Multi-Omics Identification of Genetic Alterations in Head and Neck Squamous Cell Carcinoma and Therapeutic Efficacy of HNC018 as a Novel Multi-Target Agent for c-MET/STAT3/AKT Signaling Axis.

Amongst the most prevalent malignancies worldwide, head and neck squamous cell carcinoma (HNSCC) is characterized by high morbidity and mortality. The failure of standard treatment modalities, such as surgery, radiotherapy, and chemotherapy, demands the need for in-depth understanding of the complex signaling networks involved in the development of treatment resistance. A tumor's invasive growth and high levels of intrinsic or acquired treatment resistance are the primary causes of treatment failure. This may be a result of the presence of HNSCC's cancer stem cells, which are known to have self-renewing capabilities that result in therapeutic resistance. Using bioinformatics methods, we discovered that elevated expressions of MET, STAT3, and AKT were associated with poor overall survival in HNSCC patients. We then evaluated the therapeutic potential of our newly synthesized small molecule HNC018 towards its potential as a novel anticancer drug. Our computer-aided structure characterization and target identification study predicted that HNC018 could target these oncogenic markers implicated in HNSCC. Subsequently, the HNC018 has demonstrated its anti-proliferative and anticancer activities towards the head and neck squamous cell carcinoma cell lines, along with displaying the stronger binding affinities towards the MET, STAT3, and AKT than the standard drug cisplatin. Reduction in the clonogenic and tumor-sphere-forming ability displays HNC018's role in decreasing the tumorigenicity. Importantly, an vivo study has shown a significant delay in tumor growth in HNC018 alone or in combination with cisplatin-treated xenograft mice model. Collectively with our findings, HNC018 highlights the desirable properties of a drug-like candidate and could be considered as a novel small molecule for treating head and neck squamous cell carcinoma.

HADC8 Inhibitor WK2-16 Therapeutically Targets Lipopolysaccharide-Induced Mouse Model of Neuroinflammation and Microglial Activation.

Glial activation and neuroinflammatory processes play important roles in the pathogenesis of brain abscess and neurodegenerative diseases. Activated glial cells can secrete various proinflammatory cytokines and neurotoxic mediators, which contribute to the exacerbation of neuronal cell death. The inhibition of glial activation has been shown to alleviate neurodegenerative conditions. The present study was to investigate the specific HDAC8 inhibitor WK2-16, especially its effects on the neuroinflammatory responses through glial inactivation. WK2-16 significantly reduced the gelatinolytic activity of MMP-9, and expression of COX-2/iNOS proteins in striatal lipopolysaccharide (LPS)-induced neuroinflammation in C57BL/6 mice. The treatment of WK2-16 markedly improved neurobehavioral deficits. Immunofluorescent staining revealed that WK2-16 reduced LPS-stimulated astrogliosis and microglial activation in situ. Consistently, cellular studies revealed that WK2-16 significantly suppressed LPS-induced mouse microglia BV-2 cell proliferation. WK2-16 was proven to concentration-dependently induce the levels of acetylated SMC3 in microglial BV-2 cells. It also reduced the expression of COX-2/iNOS proteins and TNF-α production in LPS-activated microglial BV-2 cells. The signaling studies demonstrated that WK2-16 markedly inhibited LPS-activated STAT-1/-3 and Akt activation, but not NF-κB or MAPK signaling. In summary, the HADC8 inhibitor WK2-16 exhibited neuroprotective effects through its anti-neuroinflammation and glial inactivation properties, especially in microglia in vitro and in vivo.

Synthesis of C-4-Substituted Steviol Derivatives and Their Inhibitory Effects against Hepatitis B Virus.

ent-13-Hydroxykaur-16-ene-19-N-butylureide (6) was one of 33 synthesized C-4-substituted steviol derivatives that were evaluated for their effects on hepatitis B virus (HBV) surface antigen (HBsAg) secretion. The IC50 (16.9 µM) and SI (57.7) values for inhibiting HBV DNA replication of compound 6 were greater than those of the reference compound, lamivudine (3-TC; IC50: 107.5 µM; SI: 22.0). Thus, the anti-HBV mechanism of 6 was investigated, and it specifically inhibited viral gene expression and reduced viral DNA levels, as well as potently attenuated all of the viral promoter activity of HBV-expressing Huh7 cells. Examination of cellular signaling pathways found that 6 inhibited the activities of the nuclear factor (NF)-κB- and activator protein (AP)-1 element-containing promoters, but had no effects on AP-2 or interferon-stimulated response element (ISRE)-containing promoters in HBV-expressing cells. Meanwhile, it significantly eliminated NF-κB and extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) signaling-related protein levels and inhibited their phosphorylation in HBV-transfected Huh7 cells. The inhibitory potency of 6 against HBV DNA replication was reversed by cotransfecting the NF-κB p65 expression plasmid. Using the MAPK-specific activator anisomycin also reversed the inhibitory effect of 6 on viral DNA replication. The present findings suggest that the anti-HBV mechanism of 6 is partly mediated through the NF-κB and MAPK signaling pathways.

Synthesis and anti-hepatitis B virus activity of C4 amide-substituted isosteviol derivatives.

A series of novel isosteviol derivatives having C4-amide substituents were synthesized in order to test for antiviral effects against the hepatitis B virus (HBV) in vitro. Among them, IN-4 [N-(propylcarbonyl)-4α-amino-19-nor-ent-16-ketobeyeran] (5) exhibited inhibitory activity against secretion of HBsAg and HBeAg as well as inhibition of HBV DNA replication. Therefore, the mechanism of its antiviral activity was further analyzed using HBV-transfected Huh7 cells. Exposure to IN-4 produced minimal inhibitory effects on viral precore/pregenomic RNA expression. However, expression levels of the 2.4/2.1-kb preS/major S RNA of the viral surface gene significantly decreased, along with intracellular levels of HBV DNA. A promoter activity analysis demonstrated that IN-4 significantly inhibited viral X, S, and preS expression levels but not viral core promoter activities. In particular, IN-4 was observed to significantly inhibit HBV gene regulation by disrupting nuclear factor (NF)-κB-associated promoter activity. In addition, the nuclear expression of p65/p50 NF-κB member proteins was attenuated following IN-4 treatment, while cytoplasmic IκBα protein levels were enhanced. Meanwhile, IN-4 was observed to inhibit the binding activity of NF-κB to putative DNA elements. Furthermore, transfection of a p65 expression plasmid into Huh7 cells significantly reversed the inhibitory effect of IN-4 on HBV DNA levels, providing further evidence of the central role of NF-κB in its antiviral mechanism. It is therefore suggested that IN-4 inhibits HBV by interfering with the NF-κB signaling pathway, resulting in downregulation of viral gene expression and DNA replication.

Increased risk of dementia in people with previous exposure to general anesthesia: a nationwide population-based case-control study.

BACKGROUND: Dementia, which leads to disability, is one of the important diseases occurring among older populations. However, the exact mechanism of the disease remains unknown. The potential risk factor of general anesthesia (GA) in the development of dementia is a controversial topic. Therefore, this study aimed to evaluate the association between previous exposure to different GA types and the incidence of dementia. METHODS: Using the claims data of 1 million insured residents covered by Taiwan's universal health insurance from 2005 to 2009, 5345 newly diagnosed dementia patients older than 50 years were eligible for the study group. The control group, which consisted of 21,380 individuals without dementia, was matched for age, gender, and index date. GA was categorized into three subtypes: endotracheal tube intubation general anesthesia (ETGA), intravenous injection general anesthesia (IVGA) or intramuscular injection general anesthesia (IMGA), and heavy sedation. The multiple logistic regression model was used for analyses. RESULTS: Individuals exposed to surgery under ETGA (odds ratio [OR], 1.34; 95% confidence interval [CI], 1.25-1.44) and those exposed to surgery under IVGA or IMGA (OR, 1.28; 95% CI, 1.14-1.43) were at significantly higher risk of dementia in a dose-response relationship (P < .0001), whereas surgery under heavy sedation was not associated with increased risk of dementia (OR, 1.04; 95% CI, 0.68-1.59). The dementia risk for subjects with diabetes mellitus who received surgery under ETGA (OR, 1.59; 95% CI, 1.42-1.78), hypertension (OR, 1.98; 95% CI, 1.78-2.21), atherosclerosis (OR, 1.35; 95% CI, 1.22-1.50), or after having experienced a stroke (OR, 3.52; 95% CI, 3.13-3.97), but no interaction was found between surgery under ETGA and depression for the risk of dementia. CONCLUSIONS: A history of previous exposure to surgery under GA might be associated with an increased risk of dementia, particularly in subjects who have undergone repeated exposure to GA. In addition, subjects who had received surgery under ETGA with comorbidities such as stroke, hypertension, diabetes mellitus, and atherosclerosis could have a potential relationship with dementia risk.

Carbamazepine attenuates inducible nitric oxide synthase expression through Akt inhibition in activated microglial cells.

UNLABELLED: Abstract Background: Carbamazepine, which was developed primarily for the treatment of epilepsy, is now also useful for the treatment of non-epileptic disorders and inflammatory hyperalgesia. However, the mechanism of its anti-neuroinflammatory action remains poorly understood. OBJECTIVE: This study elucidates the anti-neuroinflammatory capacity of carbamazepine on microglial activation and the relative mechanisms involved. MATERIALS AND METHODS: The microglial BV-2 cells were pretreated with carbamazepine for 15 min before activation by lipopolysaccharide (LPS). After LPS stimulation, the expression of inducible nitric oxide synthase (iNOS) was analyzed by Western blotting (WB) and reverse transcription-polymerase chain reaction. Signaling proteins and cyclooxygenase (COX)-2 were also evaluated by WB. The levels of nitrate and tumor necrosis factor (TNF)-α were analyzed by the Griess method and enzyme-linked immunosorbant assay, respectively. The formation of intracellular reactive oxygen species (ROS) was examined by fluorescent analysis. RESULTS: Carbamazepine strongly attenuated LPS-induced production of NO and iNOS protein at concentrations of 5, 10, and 20 µM. Consistently, it could markedly suppress iNOS mRNA expression stimulated by LPS. Among the signaling pathways, LPS-mediated IκBα degradation or JNK MAPK phosphorylation was not affected by carbamazepine. Interestingly, it was found that carbamazepine could concentration-dependently inhibit LPS-activated phospho-Akt expression. Nevertheless, LPS-induced ROS production was not affected by carbamazepine. Carbamazepine (20 µM) affected either COX-2 expression or TNF-α production induced by LPS with approximately 70% and 51% inhibition, respectively. DISCUSSION AND CONCLUSION: Our findings showed that carbamazepine exerted selective inhibition on LPS-induced microglial iNOS expression through the down-regulation of Akt activation, and thus may play a pivotal role of anti-neuroinflammation in its therapeutic efficacy.

Therapeutic potential of EGFR/mTOR/Nf-kb targeting small molecule for the treatment of non-small cell lung cancer.

Despite the therapeutic advancement with chemotherapy and targeted therapy against non-small-cell lung cancer (NSCLC), most patients ultimately develop resistance to these drugs, exhibiting disease progression, metastasis, and worse prognosis. There is, therefore, a need for the development of novel multi-targeted therapies that can offer a high therapeutic index with lesser chances of drug resistance against NSCLC. In the present study, we evaluated the therapeutic potential of a novel multi-target small molecule NLOC-015A for targeted treatment of NSCLC. Our in vitro studies revealed that NLOC-015A exhibited a broad spectrum of anticancer activities against lung cancer cell line. NLOC-015A decreased the viability of H1975 and H1299 cells with respective IC50 values of 2.07±0.19 and 1.90±0.23 µm. In addition, NLOC-015A attenuated the oncogenic properties (colony formation, migratory ability, and spheroid formation) with concomitant downregulation of expression levels of epidermal growth factor receptor (EGFR)/mammalian target of rapamycin (mTOR)/AKT, nuclear factor (NF)-κB, signaling network. In addition, the stemness inhibitory effect of NLOC0-15A was accompanied by decreased expression levels of aldehyde dehydrogenase (ALDH), MYC Proto-Oncogene (C-Myc), and (sex-determining region Y)-box 2 (SOX2) in both H1975 and H1299 cell lines. Furthermore, NLOC-015A suppressed the tumor burden and increased the body weight and survival of H1975 xenograft-bearing mice. Treatment with NLOC-015A also attenuated biochemical and hematological alterations in the tumor bearing mice. Interestingly, NLOC-015A synergistically enhanced the in vitro efficacy, and therapeutic outcome of osimertinib in vivo. In addition, the toxicity of osimertinib was significantly attenuated by combination with NLOC-015A. Altogether, our findings suggested that combining osimertinib with NLOC-015 appears to be a promising way to improve osimertinib's efficacy and achieve better therapeutic results against NSCLC. We therefore suggest that NLOC-015A might represent a new candidate for treating NSCLC via acting as a multitarget inhibitor of EGFR/mTOR/NF-Κb signaling networks and efficiently compromising the oncogenic phenotype of NSCLC.

In Silico Evaluation of HN-N07 Small Molecule as an Inhibitor of Angiogenesis and Lymphangiogenesis Oncogenic Signatures in Non-Small Cell Lung Cancer.

Tumor angiogenesis and lymphangiogenesis pathways have been identified as important therapeutic targets in non-small cell lung cancer (NSCLC). Bevacizumab, which is a monoclonal antibody, was the initial inhibitor of angiogenesis and lymphangiogenesis that received approval for use in the treatment of advanced non-small cell lung cancer (NSCLC) in combination with chemotherapy. Despite its usage, patients may still develop resistance to the treatment, which can be attributed to various histological subtypes and the initiation of treatment at advanced stages of cancer. Due to their better specificity, selectivity, and safety compared to chemotherapy, small molecules have been approved for treating advanced NSCLC. Based on the development of multiple small-molecule antiangiogenic drugs either in house and abroad or in other laboratories to treat NSCLC, we used a quinoline-derived small molecule-HN-N07-as a potential target drug for NSCLC. Accordingly, we used computational simulation tools and evaluated the drug-likeness properties of HN-N07. Moreover, we identified target genes, resulting in the discovery of the target BIRC5/HIF1A/FLT4 pro-angiogenic genes. Furthermore, we used in silico molecular docking analysis to determine whether HN-N07 could potentially inhibit BIRC5/HIF1A/FLT4. Interestingly, the results of docking HN-N07 with the BIRC5, FLT4, and HIF1A oncogenes revealed unique binding affinities, which were significantly higher than those of standard inhibitors. In summary, these results indicate that HN-N07 shows promise as a potential inhibitor of oncogenic signaling pathways in NSCLC. Ongoing studies that involve in vitro experiments and in vivo investigations using tumor-bearing mice are in progress, aiming to evaluate the therapeutic effectiveness of the HN-N07 small molecule.

Preclinical Evaluation of a Novel Small Molecule LCC-21 to Suppress Colorectal Cancer Malignancy by Inhibiting Angiogenic and Metastatic Signatures.

Colorectal cancer (CRC) is one of the most common cancers, and it frequently metastasizes to the liver and lymph nodes. Despite major advances in treatment modalities, CRC remains a poorly characterized biological malignancy, with high reported cases of deaths globally. Moreover, cancer stem cells (CSCs) and their microenvironment have been widely shown to promote colon cancer development, progression, and metastasis. Therefore, an understanding of the underlying mechanisms that contribute to the maintenance of CSCs and their markers in CRC is crucial in efforts to treat cancer metastasis and develop specific therapeutic targets for augmenting current standard treatments. Herein, we applied computational simulations using bioinformatics to identify potential theranostic markers for CRC. We identified the overexpression of vascular endothelial growth factor-α (VEGFA)/ß-catenin/matrix metalloproteinase (MMP)-7/Cluster of Differentiation 44 (CD44) in CRC to be associated with cancer progression, stemness, resistance to therapy, metastasis, and poor clinical outcomes. To further investigate, we explored in silico molecular docking, which revealed potential inhibitory activities of LCC-21 as a potential multitarget small molecule for VEGF-A/CTNNB1/MMP7/CD44 oncogenic signatures, with the highest binding affinities displayed. We validated these finding in vitro and demonstrated that LCC-21 inhibited colony and sphere formation, migration, and invasion, and these results were further confirmed by a Western blot analysis in HCT116 and DLD-1 cells. Thus, the inhibitory effects of LCC-21 on these angiogenic and onco-immunogenic signatures could be of translational relevance as potential CRC biomarkers for early diagnosis.

Multiomics Study of a Novel Naturally Derived Small Molecule, NSC772864, as a Potential Inhibitor of Proto-Oncogenes Regulating Cell Cycle Progression in Colorectal Cancer.

Colorectal cancer (CRC) is one of the most prevalent malignant tumors, and it contributes to high numbers of deaths globally. Although advances in understanding CRC molecular mechanisms have shed significant light on its pathogenicity, current treatment options, including combined chemotherapy and molecular-targeted agents, are still limited due to resistance, with almost 25% of patients developing distant metastasis. Therefore, identifying novel biomarkers for early diagnosis is crucial, as they will also influence strategies for new targeted therapies. The proto-oncogene, c-Met, a tyrosine kinase that promotes cell proliferation, motility, and invasion; c-MYC, a transcription factor associated with the modulation of the cell cycle, proliferation, apoptosis; and cyclin D1 (CCND1), an essential regulatory protein in the cell cycle, all play crucial roles in cancer progression. In the present study, we explored computational simulations through bioinformatics analysis and identified the overexpression of c-Met/GSK3ß/MYC/CCND1 oncogenic signatures that were associated with cancer progression, drug resistance, metastasis, and poor clinical outcomes in CRC. We further demonstrated the anticancer activities of our newly synthesized quinoline-derived compound, NSC772864, against panels of the National Cancer Institute's human CRC cell lines. The compound exhibited cytotoxic activities against various CRC cell lines. Using target prediction tools, we found that c-Met/GSK3ß/MYC/CCND1 were target genes for the NSC772864 compound. Subsequently, we performed in silico molecular docking to investigate protein-ligand interactions and discovered that NSC772864 exhibited higher binding affinities with these oncogenes compared to FDA-approved drugs. These findings strongly suggest that NSC772864 is a novel and potential antiCRC agent.

Diagnosis of kidney insufficiency by using the pressure waveforms of wrist-type sphygmomanometers: toward a convenient point-of-care device.

OBJECTIVES: Digital sphygmomanometers have been used for more than 40 years in Western medicine for accurately measuring systolic and diastolic blood pressures, which are vital signs observed for the diagnosis of different diseases. Similarly, traditional Chinese medicine (TCM) has been using wrist pulse diagnosis for thousands of years. Some studies have combined digital wrist pulse signals and the diagnosis method of TCM to quantify pulse waves and identify diseases. However, the effectiveness of this approach is limited because of scattered methods and complex pathological features. Moreover, the literature on TCM does not provide quantitative data or objective indicators. METHODS: In this prospective study, we developed a diagnostic system that contains a modified sphygmomanometer. In addition, we designed a procedure for analyzing pulse waves with 156 features of harmonic modes and a decision tree method for diagnosing kidney insufficiency. RESULTS: In the decision tree method, at least three features of harmonic modes can achieve an accuracy of 0.86, a specificity of 0.91, and a Cohen's kappa coefficient of 0.72. By comparison, the random forest method can achieve an accuracy of 0.99, a specificity of 0.99, and a Cohen's kappa coefficient of 0.94 within 200 trees. The results of this study indicated that even in patients with kidney insufficiency and complex etiology, common features can be distinguished by identifying changes in pulse waveforms. CONCLUSION: By using the modified sphygmomanometer to measure blood pressure, people can monitor their health status and take care of it in advance by simply measuring their blood pressure.

Harmonic effects of sham acupuncture at Tsu San Li (St-36) in the radial pulse wave.

Background and aim: Acupuncture has been criticized as a theatrical placebo for the sham effect. Unfortunately, sham tests used in control groups in acupuncture studies have always ignored the underlying biophysical factors, including resonance involved in acupuncture points and meridians. Experimental procedure: In this study, the effects of sham acupuncture at Tsu San Li (St-36) were examined by analyzing noninvasive 30-sec. recordings of the radial arterial pulses for 3 groups of patients treated with different probes (blunt, sharp, and patch) on the superficial skin of the acupuncture point. The 3 groups were then treated with the sharp probe for 3 different periods (16, 30, and 50 s). Then we compared the harmonics of the radial arterial pulse after Fourier transformation before and after the treatment. Results: Our results indicated that different probes have effects similar to needle insertion at Tsu San Li. Meanwhile, the harmonic effect of the sharp probe strengthened as time increased. Conclusions: This study revealed that the meridian effect of sham testing from mechanical stimulation, even from simple touch, on an acupuncture point, should not be overlooked. Thus, even simple touch can be added to electrical or laser acupuncture.

A Novel Isotope-labeled Small Molecule Probe CC12 for Anti-glioma via Suppressing LYN-mediated Progression and Activating Apoptosis Pathways.

Background: Glioblastoma multiforme (GBM) is the most lethal malignancy in brain, which is surrounded by the blood-brain barrier (BBB), which limits the efficacy of standard treatments. Developing an effective drug that can penetrate the blood-brain barrier (BBB) remains a critical challenge in the fight against GBM. CC12 (NSC749232) is an anthraquinone tetraheterocyclic homolog with a lipophilic structure that may facilitate penetration of the brain area. Methods: We used temozolomide sensitive and resistance GBM cells and animal model to identify the CC12 delivery, anti-tumor potential and its underlying mechanism. Results: Importantly, toxicity triggered by CC12 was not associated with the methyl guanine-DNA methyl transferase (MGMT) methylation status which revealed a greater application potential compared to temozolomide. Alexa F488 cadaverine-labelled CC12 successfully infiltrated into the GBM sphere; in addition, 68Ga-labeled CC12 was also found in the orthotopic GBM area. After passing BBB, CC12 initiated both caspase-dependent intrinsic/extrinsic apoptosis pathways and apoptosis-inducing factor, EndoG-related caspase-independent apoptosis signaling in GBM. RNA sequence analysis from The Cancer Genome Atlas indicated that LYN was overexpressed in GBM is associated with poorer overall survival. We proved that targeting of LYN by CC12 may diminish GBM progression and suppress it downstream factors such as signal transduction and activator of extracellular signal-regulated kinases (ERK)/transcription 3 (STAT3)/nuclear factor (NF)-κB. CC12 was also found to participate in suppressing GBM metastasis and dysregulation of the epithelial-mesenchymal transition (EMT) through inactivation of the LYN axis. Conclusion: CC12, a newly developed BBB-penetrating drug, was found to possess an anti-GBM capacity via initiating an apoptotic mechanism and disrupting LYN/ERK/STAT3/NF-κB-regulated GBM progression.

Computational identification of novel signature of T2DM-induced nephropathy and therapeutic bioactive compounds from Azanza garckeana.

OBJECTIVES: Diabetic nephropathy (DN) is one of the most prevalent secondary complications associated with diabetes mellitus. Decades of research have implicated multiple pathways in the etiology and pathophysiology of diabetic nephropathy. There has been no reliable predictive biomarkers for the onset or progression of DN and no successful treatments are available. METHODS: In the present study, we explored the datasets of RNA sequencing data from patients with Type II diabetes mellitus (T2DM)-induced nephropathy to identify a novel gene signature. We explored the target bioactive compounds identified from Azanza garckeana, a medicinal plant commonly used by the traditional treatment of diabetes nephropathy. RESULTS: Our analysis identified lymphotoxin beta (LTB), SRY-box transcription factor 4 (SOX4), SOX9, and WAP four-disulfide core domain protein 2 (WFDC2) as novel signatures of T2DM-induced nephropathy. Additional analysis revealed the pathological involvement of the signature in cell-cell adhesion, immune, and inflammatory responses during diabetic nephropathy. Molecular docking and dynamic simulation at 100 ns conducted studies revealed that among the three compounds, Terpinen-4-ol exhibited higher binding efficacies (binding energies (ΔG) = -3.9~5.5 kcal/mol) against the targets. The targets, SOX4, and SOX9 demonstrated higher druggability towards the three compounds. WFDC2 was the least attractive target for the compounds. CONCLUSION: The present study was relevant in the diagnosis, prognosis, and treatment follow up of patients with diabetes induced nephropathy. The study provided an insight into the therapeutic application of the bioactive principles from Azanza garckeana. Continued follow-up invitro validations study are ongoing in our laboratory.

Attenuation of hyperglycemia-associated dyslipidemic, oxidative, cognitive, and inflammatory crises via modulation of neuronal ChEs/NF-κB/COX-2/NOx, and hepatorenal functional deficits by the Tridax procumbens extract.

Tridax procumbens (cotton buttons) is a flowering plant with a medicinal reputation for treating infections, wounds, diabetes, and liver and kidney diseases. The present research was conducted to evaluate the possible protective effects of the T. procumbens methanolic extract (TPME) on an experimentally induced type 2 diabetes rat model. Wistar rats with streptozotocin (STZ)-induced diabetes were randomly allocated into five groups of five animals each, viz., a normal glycemic group (I), diabetic rats receiving distilled water group (II), diabetic rats with 150 (III) and 300 mg/kg of TPME (IV) groups, and diabetic rats with 100 mg/kg metformin group (V). All treatments were administered for 21 consecutive days through oral gavage. Results: Administration of the T. procumbens extract to diabetic rats significantly restored alterations in levels of fasting blood glucose (FBG), body weight loss, serum and pancreatic insulin levels, and pancreatic histology. Furthermore, T. procumbens significantly attenuated the dyslipidemia (increased cholesterol, low-density lipoprotein-cholesterol (LDL-C), triglycerides, and high-density lipoprotein (HDL) in diabetic rats), serum biochemical alterations (alanine transaminase (ALT), aspartate transaminase (AST), alanine phosphatase (ALP), blood urea nitrogen (BUN), creatinine, uric acid, and urea) and full blood count distortion in rats with STZ-induced diabetes. The TPME also improved the antioxidant status as evidenced by increased superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and decreased malondialdehyde (MDA); and decreased levels of cholinesterases (acetylcholinesterase (AChE) and butyrylcholinesterase (BChE)), and proinflammatory mediators including nuclear factor (NF)-κB, cyclooxygenase (COX)- 2, and nitrogen oxide (NOx) in the brain of rats with STZ-induced diabetes compared to rats with STZ-induced diabetes that received distilled water. However, TPME treatment failed to attenuate the elevated monoamine oxidases and decreased dopamine levels in the brain of rats with STZ-induced diabetes. Extract characterization by liquid chromatography mass spectrometry (LC-MS) identified isorhamnetin (retention time (RT)= 3.69 min, 8.8%), bixin (RT: 25.06 min, 4.72%), and lupeol (RT: 25.25 min, 2.88%) as the three most abundant bioactive compounds that could be responsible for the bioactivity of the plant. In conclusion, the TPME can be considered a promising alternative therapeutic option for managing diabetic complications owing to its antidiabetic, antihyperlipidemic, antioxidant, and anti-inflammatory effects in rats with STZ-prompted diabetes.

Harnessing Nuclear Energy to Gold Nanoparticles for the Concurrent Chemoradiotherapy of Glioblastoma.

Nuclear fission reactions can release massive amounts of energy accompanied by neutrons and γ photons, which create a mixed radiation field and enable a series of reactions in nuclear reactors. This study demonstrates a one-pot/one-step approach to synthesizing radioactive gold nanoparticles (RGNP) without using radioactive precursors and reducing agents. Trivalent gold ions are reduced into gold nanoparticles (8.6-146 nm), and a particular portion of 197Au atoms is simultaneously converted to 198Au atoms, rendering the nanoparticles radioactive. We suggest that harnessing nuclear energy to gold nanoparticles is feasible in the interests of advancing nanotechnology for cancer therapy. A combination of RGNP applied through convection-enhanced delivery (CED) and temozolomide (TMZ) through oral administration demonstrates the synergistic effect in treating glioblastoma-bearing mice. The mean survival for RGNP/TMZ treatment was 68.9 ± 9.7 days compared to that for standalone RGNP (38.4 ± 2.2 days) or TMZ (42.8 ± 2.5 days) therapies. Based on the verification of bioluminescence images, positron emission tomography, and immunohistochemistry inspection, the combination treatment can inhibit the proliferation of glioblastoma, highlighting the niche of concurrent chemoradiotherapy (CCRT) attributed to RGNP and TMZ.

Art therapy for terminal cancer patients in a hospice palliative care unit in Taiwan.

OBJECTIVE: Even though terminal cancer patients receive help from a hospice palliative care team, they have to suffer the pressure of death with deteriorating conditions. This study aims to evaluate the effect of art therapy for these terminal cancer patients. METHOD: The patients involved were terminal cancer patients who were under the care of team members, which included physicians, nurses, social workers, clergy, art therapists, and volunteers in a hospice palliative care unit in Taiwan. The art therapy in our study took the form of visual fine art appreciation and hands-on painting. The effects of the art therapy were evaluated according to patients' feelings, cognitions, and behaviors. RESULTS: There were 177 patients (105 males and 72 females; mean age: 65.4 ±15.8 years) in the study. Each patient received a mean of 2.9 ± 2.0 sessions of the art therapy and produced a mean of 1.8 ± 2.6 pieces of art. During the therapy, most patients described their feelings well, and created art works attentively. Patients expressed these feelings through image appreciation and hands-on painting, among which the landscape was the most common scene in their art. After the therapy, the mean score of patients' artistic expressions (one point to each category: perception of beauty, art appreciation, creativity, hands-on artwork, and the engagement of creating artwork regularly) was 4.0 ± 0.7, significantly higher than the score before therapy (2.2 ± 1.4, p < 0.05). During the therapy, 70% of patients felt much or very much relaxed in their emotional state and 53.1% of patients felt much or very much better physically. SIGNIFICANCE OF RESULTS: Terminal cancer patients in a hospice palliative care unit in Taiwan may benefit from art therapy through visual art appreciation and hands-on creative artwork.

Revealing the suppressive role of protein kinase C delta and p38 mitogen-activated protein kinase (MAPK)/NF-κB axis associates with lenvatinib-inhibited progression in hepatocellular carcinoma in vitro and in vivo.

Nuclear factor-kappa B (NF-κB), an oncogenic transcription factor, modulates tumor formation and progression by inducing the expression of oncogenes involved in proliferation, survival, angiogenesis, and metastasis. Oral multikinase inhibitors, such as sorafenib, regorafenib, and lenvatinib have been used for the treatment of hepatocellular carcinoma (HCC). Both sorafenib and regorafenib were shown to abolish the NF-κB-mediated progression of HCC. However, the effect of lenvatinib on NF-κB-mediated progression of HCC is ambiguous. Therefore, the primary purpose of the present study was to evaluate the inhibitory effect of lenvatinib and its inhibitory mechanism on the NF-κB-mediated progression of HCC in vitro and in vivo. Here, we used two HCC cell lines to identify the cytotoxicity, apoptosis and metastasis effect of lenvatinib. We also applied a Hep3B-bearing animal model to investigate the therapeutic efficacy of lenvatinib on in vivo model. An NF-κB translocation assay, NF-κB reporter gene assay, a Western blotting assay and immunohistochemistry staining were used to investigate the underlying mechanism by which lenvatinib acts on HCC. In this study, we demonstrated that lenvatinib induced extrinsic/intrinsic apoptosis and suppressed the metastasis of HCC both in vitro and in vivo. Lenvatinib may also suppress NF-κB translocation and activation. We also found both protein kinase C delta (PKC-δ) and p38 mitogen-activated protein kinase (MAPK) inactivation participated in lenvatinib-reduced NF-κB signaling. In conclusion, this study reveals that the suppression of PKC-δ, and the p38 MAPK/NF-κB axis is associated with the lenvatinib-inhibited progression of HCC in vitro and in vivo.

Identification of a novel immune-inflammatory signature of COVID-19 infections, and evaluation of pharmacokinetics and therapeutic potential of RXn-02, a novel small-molecule derivative of quinolone.

Coronavirus disease 2019 (COVID-19) is a global pandemic and respiratory infection that has enormous damage to human lives and economies. It is caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), a non-pair-stranded positive-sense RNA virus. With increasing global threats and few therapeutic options, the discovery of new potential drug targets and the development of new therapy candidates against COVID-19 are urgently needed. Based on these premises, we conducted an analysis of transcriptomic datasets from SARS-CoV-2-infected patients and identified several SARS-CoV-2 infection signatures, among which TNFRSF5/PTPRC/IDO1/MKI67 appeared to be the most pertinent signature. Subsequent integrated bioinformatics analysis identified the signature as an important immunomodulatory and inflammatory signature of SARS-CoV-2 infection. It was suggested that this gene signature mediates the interplay of immune and immunosuppressive cells leading to infiltration-exclusion of effector memory T cells in the lungs, which is of translation relevance for developing novel SARS-CoV-2 drug and vaccine candidates. Consequently, we designed and synthesized a novel small-molecule quinoline derivative (RXn-02) and evaluated its pharmacokinetics in rats, revealing a peak plasma concentration (Cmax) and time to Cmax (Tmax) of 1.756 µg/mL and 0.6 h, respectively. Values of the area under the curve (AUC) (0-24 h) and AUC (0 h∼∞) were 18.90 and 71.20 µg h/mL, respectively. Drug absorption from the various regional segments revealed that the duodenum (49.84%), jejunum (47.885%), cecum (1.82%), and ileum (0.32%) were prime sites of RXn-02 absorption. No absorption was detected from the stomach, and the least was from the colon (0.19%). Interestingly, RXn-02 exhibited in vitro antiproliferative activities against hub gene hyper-expressing cell lines; A549 (IC50 = 48.1 µM), K-562 (IC50 = 100 µM), and MCF7 (IC50 = 0.047 µM) and against five cell lines originating from human lungs (IC50 range of 33.2-69.5 µM). In addition, RXn-02 exhibited high binding efficacies for targeting the TNFRSF5/PTPRC/IDO1/MK signature with binding affinities (ΔG) of -6.6, -6.0, -9.9, -6.9 kcal/mol respectively. In conclusion, our study identified a novel signature of SARS-CoV-2 pathogenesis. RXn-02 is a drug-like candidate with good in vivo pharmacokinetics and hence possesses great translational relevance worthy of further preclinical and clinical investigations for treating SARS-CoV-2 infections.

Inactivation of AKT/ERK Signaling and Induction of Apoptosis Are Associated With Amentoflavone Sensitization of Hepatocellular Carcinoma to Lenvatinib.

BACKGROUND/AIM: AKT/ERK signaling transduction and anti-apoptosis effects have both been recognized as important mediators of hepatocellular carcinoma (HCC) progression. Targeting AKT/ERK signaling and mediating apoptosis may be beneficial for alleviating HCC growth. Lenvatinib, a tyrosine kinase inhibitor, has been approved by the FDA to treat HCC since 2018 as a monotherapy with limited efficacy. Amentoflavone, a biflavonoid in natural plants, has been shown to have the potential to suppress HCC progression in previous studies. Whether the combination of lenvatinib and amentoflavone may show superior HCC suppression is unclear. MATERIALS AND METHODS: We used MTT, flow cytometry and western blotting assays to identify the role of lenvatinib and amentoflavone in both Hep3B and Huh7 cells. RESULTS: We found that amentoflavone enhances the suppressive effect of AKT/ERK signaling induced by lenvatinib and, thus, sensitizes HCC to lenvatinib. The intrinsic/extrinsic apoptosis pathways induced by lenvatinib were also boosted by amentoflavone. CONCLUSION: Amentoflavone sensitization of HCC to lenvatinib is associated with AKT/ERK inactivation and apoptosis induction.