Reactive Inhibition Research Articles

Involvement of neurons in the non-human primate anterior striatum in proactive inhibition.

Behaving as desired requires selecting the appropriate behavior and inhibiting the selection of inappropriate behavior. This inhibitory function involves multiple processes, such as reactive and proactive inhibition, instead of a single process. In this study, two male macaque monkeys were required to perform a task in which they had to sequentially select (accept) or refuse (reject) a choice. Neural activity was recorded from the anterior striatum, which is considered to be involved in behavioral inhibition, focusing on the distinction between proactive and reactive inhibitions. We identified neurons with significant activity changes during the rejection of bad objects. Cluster analysis revealed three distinct groups, of which only one showed increased activity during object rejection, suggesting its involvement in proactive inhibition. This activity pattern was consistent irrespective of the rejection method, indicating a role beyond saccadic suppression. Furthermore, minimal activity changes during the fixation task indicated that these neurons were not primarily involved in reactive inhibition. In conclusion, these findings suggest that the anterior striatum plays a crucial role in cognitive control and orchestrates goal-directed behavior through proactive inhibition, which may be critical in understanding the mechanisms of behavioral inhibition dysfunction that occur in patients with basal ganglia disease.Significance statement This study revealed a group of neurons in the anterior striatum that plays a crucial role in cognitive control by actively participating in the rejection of unfavorable choices. Contrary to previous belief, these neurons were involved in proactive inhibition (i.e., the process of discarding unnecessary options), instead of suppressing automatic responses, to achieve a goal. This distinction is vital for understanding the mechanisms by which the brain makes decisions and may have implications for addressing neurological disorders associated with impaired decision-making and inhibitory control. Our findings provide new insights into the neural mechanisms underlying goal-directed behavior and highlight the importance of the anterior striatum in orchestrating complex cognitive functions.

Jing-Si Herbal Tea attenuates oral cancer cell viability, migration, and invasion by regulating epithelial-to-mesenchymal transition and reactive oxygen species accumulation

Background/purposeOral cancer is the sixth most common cancer worldwide and can be life-threatening if not diagnosed and treated in its early stages. Jing-Si Herbal Tea (JSHT), containing eight traditional Chinese medicine-based herbs, is known to suppress the malignancy, growth, and metastasis of several tumor cells, including breast, lung, and colon cancer cells. However, the pharmacological effect of JSHT on oral cancer progression is still unclear. Materials and methodsIn this study, we evaluated the potential of JSHT to arrest the development of oral cancer via induction of cell death by reactive oxygen species (ROS) accumulation and inhibition of migration, invasion, and epithelial-to-mesenchymal transition (EMT). For this purpose, we employed the human tongue squamous cell carcinoma SAS cell line, which we treated with different JSHT concentrations for 24 h, and assessed cell viability, migration, and wound healing capabilities, together with western blotting for measuring expression levels of EMT markers. ResultsSurvival, migration/invasion ability, EMT, and ROS production in the SAS human tongue squamous carcinoma and FaDu human pharynx squamous cell carcinoma cell line were decreased by JSHT treatment via Lon protease-independent mechanisms. ConclusionThis study demonstrates that JSHT could be regarded as a candidate new supplement to existing anticancer therapies and an alternative, orally administered healthcare product for treating oral squamous cell carcinoma.

Gold(I) complexes of the type [AuL{κC-2-C6H4P(S)Ph2}] [L = PTA, PPh3, PPh2(C6H4-3-SO3Na) and PPh2(2-py)]: Synthesis, characterisation, crystal structures, and In Vitro and In Vivo anticancer properties

Four new mononuclear gold (I) compounds of the type [AuL{κC-2-C6H4P(S)Ph2}] {L = PTA (1), PPh3 (2), PPh2(C6H4-3-SO3Na) (3), and PPh2(2-py) (4)} were prepared by scission of the dinuclear compound [Au2{μ-2-C6H4P(S)Ph2}2] by L or via a transmetalation reaction using the organotin reagent 2-Me3SnC6H4P(S)Ph2 and a suitable gold halide precursor. The cytotoxic potential of complexes 1–4 was evaluated against four human cancer cell lines of diverse cellular origin: cervical (HeLa), prostate (PC-3), non-small cell lung adenocarcinoma (A549), and fibrosarcoma (HT-1080). The in vitro cytotoxicity results showed that 1 demonstrated exceptional anticancer activity with IC50 values ranging from 0.08 to 3.5 μM. Complex 3, which contains a sulfonated triphenyl phosphine ligand, displayed the weakest anticancer activity with IC50 values ranging from 3.1 to >50 μM. When compared to the standard chemotherapeutic drug cisplatin, 1 displayed approximately 27-fold greater cytotoxic activity against cervical cancer cells and 3.5- and 7.5-fold greater activities against prostate and fibrosarcoma cancer cells, respectively. Additionally, 1 exhibited 3-fold selectivity for cervical cancer cells compared to non-cancerous HEK-293 cells. Mechanistic investigations revealed that 1 induced apoptosis, which was associated with elevated reactive oxygen species (ROS) and inhibition of the intracellular enzyme thioredoxin reductase. Furthermore, 1 exhibited notable antiangiogenic characteristics in an in vivo model using transgenic zebrafish Tg(fli1a:EGFP). In vivo studies using mouse xenograft models showed that complex 1 displayed superior inhibition of tumour growth (82 %) compared to the clinical drug cisplatin (29 %). Overall, these results highlight the potential of gold (I) compounds as novel antitumour agents.

Dorsolateral prefrontal cortex to ipsilateral primary motor cortex intercortical interactions during inhibitory control enhance response inhibition in open-skill athletes

Numerous studies have reported that long-term sports training can affect inhibitory control and induce brain functional alterations. However, the influence of environmental dynamics in sports training on inter-cortical connectivity has not been well studied. In the current study, we used twin-coil transcranial magnetic stimulation to investigate the functional connectivity between dorsolateral prefrontal cortex (DLPFC) and ipsilateral primary motor cortex (M1) during proactive and reactive inhibition in participants with sports skills in dynamic environment (open-skill experts), stable environment (closed-skill experts), and no sports skills (controls). Using a modified stop signal task, proactive inhibition was measured by the response delay effect (RDE), and reactive inhibition was measured by the stop-signal reaction time (SSRT). Intra-hemispheric DLPFC-M1 interactions and single pulse motor-evoked potentials (MEPs) were measured during the task. A stronger inhibitory effect of the DLPFC over M1 was observed during early reactive control stages compared to baseline levels. In addition, this inhibitory effect was pronounced when comparing open-skill experts to non-athlete controls, a relationship that was significantly correlated with superior reactive control performance. Furthermore, DLPFC to M1 influencing direction shifted from late proactive control to reactive control. Behavioral results also demonstrated enhanced proactive control abilities in open-skill experts relative to controls. Such enhancement may be due to the combination of environmental complexity and physical fitness in long-term skill training.

Neural Correlates of Reactive Inhibition in Gambling Disorder: An FMRI Study with Transcranial Magnetic Stimulation (TMS)

Gambling Disorder (GD) is a condition characterized by a persistent and recurrent pattern of problematic gambling behavior. Despite significant advances in understanding the neurobiological correlates of Gambling Disorder phenomenological manifestation, there are still several unanswered questions regarding the pathophysiological mechanisms underlying GD. There is substantial evidence from fMRI studies on the role of pre-SMA stimulation in psychiatric conditions with impairments in response inhibition such as behavioral addictions on enhancing the activity of the brain circuitry involving the right inferior (IFG) and middle frontal gyrus (MFG) (two cortical areas are differentially associated with two distinct aspects of control inhibition). In this study we utilized task-related functional Magnetic Resonance Imaging (fMRI) to explore the impact of continuous Theta-Burst Stimulation (cTBS) on the pre-Supplementary Motor Area (pre-SMA) in patients with Gambling Disorder (GD). Four GD patients underwent cTBS on bilateral pre-SMA, administered with the MagVenture MagPro R30 stimulator with add-on theta-burst option (MagVenture INC.) using a Cool D-B80 figure-of-eight coil. cTBS consists of bursts of 3 pulses separated by 20 ms (i.e., 50 Hz) delivered repeatedly at theta frequency on the pre-SMA bilaterally. Changes in Functional Connectivity (FC) were assessed before and after Real or Sham treatment using CONN functional connectivity toolbox and Statistical Parametric Mapping (SPM). The study aimed to determine whether cTBS influences the functional connectivity between pre-SMA and right prefrontal areas, specifically the right Inferior Frontal Gyrus (rIFG) and right Middle Frontal Gyrus (rMFG), and whether these changes correlate with treatment outcomes. Results indicated that real cTBS treatment increased functional connectivity between pre-SMA and both rIFG and rMFG, suggesting enhanced control inhibition. This was associated with a reduction in Gambling Disorder symptom severity, assessed with the Pathological Gambling version of the Yale-Brown Obsessive-Compulsive Scale (PG-YBOCS) and the Gambling Urges Questionnaire (GUQ), indicating a treatment response. Conversely, sham cTBS did not elicit the same positive FC changes in the reactive control inhibition network, aligning with behavioral measures. The study highlighted the potential of cTBS on pre-SMA in modulating inhibitory control circuit. Overall, this preliminary investigation provides a foundation for future investigations into the neurobiological mechanisms underlying GD and the potential efficacy of TMS interventions.

Melastoma dodecandrum lour. Protects against cerebral ischemia–reperfusion injury by ameliorating oxidative stress and endoplasmic reticulum stress

Ethnopharmacological relevanceMelastoma dodecandrum Lour. (MD), a traditional Chinese medicine used by the She ethnic group, has been used to treat cerebral ischemia-reperfusion (CIR) injury due to its efficacy in promoting blood circulation and removing blood stasiss; however, the therapeutic effects and mechanisms of MD in treating CIR injury remain unclear. AimTo investigate the protective effects of MD on CIR injury, in addition to its impact on oxidative stress, endoplasmic reticulum (ER) stress, and cell apoptosis. Materials and methodsThe research was conducted using both cell experiments and animal experiments. The CCK-8 method, immunofluorescence staining, and flow cytometry were used to analyze the effects of MD-containing serum on oxygen-glucose deprivation/reperfusion (OGD/R)-induced PC12 cell viability, reactive oxygen species (ROS) clearance, anti-inflammatory, neuroprotection and inhibition of apoptosis. Furthermore, 2,3,5-Triphenyl tetrazolium chloride staining, hematoxylin and eosin staining, Nissl staining, and immunohistochemistry were used to detect infarct size, pathological changes, Nissl corpuscula and neuronal protein expression in middle cerebral artery occlusion (MCAO) rats. Polymerase chain reaction and Western Blotting were conducted in cell and animal experiments to detect the expression levels of ER stress-related genes and proteins. ResultsThe MD extract enhanced the viability of PC12 cells under OGD/R modeling, reduced ROS and IL-6 levels, increased MBP levels, and inhibited cell apoptosis. Furthermore, MD improved the infarct area in MCAO rats, increased the number of Nissl bodies, and regulated neuronal protein levels including Microtubule-Associated Protein 2 (MAP-2), Myelin Basic Protein (MBP), Glial Fibrillary Acidic Protein (GFAP), and Neurofilament 200 (NF200). Additionally, MD could regulate the expression levels of oxidative stress proteins malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD), and catalase (CAT). Both cell and animal experiments demonstrated that MD could inhibit ER stress-related proteins (GRP78, ATF4, ATF6, CHOP) and reduce cell apoptosis. ConclusionThis study confirmed that the therapeutic mechanism of the MD extract on CIR injury was via the inhibition of oxidative stress and the ER stress pathway, in addition to the inhibition of apoptosis.

Involvement of BcNAC083 in 1-MCP-induced delayed yellowing of pak choi (Brassica rapa subsp. Chinensis) through the regulation of reactive oxygen species metabolism and inhibition of major chlorophyll catabolic genes

Leaf yellowing is a typical senescence feature in postharvest pak choi. Plant-specific NAC transcription factors (TFs) are crucial regulators of plant senescence. In this study, a senescence-related NAC TF, BcNAC083, was investigated to identify its transcriptional regulation effects on the yellowing of pak choi by treatment with 1-methylcyclopropene (1-MCP). Applying 5.0 µL L–1 1-MCP alleviated yellowing and maintained a low respiration rate, high chlorophyll content, and relatively complete chloroplast structure in pak choi during storage. However, 10 μL L–1 ethylene accelerated yellowing, as demonstrated by the higher respiration rate, lower chloroplast structural integrity and chlorophyll content. In contrast to ethylene treatment, 1-MCP suppressed the activity of the reactive oxygen species (ROS) metabolism-related enzymes superoxide dismutase (SOD), catalase (CAT), ascorbic peroxidase (APX), and lipoxygenase (LOX), and correspondingly reduced superoxide anion (O2·–), hydrogen peroxide (H2O2), and malondialdehyde (MDA) accumulation. 1-MCP treatment also suppressed the transcript levels of ROS metabolic genes, including BcRBOHC, BcRBOHD, BcSOD, BcCAT, BcAPX, and BcLOX, and inhibited the activity of the chlorophyll catabolic enzymes chlorophyllase (CLH), Mg-de-chelatase, and pheophytin pheophorbide hydrolase (PPH) and transcript levels of associated genes, including BcCLH1/2, BcPPH1/2, BcPAO, BcNYC1, BcSGR1/2, BcHCAR, BcRCCR, and BcCAO. The expression of BcNAC083 was probably induced by ROS and was downregulated by 1-MCP and upregulated by ethylene. Molecular biology experiments determined that BcNAC083 bound directly to and activated the promoters of the chlorophyll metabolism-related genes BcCLH1, BcPPH1, BcNYC1, and BcHCAR. Importantly, transient overexpression of BcNAC083 stimulated the endogenous genes (NbCLH1, NbPPH1, NbNYC1, and NbHCAR) expression in tobacco leaves, resulting in rapid chlorophyll breakdown and leaf degreening. Treatment with 1-MCP may alleviated the yellowing of pak choi by inhibiting ROS accumulation and the transcriptional regulation of BcNAC083, which had positive regulatory effects on major chlorophyll metabolic genes.

Mesenchymal Stem Cell Membrane-Camouflaged Liposomes for Biomimetic Delivery of Cyclosporine A for Hepatic Ischemia-Reperfusion Injury Prevention.

Hepatic ischemia-reperfusion injury (HIRI) is a prevalent issue during liver resection and transplantation, with currently no cure or FDA-approved therapy. A promising drug, Cyclosporin A (CsA), ameliorates HIRI by maintaining mitochondrial homeostasis but has systemic side effects due to its low bioavailability and high dosage requirements. This study introduces a biomimetic CsA delivery system that directly targets hepatic lesions using mesenchymal stem cell (MSC) membrane-camouflaged liposomes. These hybrid nanovesicles (NVs), leveraging MSC-derived proteins, demonstrate efficient inflammatory chemotaxis, transendothelial migration, and drug-loading capacity. In a HIRI mouse model, the biomimetic NVs accumulated at liver injury sites entered hepatocytes, and significantly reduced liver damage and restore function using only one-tenth of the CsA dose typically required. Proteomic analysis verifies the protection mechanism, which includes reactive oxygen species inhibition, preservation of mitochondrial integrity, and reduced cellular apoptosis, suggesting potential for this biomimetic strategy in HIRI intervention.

Inhibitory control of gait initiation in humans: An electroencephalography study.

Response inhibition is a crucial component of executive control. Although mainly studied in upper limb tasks, it is fully implicated in gait initiation. Here, we assessed the influence of proactive and reactive inhibitory control during gait initiation in healthy adult participants. For this purpose, we measured kinematics and electroencephalography (EEG) activity (event-related potential [ERP] and time-frequency data) during a modified Go/NoGo gait initiation task in 23 healthy adults. The task comprised Go-certain, Go-uncertain, and NoGo conditions. Each trial included preparatory and imperative stimuli. Our results showed that go-uncertainty resulted in delayed reaction time, without any difference for the other parameters of gait initiation. Proactive inhibition, that is, Go uncertain versus Go certain conditions, influenced EEG activity as soon as the preparatory stimulus. Moreover, both proactive and reactive inhibition influenced the amplitude of the ERPs (central P1, occipito-parietal N1, and N2/P3) and theta and alpha/low beta band activities in response to the imperative-Go-uncertain versus Go-certain and NoGo versus Go-uncertain-stimuli. These findings demonstrate that the uncertainty context; induced proactive inhibition, as reflected in delayed gait initiation. Proactive and reactive inhibition elicited extended and overlapping modulations of ERP and time-frequency activities. This study shows the protracted influence of inhibitory control in gait initiation.

Antioxidant Activity, Antiproliferative Activity, Antiviral Activity, NO Production Inhibition, and Chemical Composition of Essential Oils and Crude Extracts of Leaves, Flower Buds, and Stems of Tetradenia riparia.

The chemical composition of extracts (CEs) and essential oils (EOs) from Tetradenia riparia leaves, flower buds, and stems was analyzed. Antiproliferative activity against tumor cell lines, NO production inhibition, and antioxidant and antiviral activities were assessed. The CEs contained flavonoids, phenolic acids, coumarins, and saturated fatty acids. The EOs included monoterpenes, oxygenated sesquiterpenes, and diterpenes. NO production inhibition ranged from 76 to 247 µg mL-1, and antiproliferative activity exhibited GI50 between 20 and >204 µg mL-1, with low cytotoxicity (SI: 1.08 to 4.75). Reactive oxygen species inhibition ranged from 45 to 82%. Antioxidant activity varied when determined by the 2,2-diphenyl-1-picrylhydrazyl radical scavenging assay (IC50: 0.51 to 8.47 mg mL-1) and ferric reducing antioxidant power (0.35 to 0.81 µM ferrous sulfate per mg). The reduction in β-carotene-linoleic acid co-oxidation varied between 76.13 and 102.25%. The total phenolic content of CEs and EOs was 10.70 to 111.68 µg gallic acid mg-1. Antiviral activity against herpes simplex virus type 1 (HSV-1) showed an EC50 between 9.64 and 24.55 µg mL-1 and an SI between 8.67 and 15.04. Leaf EOs exhibited an EC50 of 9.64 µg mL-1 and an SI of 15.04. Our study unveils the diverse chemical composition and multifaceted pharmacological properties of T. riparia, demonstrating its potential as a valuable source of bioactive compounds for therapeutic applications.

Characterization of Rhodiola heterodonta (Crassulaceae): Phytocomposition, Antioxidant and Antihyperglycemic Activities.

Plant extracts have been widely used in traditional medicine to prevent diabetes. The present study aimed to examine the antihyperglycemic properties of an ethanolic extract from Rhodiola heterodonta roots. In vitro evaluation revealed that treatment with the R. heterodonta extract resulted in significant reactive oxygen species inhibition, glucose binding, glucose transporter activation, and suppression of α-amylase and α-glucosidase. Moreover, the treatment with 100 mg/kg of R. heterodonta extract dramatically decreased glucose levels in glucose-, alloxan-, or adrenaline-induced diabetic rats. The information gathered in this study bridges the knowledge gap between traditional healers in Uzbekistan who utilize R. heterodonta and its potential for future medication development.

Antioxidant and antibacterial effects of a new macrocyclic bis(bibenzyl) ether from Combretum molle (Combretaceae).

A new compound, combrebisbibenzyl (1) as well as two sterols including stigmasterol (2) and 3-O-β-D-glucopyranoside of β-sitosterol (3) and seven triterpenoids namely mollic acid (4), oleanolic acid (5), ursolic acid (6), arjunglucoside I (7), arjungenin (8), bellericagenin B (9) and combregenin (10) were isolated from the root of Combretum molle. Compounds 1, 7 and 9, AcOEt and MeOH extracts exhibited moderate antioxidant activity with an IC50 value of 179.32, 185.21, 195.11 197.41 and 170.21 μg/mL, respectively, for reactive oxygen species inhibition and, inhibition percent value of 57.23, 64.52, 53.55, 67.42 and 65.04, respectively, for DPPH free-radical scavenging. The E. MeOH presented a moderate antibacterial activity against Staphylococcus aureus with DIZs value of 10.1±0.2 from 800 μg/mL while the others tested strains were not sensitive. However, most of the tested bacteria, (S.aureus, Escherichia coli and Salmonella typhimurium) were moderately sensitive to E. AcOEt from 800 μg/mL with DIZs value of 8.2±0.1. From the E. AcOEt, five of the isolated compounds were tested against four bacteria strains using the disc-dilusion method. The results showed that compound 1 and 2 exhibited very good antibacterial activity against all the tested bacteria at the concentration of 30 μg/mL with respective DIZ value of 22.2 and 25.4 for E.coli, 20.2 and 30.2 for S.typhimurium, 22.3 and 23.1 for S.aureus and, 22.1 and 24.1 for Streptococcus faecalis. This antibacterial activity significantly depends on the concentration.

Exploring the Therapeutic Potential of Triptonide in Salivary Adenoid Cystic Carcinoma: A Comprehensive Approach Involving Network Pharmacology and Experimental Validation.

Salivary Adenoid Cystic Carcinoma (ACC) is characterized by a highly invasive and slow-growing pattern, and its etiology remains unidentified. Triptonide (TN) has demonstrated efficacy as a pharmacotherapeutic agent against ACC. Nonetheless, the specific targets and mechanism of molecular action underlying the effectiveness of TN in treating ACC have not been elucidated. By integrating network pharmacology within laboratory experiments, this research delves into the prospective targets and molecular mechanisms associated with the application of TN in treating ACC. Initially, pertinent targets associated with TN against ACC were acquired from public databases. Subsequently, a combination of network pharmacology and bioinformatics analysis was utilized to screen the top 10 hub targets and key signal pathways of TN-treating ACC. Finally, in vitro experiments involving various molecular assays were conducted to evaluate the biological phenotypes of cells following TN treatment, encompassing assessments of apoptosis levels, plate migration, and other parameters, thereby validating pivotal genes and pathways. A total of 23 pertinent targets for TN in relation to ACC were identified, with the top 10 hub genes being MAPK8, PTGS2, RELA, MAPK14, NR3C1, HDAC1, PPARG, NFKBIA, AR, and PGR. There was a significant correlation between the TNF signaling pathway and the treatment of ACC with TN. In vitro experiments demonstrated that TN treatment elevated RELA phosphorylation while concurrently reducing MAPK14 phosphorylation and inducing G2/M arrest. TN exhibited the ability to enhance the apoptosis rate through increased caspase-3 activity, elevated levels of Reactive Oxygen Species (ROS), mitochondrial dysfunction, and inhibition of cell migration. There is a potential therapeutic role for TN in the treatment of ACC through the activation of the TNF signaling pathway. Among the identified candidates, MAPK8, HDAC1, PTGS2, RELA, NR3C1, PPARG, NFKBIA, AR, and PGR emerge as the most pertinent therapeutic targets for TN in the context of ACC treatment.

Interleukin-33 increases the sensitivity of multiple myeloma cells to the proteasome inhibitor bortezomib through reactive oxygen species-mediated inhibition of nuclear factor kappa-B signal and stemness properties.

The proteasome inhibitor bortezomib (BTZ) is the first-line therapy for multiple myeloma (MM). BTZ resistance largely limits its clinical application in MM. Interleukin-33 (IL-33) exerts antitumor effects through various mechanisms, including enhancing antitumor immunity and promoting the apoptosis of cancer cells. Here, the synergistic anti-MM effect of IL-33 and BTZ was verified, and the underlying mechanisms were elucidated. Bioinformatic analysis indicated that IL-33 expression levels were downregulated in MM, and that BTZ-treated MM patients with high IL-33 levels had better prognosis than those with low IL-33 levels. Moreover, the patients with high IL-33 levels had a better treatment response to BTZ. Further immune analysis suggested that IL-33 can enhance the anti-MM immunity. IL-33 and BTZ synergistically inhibited proliferation and induced apoptosis of MM cells, which was mediated by the excessive accumulation of cellular reactive oxygen species (ROS). Furthermore, increased ROS hindered the nuclear translocation of NF-κB-p65, thereby decreasing the transcription of target stemness-related genes (SOX2, MYC, and OCT3/4). These effects induced by the combination therapy could be reversed by eliminating ROS by N-acetylcysteine. In conclusion, our results indicated that IL-33 enhanced the sensitivity of MM to BTZ through ROS-mediated inhibition of nuclear factor kappa-B (NF-κB) signal and stemness properties.

Underlying Neural Mechanisms of Cognitive Improvement in Fronto-striatal Response Inhibition in People Living with HIV Switching Off Efavirenz: A Randomized Controlled BOLD fMRI Trial.

It is unclear whether neurotoxicity due to the antiretroviral drug efavirenz (EFV) results in neurocognitive impairment in people living with HIV (PLWH). Previously, we found that discontinuing EFV was associated with improved processing speed and attention on neuropsychological assessment. In this imaging study, we investigate potential neural mechanisms underlying this cognitive improvement using a BOLD fMRI task assessing cortical and subcortical functioning. Asymptomatic adult PLWH stable on emtricitabine/tenofovirdisoproxil/efavirenz were randomly (1:2) assigned to continue their regimen (n = 12) or to switch to emtricitabine/tenofovirdisoproxil/rilpivirine (n = 28). At baseline and after 12weeks, both groups performed the Stop-Signal Anticipation Task, which tests reactive and proactive inhibition (indicative of subcortical and cortical functioning, respectively), involving executive functioning, working memory, and attention. Behavior and BOLD fMRI activation levels related to processing speed and attention Z-scores were assessed in 17 pre-defined brain regions. Both groups had comparable patient and clinical characteristics. Reactive inhibition behavioral responses improved for both groups on week12, with other responses unchanged. Between-group activation did not differ significantly. For reactive inhibition, positive Pearson coefficients were observed for the change in BOLD fMRI activation levels and change in processing speed and attention Z-scores in all 17 regions in participants switched to emtricitabine/tenofovir disoproxil/rilpivirine, whereas in the control group, negative correlation coefficients were observed in 10/17 and 13/17 regions, respectively. No differential pattern was observed for proactive inhibition. Potential neural mechanisms underlying cognitive improvement after discontinuing EFV in PLWH were found in subcortical functioning, with our findings suggesting that EFV's effect on attention and processing speed is, at least partially, mediated by reactive inhibition. Clinicaltrials.gov identifier [NCT02308332].

Karanjin, A Promising Bioactive Compound Possessing Anti-cancer Activity against Experimental Model of Non-small Cell Lung Cancer Cells.

The aim of this study is to isolate the Millettia pinnata (Karanj) leaf extract for pure compound with anticancer properties and to study the molecular target of the isolates in non-small cell lung cancer cell lines. In our earlier research Millettia pinnata leaf extract has demonstrated potential anticancer activities. Thus, in pursuit of the bioactive compounds, the most potential active extract from our previous study was purified. Furthermore, the anticancer properties of the isolated compound karanjin was studied and aimed for apoptosis and restraining growth. A novel method was developed through column chromatography for isolation and purification of the compound karanjin from leaf chloroform extract. The purified component was then characterised using FTIR, mass spectrometry, and NMR. An MTT-based cytotoxicity assay was used to analyse cell cytotoxicity, whereas fluorescence staining was used for apoptosis and reactive oxygen species inhibition quantification. Furthermore, the real-time PCR assay was used to determine the molecular mechanism of action in cells causing cytotoxicity induced by karanjin dosing. The anticancer activity of karanjin in A549 cell line exhibited prominent activity revealing IC50 value of 4.85 μM. Conferring the predicted molecular pathway study, karanjin restrains the proliferation of cancer cells through apoptosis, which is controlled by extrinsic pathway proteins FAS/FADD/Caspases 8/3/9. Downregulation of KRAS and dependent gene expression also stopped cell proliferation. Karanjin has been identified as a compound with potential effect in non-small cell lung cancer cells. Molecular mechanism for apoptosis and inhibition of reactive oxygen species induced through H2O2 were observed, concluding karanjin have medicinal and antioxidant properties.

Astragalus membranaceus Extract Induces Apoptosis via Generation of Reactive Oxygen Species and Inhibition of Heat Shock Protein 27 and Androgen Receptor in Prostate Cancers.

Although Astragalus membranaceus is known to have anti-inflammatory, anti-obesity, and anti-oxidant properties, the underlying apoptotic mechanism of Astragalus membranaceus extract has never been elucidated in prostate cancer. In this paper, the apoptotic mechanism of a water extract from the dried root of Astragalus membranaceus (WAM) was investigated in prostate cancer cells in association with heat shock protein 27 (HSP27)/androgen receptor (AR) signaling. WAM increased cytotoxicity and the sub-G1 population, cleaved poly (ADP-ribose) polymerase (PARP) and cysteine aspartyl-specific protease 3 (caspase 3), and attenuated the expression of B-cell lymphoma 2 (Bcl-2) in LNCaP cells after 24 h of exposure. Consistently, WAM significantly increased the number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive LNCaP cells. WAM decreased the phosphorylation of HSP27 on Ser82 and inhibited the expression of the AR and prostate-specific antigen (PSA), along with reducing the nuclear translocation of p-HSP27 and the AR via the disturbed binding of p-HSP27 with the AR in LNCaP cells. WAM consistently inhibited the expression of the AR and PSA in dihydrotestosterone (DHT)-treated LNCaP cells. WAM also suppressed AR stability, both in the presence and absence of cycloheximide, in LNCaP cells. Taken together, these findings provide evidence that WAM induces apoptosis via the inhibition of HSP27/AR signaling in prostate cancer cells and is a potent anticancer candidate for prostate cancer treatment.

Comparison of online, offline, and hybrid hypotheses of motor sequence learning using a quantitative model that incorporate reactive inhibition

Two hypotheses have been advanced for when motor sequence learning occurs: offline between bouts of practice or online concurrently with practice. A third possibility is that learning occurs both online and offline. A complication for differentiating between those hypotheses is a process known as reactive inhibition, whereby performance worsens over consecutively executed sequences, but dissipates during breaks. We advance a new quantitative modeling framework that incorporates reactive inhibition and in which the three learning accounts can be implemented. Our results show that reactive inhibition plays a far larger role in performance than is appreciated in the literature. Across four groups of participants in which break times and correct sequences per trial were varied, the best overall fits were provided by a hybrid model. The version of the offline model that does not account for reactive inhibition, which is widely assumed in the literature, had the worst fits. We discuss implications for extant hypotheses and directions for future research.

Preparation of Lutein Nanoparticles by Glycosylation of Saccharides and Casein for Protecting Retinal Pigment Epithelial Cells.

Age-related macular degeneration (AMD), a leading cause of visual impairment in the aging population, lacks effective treatment options due to a limited understanding of its pathogenesis. Lutein, with its strong antioxidant properties and ability to mitigate AMD by absorbing ultraviolet (UV) rays, faces challenges related to its stability and bioavailability in functional foods. In this study, we aimed to develop delivery systems using protein-saccharide conjugates to enhance lutein delivery and protect adult retinal pigment epithelial (ARPE-19) cells against sodium iodate (NaIO3)-induced damage. Various saccharides, including mannose, galactose, lactose, maltose, dextran, and maltodextrin, were conjugated to casein via the Maillard reaction for lutein delivery. The resulting lutein-loaded nanoparticles exhibited small size and spherical characteristics and demonstrated improved thermal stability and antioxidant capacity compared to free lutein. Notably, these nanoparticles were found to be nontoxic, as evidenced by reduced levels of cellular reactive oxygen species production (167.50 ± 3.81, 119.57 ± 3.45, 195.15 ± 1.41, 183.96 ± 3.11, 254.21 ± 3.97, 283.56 ± 7.27%) and inhibition of the mitochondrial membrane potential decrease (58.60 ± 0.29, 65.05 ± 2.91, 38.88 ± 1.81, 42.95 ± 1.39, 23.52 ± 1.04, 25.24 ± 0.08%) caused by NaIO3, providing protection against cellular damage and death. Collectively, our findings suggest that lutein-loaded nanoparticles synthesized via the Maillard reaction hold promise for enhanced solubility, oral bioavailability, and biological efficacy in the treatment of AMD.

Transethosome‐Based Topical Administration Systems with Enhanced Penetration and Dual Actions for Treating EGFR‐Overexpressed Cutaneous Squamous Cell Carcinoma

AbstractEpidermal growth factor receptor (EGFR)‐overexpressing cutaneous squamous cell carcinoma (CSCC) necessitates more effective therapies due to its elevated metastasis risk compared to the conventional CSCC. While photodynamic therapy (PDT) is a promising way to treat CSCC, effectively administering photosensitizers to reach deeper skin malignancies remains a challenge. Herein, BE‐TEL is reported, a transethosome formulation designed to enhance skin and cutaneous tumor permeability, for targeted treatment of EGFR‐overexpressed CSCC. The formulation is co‐loaded with Erlotinib (Erb), a hydrophobic EGFR inhibitor, and BODIPY (BPY), a photosensitizer. Upon skin penetration and subsequent exposure to 660 nm light, BE‐TEL induces tumor cell apoptosis by reactive oxygen species (ROS) generation and EGFR pathway inhibition. ROS and Erb‐induced metabolic oxidative stress by upregulating the expression of NADPH oxidase 4 (NOX4) can enhance immunogenic cell death (ICD) and promote dendritic cell maturation for tumor‐specific immune response. Furthermore, the EGFR downregulation further mitigated the risk of metastasis and recurrence. In conclusion, BE‐TEL's superior penetration ability together with its combined PDT and EGFR targeted approach paves the way for an efficient strategy against EGFR‐overexpressed CSCC.