this study, we examined the proportion of and factors associated with unexpected exposure to Mycobacterium tuberculosis during bronchoscopy using radial probe EBUS. METHODS: This retrospective study included 970 patients who received bronchoscopy using radial probe EBUS between December 2015 and November 2018. Clinical, histological, radiological, and microbiological data were reviewed. RESULTS: Pulmonary tuberculosis was diagnosed in 31 patients (3.2%) during bronchoscopy using radial probe EBUS. Patients with a lower age were significantly more likely to be diagnosed with tuberculosis than elderly patients (odds ratio [OR], 0.951; 95% confidence interval [CI], 0.924-0.978; P = 0.001). Among the various CT findings, a low HUs difference between pre- and post-enhanced CT (OR, 0.976; 95% CI, 0.955-0.996; P = 0.022), the presence of concentric cavitation (OR, 5.211; 95% CI, 1.447-18.759; P = 0.012), and the presence of satellite centrilobular nodules (OR, 22.925; 95% CI, 10.556-49.785; P < 0.001) were independently associated with diagnosis of tuberculosis. CONCLUSIONS: The proportion of unexpected exposure to Mycobacterium tuberculosis during bronchoscopy using radial probe EBUS was 3.2%. A higher risk was independently associated with a younger age and CT findings of a small difference in HUs between pre- and post-enhancement images, concentric cavitation, and the presence of a satellite centrilobular nodule.

The GCN5: its biological functions and therapeutic potentials.

General control non-depressible 5 (GCN5) or lysine acetyltransferase 2A (KAT2A) is one of the most highly studied histone acetyltransferases. It acts as both histone acetyltransferase (HAT) and lysine acetyltransferase (KAT). As an HAT it plays a pivotal role in the epigenetic landscape and chromatin modification. Besides, GCN5 regulates a wide range of biological events such as gene regulation, cellular proliferation, metabolism and inflammation. Imbalance in the GCN5 activity has been reported in many disorders such as cancer, metabolic disorders, autoimmune disorders and neurological disorders. Therefore, unravelling the role of GCN5 in different diseases progression is a prerequisite for both understanding and developing novel therapeutic agents of these diseases. In this review, we have discussed the structural features, the biological function of GCN5 and the mechanical link with the diseases associated with its imbalance. Moreover, the present GCN5 modulators and their limitations will be presented in a medicinal chemistry perspective.

Evaluation of factors affecting the visualization of dye after transbronchial dye injection: an animal experiment.

BACKGROUND: Since peripheral lung lesions can be frequently visualized on computed tomography (CT), various methods of localization for thoracoscopic surgery have been developed. In the case of transbronchial dye injection (TDI), there can be difficulties with dye visualization through the thoracoscope depending on early disappearance of the dye due to diffusion before field exposure. Herein, we performed an animal experiment to determine the appropriate dye amount and the duration of visualization. METHODS: Twelve pigs were experimented as following four groups (n=3): group 1 received 0.6 mL of dye; group 2 as 0.8 mL; and group 3 as 1.0 mL, all followed by 2.0 mL of air injection and group 4, with 1.0 mL of dye followed no air injection to evaluate the utility of air injection. The detection, the peak time, the wash-out time were measured. RESULTS: The mean detection times, the peak time, and the mean wash-out times for 0.6, 0.8, and 1.0 mL of dye were not significantly different (P=0.195, 0.092, 0.06). However, regardless of the injected amount, it usually lasts in 2 hours. Comparing with non-air injection group, the peak time and wash-out time were statistically significantly different in injected group; P=0.07 and 0.001. CONCLUSIONS: The marking could be identified clearly at about 2 hours after TDI regardless of the amount of indigo carmine injected. However, in cases with longer duration to exposure, especially in cases with severe adhesions, it might be necessary to discover the mixture of dye which will last longer for visualization of lung nodules.

Therapeutic Potential of Lindera obtusiloba: Focus on Antioxidative and Pharmacological Properties.

Lindera obtusiloba (LO) BLUME from the genus Lindera (Lauraceae) is a medicinal herb traditionally used in Southeast Asian countries. Indigenously, extracts of different parts of the plant have been used to improve blood circulation and treat allergy, inflammation, rheumatism, and liver diseases. LO is a rich source of therapeutically beneficial antioxidative phytochemicals, such as flavonoids, butenolides, lignans and neolignans. Moreover, recent studies have unravelled the pharmacological properties of several newly found active constituents of LO, such as anti-inflammatory antioxidants (+)-syringaresinol, linderin A, anti-atherosclerotic antioxidant (+)-episesamin, anti-melanogenic antioxidants quercitrin and afzelin, cytotoxic 2-(1-methoxy-11-dodecenyl)-penta-2,4-dien-4-olide, (2Z,3S,4S)-2-(11-dodecenylidene)-3-hydroxy-4-methyl butanolide, anti-allergic koaburaside, (6-hydroxyphenyl)-1-O-beta-d-glucopyranoside and 2,6-dimethoxy-4-hydroxyphenyl-1-O-beta-d-glucopyranoside and the antiplatelet-activity compound Secolincomolide A. These findings demonstrate that LO can be a potential source of antioxidants and other prospective therapeutically active constituents that can lead to the development of oxidative stress-mediated diseases, such as cardiovascular disorders, neurodegenerative disorders, allergies, inflammation, hepatotoxicity, and cancer. Here, the antioxidant properties of different species of Lindera genus are discussed briefly. The traditional use, phytochemistry, antioxidative and pharmacological properties of LO are also considered to help researchers screen potential lead compounds and design and develop future therapeutic agents to treat oxidative stress-mediated disorders.

2-Hydroxy-4-Methylbenzoic Anhydride Inhibits Neuroinflammation in Cellular and Experimental Animal Models of Parkinson's Disease.

Microglia-mediated neuroinflammation is one of the key mechanisms involved in acute brain injury and chronic neurodegeneration. This study investigated the inhibitory effects of 2-hydroxy-4-methylbenzoic anhydride (HMA), a novel synthetic derivative of HTB (3-hydroxy-4-trifluoromethylbenzoic acid) on neuroinflammation and underlying mechanisms in activated microglia in vitro and an in vivo mouse model of Parkinson's disease (PD). In vitro studies revealed that HMA significantly inhibited lipopolysaccharide (LPS)-stimulated excessive release of nitric oxide (NO) in a concentration dependent manner. In addition, HMA significantly suppressed both inducible NO synthase and cyclooxygenase-2 (COX-2) at the mRNA and protein levels in LPS-stimulated BV-2 microglia cells. Moreover, HMA significantly inhibited the proinflammatory cytokines such as interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha in LPS-stimulated BV-2 microglial cells. Furthermore, mechanistic studies ensured that the potent anti-neuroinflammatory effects of HMA (0.1, 1.0, and 10 µM) were mediated by phosphorylation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) in LPS-stimulated BV-2 cells. In vivo evaluations revealed that intraperitoneal administration of potent neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 20 mg/kg, four times a 1 day) in mice resulted in activation of microglia in the brain in association with severe behavioral deficits as assessed using a pole test. However, prevention of microglial activation and attenuation of Parkinson's disease (PD)-like behavioral changes was obtained by oral administration of HMA (30 mg/kg) for 14 days. Considering the overall results, our study showed that HMA exhibited strong anti-neuroinflammatory effects at lower concentrations than its parent compound. Further work is warranted in other animal and genetic models of PD for evaluating the efficacy of HMA to develop a potential therapeutic agent in the treatment of microglia-mediated neuroinflammatory disorders, including PD.

GPR4 Knockout Improves the Neurotoxin-Induced, Caspase-Dependent Mitochondrial Apoptosis of the Dopaminergic Neuronal Cell.

In Parkinson's disease, mitochondrial oxidative stress-mediated apoptosis is a major cause of dopaminergic neuronal loss in the substantia nigra (SN). G protein-coupled receptor 4 (GPR4), previously recognised as an orphan G protein coupled-receptor (GPCR), has recently been claimed as a member of the group of proton-activated GPCRs. Its activity in neuronal apoptosis, however, remains undefined. In this study, we investigated the role of GPR4 in the 1-methyl-4-phenylpyridinium ion (MPP+) and hydrogen peroxide (H2O2)-treated apoptotic cell death of stably GPR4-overexpressing and stably GPR4-knockout human neuroblastoma SH-SY5Y cells. In GPR4-OE cells, MPP+ and H2O2 were found to significantly increase the expression levels of both mRNA and proteins of the pro-apoptotic Bcl-2-associated X protein (Bax) genes, while they decreased the anti-apoptotic B-cell lymphoma 2 (Bcl-2) genes. In addition, MPP+ treatment activated Caspase-3, leading to the cleavage of poly (ADP-ribose) polymerase (PARP) and decreasing the mitochondrial membrane potential (ΔΨm) in GPR4-OE cells. In contrast, H2O2 treatment significantly increased the intracellular calcium ions (Ca2+) and reactive oxygen species (ROS) in GPR4-OE cells. Further, chemical inhibition by NE52-QQ57, a selective antagonist of GPR4, and knockout of GPR4 by clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 decreased the Bax/Bcl-2 ratio and ROS generation, and stabilised the ΔΨm, thus protecting the SH-SY5Y cells from MPP+- or H2O2-induced apoptotic cell death. Moreover, the knockout of GPR4 decreased the proteolytic degradation of phosphatidylinositol biphosphate (PIP2) and subsequent release of the endoplasmic reticulum (ER)-stored Ca2+ in the cytosol. Our results suggest that the pharmacological inhibition or genetic deletion of GPR4 improves the neurotoxin-induced caspase-dependent mitochondrial apoptotic pathway, possibly through the modulation of PIP2 degradation-mediated calcium signalling. Therefore, GPR4 presents a potential therapeutic target for neurodegenerative disorders such as Parkinson's disease.