Potential Mechanisms Research Articles

In vitro study on anti-proliferative and anti-cancer activity of picrosides in triple-negative breast cancer.

Picrorhiza kurroa, an "Indian gentian," a known Himalayan medicinal herb with rich source of phytochemicals like picrosides I, II, and other glycosides, has been traditionally used for the treatment of liver and respiratory ailments. Picrosides anti-proliferative, anti-oxidant, anti-inflammatory and other pharmacological properties were evaluated in treating triple-negative breast cancer (TNBC). Picroside I and II were procured from Sigma-Aldrich and were analyzed for anti-cancer activity in triple-negative breast cancer (MDA-MB-231) cells. Cell viability was analyzed using MTT and trypan blue assays. Apoptosis was analyzed through DNA fragmentation and Annexin V/PI flow cytometric analysis. Wound healing and cell survival assays were employed to determine the inhibition of invasion capacity and anti-proliferative activity of picrosides in MDA-MB-231 cells. Measurement of intracellular ROS was studied through mitochondrial membrane potential assessment using DiOC6 staining for anti-oxidant activity of picrosides in MDA-MB-231 cells. Both Picroside I and II have shown decreased cell viability of MDA-MB-231 cells with increasing concentrations. IC50 values of 95.3µM and 130.8µM have been obtained for Picroside I and II in MDA-MB-231 cells. Early apoptotic phase have shown an increase of 20% (p < 0.05) with increasing concentrations (0, 50, 75, and 100µM) of Picroside I and 15% (p < 0.05) increase with Picroside II. Decrease in mitochondrial membrane potential of 2-2.5-fold (p < 0.05) was observed which indicated decreased reactive oxygen species (ROS) generation with increasing concentrations of Picroside I and II. An increasing percentage of 70-80% (p < 0.05) cell population was arrested in G0/G1 phase of cell cycle after Picroside I and II treatment in cancer cells. Our results suggest that Picroside I and II possess significant anti-proliferative and anti-cancer activity which is mediated by inhibition of cell growth, decreased mitochondrial membrane potential, DNA damage, apoptosis, and cell cycle arrest. Therefore, Picroside I and II can be developed as a potential anti-cancer drug of future and further mechanistic studies are underway to identify the mechanism of anti-cancer potential.

Synthesis, Characterization and Biological Activities of Nitrophenol-Substituted Phosphazene Dendrimers

This study introduces the synthesis and characterization of two novel nitrophenol-substituted phosphazene dendrimers, [N3P3(OC6H5NO2)6] (III) and [N3P3(OC6H5(NO2)2)5O]ˉ.C6H16N+.H2O (IV), derived from hexachlorocyclotriphosphazene (HCCP). The structures of the compounds were determined using elemental analysis, infrared spectroscopy, and X-ray crystallography. The optical properties of the crystals were investigated by photophysical methods. The thermal properties of the compounds were measured by thermogravimetry-differential thermal analysis (TG-DTA). The antibacterial and anticancer properties of the compounds were tested based on the antibacterial tests against Gram-negative (Escherichia coli ATCC 8739 G(-)) and Gram-positive (Staphylococcus aureus ATCC 6538 G(+), Bacillus subtilis 2a ATCC 23857 G(+)) bacteria, as well as the MTT assay test on K562 leukemia cells (ATCC: CCL-243) and MCF-7 breast cancer cells (ATCC: HTB-22). The presence of six homogeneous 2-nitrophenol substitutions in compound III reduces the fluorescence of the phosphazene ring. The results showed that compound IV has a higher fluorescence intensity and similar toxicity to MCF-7 and HDF cells. The structural differences and the number of nitro groups in the nitrophenol ligands account for these variations. Our results suggest that these cyclophosphazene derivatives have promising properties for biomedical applications and further studies are warranted to explore their mechanisms of action and therapeutic potential.

Up-regulation of Trim28 in pregnancy-induced hypertension is involved in the injury of human umbilical vein endothelial cells through the p38 signaling pathway.

The present study is to analyze the regulation and potential molecular mechanism of Trim28 on vascular endothelial injury induced by pregnancy-induced hypertension (PIH). Trim28 mRNA in placental tissues and peripheral blood from PIH patients were determined by quantitative real-time polymerase chain reaction. The serum from PIH was used to stimulate human umbilical vein endothelial cells (HUVECs). After silencing Trim28 in HUVECs, we used CCK-8 assay, Transwell assay and flow cytometry to investigate proliferation, migration and apoptosis. Western blotting was used to measure Trim28 protein level and p38 phosphorylation level. After addition of p38 inhibitor, the proliferation, migration and apoptosis of HUVECs with silenced Trim28 were studied again. Trim28 expression in placental tissues and peripheral blood from PIH patients is elevated, and serum from these patients can up-regulate the expression of Trim28 in HUVECs in vitro. Trim28 silencing significantly inhibits the proliferation and migration of HUVECs by affecting the cell cycle. Down-regulation of Trim28 expression promotes the apoptosis of HUVECs. Trim28 regulates the biological function of HUVECs by affecting the activity of the p38 signaling pathway. The present study demonstrates that Trim28 is up-regulated in peripheral blood of patients with PIH and participates in HUVECs injury through the p38 signaling pathway.

Identifying the Anti-inflammatory Effects of Astragalus Polysaccharides in Anti-N-Methyl-D-Aspartate Receptor Encephalitis: Network Pharmacology and Experimental Validation.

Astragalus polysaccharides (APS), a group of bioactive compounds obtained from the natural source Astragalus membranaceus(AM), exhibits numerous pharmacological actions in the central nervous system, such as anti-inflammatory, antioxidant, and immunomodulatory properties. Despite the remarkable benefits, the effectiveness of APS in treating anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis and the corresponding mechanism have yet to be fully understood. As such, this study aims to investigate the impact of APS on anti-NMDAR encephalitis and explore the potential molecular network mechanism. The impact of APS intervention on mice with anti-NMDAR encephalitis was assessed, and the possible molecular network mechanism was investigated utilizing network pharmacology and bioinformatics techniques such as Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG),protein-protein interaction (PPI) network, and molecular docking. Enzyme-linked immunosorbent assay (ELISA) was applied to detect the expression of core target proteins. APS significantly ameliorated cognitive impairment and reduced susceptibility to PTZ-induced seizures in mice with anti-NMDAR encephalitis, confirming the beneficial effect of APS on anti-NMDAR encephalitis. Seventeen intersecting genes were identified between APS and anti-NMDAR encephalitis. GO and KEGG analyses revealed the characteristics of the intersecting gene networks. STRING interaction in the PPI network was applied to find crucial molecules. The results of molecular docking suggested that APS may regulate interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) as potential targets in anti-NMDAR encephalitis. Furthermore, the levels of IL-1β, IL-6, and TNF-α detected by ELISA in anti-NMDAR encephalitis mice were significantly downregulated in response to the administration of APS. The findings of this study demonstrate the significant role of APS in the treatment of anti-NMDAR encephalitis, as it effectively suppresses inflammatory cytokines. These results suggest that APS has the potential to be considered as a viable herbal medication for the treatment of anti-NMDAR encephalitis.

Electric-thermal-mechanics modeling for in-process phenomena during micro resistance spot welding spark plug of Pt and Inconel600

The spark plug is one of the important components in the gasoline engine's combustion chamber. To reduce vehicle emissions, the platinum spark plug is selected due to its good performance. Due to the high productivity of resistance spot welding (RSW), a micro-scale RSW process is employed to assemble the platinum tip to Inconel600 part in the production of spark plugs. In order to understand the electric-thermal-mechanics phenomena during micro resistance spot welding spark plug for controlling the welding quality and saving electric energy, a three-dimensional simulation model and the in-house finite element program JWRIAN-RSW3D were developed. The potential history and upper electrode displacement results were verified with experiments. Numerical case studies were made to investigate the influence magnitude of welding current on the electric-thermal-mechanics phenomena. The developed model reveals inside phenomena to clearly understand the welding mechanism for potential, current density, temperature, electrode displacement and their distribution/history as well as the molten zone. The comprehensive phenomena of maximum temperature distribution on both base metals and Inconel600 were clarified using a top perspective, revealing differences in distribution on the contact surface between horizontal and vertical sections. To achieve a complete welding joint, the molten zone on the contact area is required carefully in order to facilitate the bonding of both base metals. Based on simulation results for three welding conditions, the alternating current at the magnitude of 1.2 kA with the welding time of 0.1 s is recommended to obtain the welded joint with minimized energy consumption in production.

Structural insights on anti-biofilm mechanism of heated slightly acidic electrolyzed water technology against multi-resistant Staphylococcus aureus biofilm on food contact surface

Slightly acidic electrolyzed water (SAEW) has proven to be an efficient and novel sanitizer in food and agriculture field. This study assessed the efficacy of SAEW (30 mg/L) at 40 °C on the inactivation of foodborne pathogens and detachment of multi-resistant Staphylococcus aureus (MRSA) biofilm. Furthermore, the underlying mechanism of MRSA biofilm under heated SAEW at 40 °C treatment on metabolic profiles was investigated. The results showed that the heated SAEW at 40 °C significantly effectively against foodborne pathogens of 1.96–7.56 (lg (CFU/g)) reduction in pork, chicken, spinach, and lettuce. The heated SAEW at 40 °C treatment significantly reduced MRSA biofilm cells by 2.41 (lg (CFU/cm2)). The synergistic effect of SAEW treatment showed intense anti-biofilm activity in decreasing cell density and impairing biofilm cell membranes. Global metabolic response of MRSA biofilms, treated by SAEW at 40 °C, revealed the alterations of intracellular metabolites, including amino acids, organic acid, fatty acid, and lipid. Moreover, signaling pathways involved in amino acid metabolism, energy metabolism, nucleotide synthesis, carbohydrate metabolites, and lipid biosynthesis were functionally disrupted by the SAEW at 40 °C treatment. As per our knowledge, this is the first research to uncover the potential mechanism of heated SAEW treatment against MRSA biofilm on food contact surface.

Dapagliflozin Alleviates Myocardial Ischaemia Reperfusion Injury by Activating Mitophagy via the AMPK-PINK1/Parkin Signalling Pathway.

Myocardial ischaemia reperfusion injury (MIRI) determines infarct size and long-term outcomes after acute myocardial infarction (AMI). Dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, alleviates MIRI in animal models. We investigated the potential mechanisms underlying the cardioprotective effect of dapagliflozin against MIRI, focusing on mitochondrial injury and mitophagy. MIRI mouse and H9C2 cell models were established. 2,3,5-Triphenyltetrazolium chloride (TTC) staining showed a significant alleviation of MIRI after pre-treatment of dapagliflozin compared to the model group (14.91±1.76 vs. 40.47±3.69%). Data from the pre-treatment dapagliflozin group showed a significant decrease in left ventricular ejection fraction (LVEF) (44.8±2.7 vs. 28.5±5.3%, P<0.01), left ventricular end-diastolic volume (LVEDV) (70.6±9.5 vs. 93.5±13.8 ul, P<0.05), and left ventricular end-systolic volume (LVESV) (39.0± 8.3 vs. 67.9±13.7 ul, P<0.05) compared to the model group. Dapagliflozin also reduced the levels of reactive oxygen species (ROS) and fragmented mitochondrial DNA, reversed the decrease in mitochondrial membrane potential, and suppressed apoptosis. Further study showed that dapagliflozin could protect against mitochondrial injury by rapidly clearing damaged mitochondria via mitophagy in a phosphatase and tensin homologue (PTEN)-induced putative kinase 1 (PINK1)/parkindependent manner. Dapagliflozin regulated mitophagy in cardiomyocytes by suppressing the adenosine 5'monophosphate-activated protein kinase (AMPK)-PINK1/parkin signalling pathway, resulting in attenuated MIRI. Dapagliflozin alleviated MIRI by activating mitophagy via the AMPK-PINK1/parkin signalling pathway.

Who will Spend more Pollution Abatement Costs: does Size Matter?

This paper looks at the relationship between enterprise size and pollution abatement costs using firm-level datasets in China, where size-dependent distortions may exist in the distribution of enterprises of different sizes. We find that the pollution abatement costs decrease with enterprise size. Compared to the smallest size, the magnitudes of marginal decreases in pollution abatement costs per 1000 CNY of industrial output in the largest size are 3.29 CNY, 0.54 CNY and 2.60 CNY for gas, SO2 and dust, respectively. Moreover, we further explore the potential mechanisms for the decrease of pollution abatement costs from three perspectives: environmental protection-related investment, regulation intensity, and technological capability. Our findings suggest that the decrease in the intensity of environmental protection-related investment for large enterprises may be directly reduce the intensity of pollution abatement costs. Although large enterprises have low intensity of pollution abatement costs, this does not mean that they are subject to weaker environmental regulation. More importantly, we find that large enterprises may have more adoption of abatement technologies. For SO2 and dust, the pollutant removal efficiency of the largest enterprises is 4.92% and 1.82% higher than that of the smallest enterprises, respectively. Our results are robust to different specifications. These findings help us enact appropriate policies for enterprises based on their size, thereby improving the efficacy of pollution abatement and achieving the optimal level of pollution abatement for the entire society.

Persist Or Perish: Mechanisms of Persistence And Recovery Potential in Bats Threatened with Extinction by White-nose Syndrome.

Emerging mycoses are an increasing concern in wildlife and human health. Given the historical rarity of fungal pathogens in warm-bodied vertebrates, there is a need to better understand how to manage mycoses and facilitate recovery in affected host populations. We explore challenges to host survival and mechanisms of host recovery in three bat species (Myotis lucifugus, Perimyotis subflavus, and M. septentrionalis) threatened with extinction by the mycosis, White-nose Syndrome (WNS) as it continues to spread across North America. We present evidence from the literature that bats surviving WNS are exhibiting mechanisms of avoidance (by selecting microclimates within roosts) and tolerance (by increasing winter fat reserves), which may help avoid costs of immunopathology incurred by a maladaptive host resistance response. We discuss management actions for facilitating species recovery that take into consideration disease pressures (e.g., environmental reservoir) and mechanisms underlying persistence, and suggest strategies that alleviate costs of immunopathology and target mechanisms of avoidance (protect or create refugia) and tolerance (increase body condition). We also propose strategies that target population and species-level recovery, including increasing reproductive success and reducing other stressors (e.g., wind turbine mortality). The rarity of fungal pathogens paired with the increasing frequency of emerging mycoses in warm-bodied vertebrate systems, including humans, requires a need to challenge common conventions about how diseases operate, how hosts respond, and how these systems could be managed to increase probability of recovery in host populations.

Role of delay discounting in resisting in-class media multitasking under contextual control: a cluster analysis

ABSTRACT The present study examined a potential mechanism underlying college students’ resisting in-class media multitasking under contextual control from a behavioural economic perspective. Using a hierarchical cluster analysis, we first identified subgroups of students who differed in frequencies of media multitasking across two contexts (preferred and non-preferred classes). We then compared a subgroup of students who could resist media multitasking in one context but not in another context with other subgroups of students in terms of rates of delay discounting and levels of impulse control. In the delay-discounting task, participants made a series of choices between smaller amounts of hypothetical monetary rewards available immediately and a larger amount of hypothetical monetary rewards available after a delay. Impulse control was measured by a self-reported scale. The primary finding was that the subgroup of students who could resist media multitasking in preferred but not non-preferred classes showed significantly lower rates of delay discounting than the subgroup of students who frequently engaged in media multitasking in both preferred and non-preferred classes. Implications for developing effective intervention strategies from a behavioural economic perspective are discussed.

WITHDRAWN: Transdifferentiation of Human Neonatal Foreskin Fibroblasts into Keratinocyte-like Cells via Regulating the AKT/P53/WNT/LEF1 Axis

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Association of Antipsychotic Drugs with Venous Thromboembolism: Data Mining of Food and Drug Administration Adverse Event Reporting System and Mendelian Randomization Analysis.

Past observational studies have reported on the association between antipsychotic drugs and venous thromboembolism (VTE); however, the conclusions remain controversial, and its mechanisms are yet to be fully understood. Thus, in this study, we aim to determine the associations of antipsychotic drugs with VTE, including deep vein thrombosis (DVT) and pulmonary embolism (PE), and their potential mechanisms. We first mined the adverse event signals of VTE, DVT, and PE caused by antipsychotic drugs in Food and Drug Administration Adverse Event Reporting System (FAERS). Next, we used two-sample Mendelian randomization (MR) method to investigate the association of antipsychotic drug target gene expression with VTE, DVT, and PE, using single-nucleotide polymorphisms as genetic instruments. We not only used the expression of all antipsychotic drug target genes as exposure to perform MR analyses but also analyzed the effect of single target gene expression on the outcomes. In the FAERS, 1694 cases of VTE events were reported by 16 drugs. However, using the MR approach, no significant association was determined between the expression of all antipsychotic target genes and VTE, DVT, or PE, either in blood or brain tissue. Although the analysis of single gene expression data showed that the expression of nine genes was associated with VTE events, these targets lacked significant pharmacological action. Adverse event mining results have supported the claim that antipsychotic drugs can increase the risk of VTE. However, we failed to find any genetic evidence for this causal association and potential mechanisms. Thus, vigilance is still needed for antipsychotic drug-related VTE despite the limited supporting evidence.

Childhood trauma, stressful life events, and depression: Exploring the mediating effect of cognitive flexibility.

Childhood trauma and stressful life events have been identified as risk factors for the development of depression. However, little is known about the potential cognitive mechanisms underlying these associations. This study aims to investigate the associations among childhood trauma, stressful life events, and depression and to test a mediating model to examine the roles of cognitive flexibility in these associations. First-year university students (n = 2627; Mage = 18.29, SDage = .86) were recruited from a medical university in Guangzhou, China. A total of 1,600 (60.9%) females and 1,027 (39.1%) males participated in the survey. Participants were administered self-report measures assessing childhood trauma, stressful life events, cognitive flexibility, and depression. Childhood trauma and stressful life events were both negative predictors of cognitive flexibility (β = -.32, β = -.19, respectively; ps < .01), which in turn was a negative predictor of depression (β = -.50, p < .01). Cognitive flexibility partially mediated the relationship between childhood trauma and depression (with the indirect effect = .161, 95% confidence interval, CI [.139, .185]) as well as the relationship between stressful life events and depression (with the indirect effect = .097, 95% CI [.078, .118]). This study reveals that childhood trauma and stressful life events not only have a direct effect on depression but also increase individuals' risk of depression by decreasing their cognitive flexibility. These findings shed light on the possible potential mechanism underlying the suicide process and highlight the important role of cognitive flexibility in suicide prevention and intervention. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Natural Polyphenols in Cancer Management: Promising Role, Mechanisms, and Chemistry.

Although cancers emerge rapidly and cancer cells divide aggressively, which affects our vital organ systems. Recently, cancer treatments are targeted immune systems mediating intrinsic cellular mechanisms. Natural efficacious polyphenols have been exhibited to help prevent most cancers and reverse the progression of cancers. Many resources have been used to know the promising role of polyphenols in preventing and treating cancers. The electronic databases include Science Direct, Google, Google Scholar, PubMed, and Scopus. The search was limited to the English language only. Polyphenols have been reported as anti-metastatic agents that explore the promising role of these compounds in cancer prevention. Such agents act through many signaling pathways, including PI3K/Akt and TNF-induced signaling pathways. The chemical modifications of polyphenols and the structure-activity relationships (SARs) between polyphenols and anti-cancer activities have also been discussed. Many research papers were reported to explain the anti-cancer potential of Polyphenols, The SARs between polyphenols and anti-cancer activities, which correlate structures of polyphenols with significant chemotherapeutic action. The mechanism of anti-cancer potential is to be added for searching for new anti-cancer natural products.

Sulfonamide Derivatives: Recent Compounds with Potent Anti- Alzheimer's Disease Activity.

Facile synthetic procedures and broad spectrum of biological activities are special attributes of sulfonamides. Sulfonamide derivatives have demonstrated potential as a class of compounds for the treatment of Alzheimer's disease (AD). Recent sulfonamide derivatives have been reported as prospective anti-AD agents, with a focus on analogues that significantly inhibit the function of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes and exhibit remarkable antioxidant and anti-inflammatory properties, all of which are critical for the treatment of AD. Sulfonamide- mediated activation of nuclear factor erythroid 2-related factor 2 (NRF2), a key regulator of the endogenous antioxidant response, has also been suggested as a potential therapeutic approach in AD. Additionally, it has been discovered that a number of sulfonamide derivatives show selectivity for the β- and γ-secretase enzymes and a significant reduction of amyloid B (Aβ) aggregation, which have been implicated in AD. The comparative molecular docking of benzenesulfonamide and donepezil, an AD reference drug showed comparable anti-AD activities. These suggest that sulfonamide derivatives may represent a new class of drugs for the treatment of AD. Thus, the current review will focus on recent studies on the chemical synthesis and evaluation of the anti-AD properties, molecular docking, pharmacological profile, and structure-activity relationship (SAR) of sulfonamide derivatives, as well as their potential anti-AD mechanisms of action. This paper offers a thorough assessment of the state of the art in this field of study and emphasizes the potential of sulfonamide derivatives synthesized during the 2012-2023 period as a new class of compounds for the treatment of AD.

Fluoroquinolone and enoxacin molecules are potential urease inhibitors for treating ureolytic bacterial infections

Urease, a nickel-dependent metalloenzyme, has emerged as a significant therapeutic target due to its role in promoting the pathogenesis of various human health conditions. These include the development of pyelonephritis, urolithiasis, peptic ulcers, hepatic encephalopathy, and gastric ulcers. The currently available treatment involved the usage of strong antibiotics along with proton pump inhibitors to cope with the infection of urease producing bacteria. These conventional treatments are becoming less effective as bacteria are gaining multiple drug resistance. Therefore, there is a crucial need to identify alternative compounds with potential anti-urease activity and minimal side effects. Fluoroquinolones and Enoxacin derivatives offer antimicrobial, anti-inflammatory, antioxidant, anti-diabetic, and anti-urease activities. To improve the chemical diversity of urease inhibitors, different series of fluoroquinolones and Enoxacin derivatives were evaluated against urease and their antioxidant activity was also evaluated. To achieve this objective, in-silico studies were conducted utilizing molecular docking and adsorption, distribution, metabolism, excretion, and toxicology (ADMET) models. These analyses were employed to explore potential binding mechanisms and assess the drug-likeness of the compounds against urease enzymes. The inhibitory effect of docked heterocyclic compounds was also verified in-vitro against urease enzyme. Fluoroquinolones derivatives were found to be active inhibitors at high dose levels but showed minimum inhibition at low concentration. The compound EN from the Enoxacin series exhibited the highest potency as a urease inhibitor, with an IC50 of 45.86 μM, out-performing the standard drug thiourea, which had an IC50 of 52.20 μM. Additionally, compounds NOX-3 and FB-17 from the fluoroquinolone and Enoxacin series demonstrated significant DPPH free radical scavenging activity, with IC50 values of 98.17 μM and 97.98 μM, respectively. These results were comparable to the positive control ascorbic acid, which had an IC50 of 48.15 μM. This study demonstrates that Enoxacin derivatives can be further analyzed as potent urease inhibitors, while both Enoxacin and fluoroquinolone derivatives can be developed into more effective drugs to overcome oxidative stress.

Cultural mechanisms linking mothers' familism values to externalizing behaviors among Midwest U.S. Latinx adolescents.

This study was designed to examine associations among parents' familism values, adolescents' cultural resources, and externalizing behavior among Latinx youth in the Midwestern United States. Participants were 267 Latinx adolescents (M age = 15.58 years; SD = 1.28 years; 45% girls; 82.8% Mexican American) and their mothers/mother figures who completed individually administered interviews comprised of standardized measures. Structural equation modeling was used to test several alternative mediational models in which youth ethnic identity and familism values served as potential cultural mechanisms linking parents' familism values to lower levels of youth externalizing behavior. Results showed that mothers' familism values were positively associated with youth ethnic identity which was positively associated with youth familism values; in turn, youth familism values were inversely associated with externalizing behavior. The findings did not differ by youth gender or nativity (U.S.-born vs. foreign-born youth). These findings provide support for cultural resilience perspectives by highlighting the protective role of ethnic identity and familism values among U.S. Latinx adolescents. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Crosstalk of lysyl oxidase-like 1 and lysyl oxidase prolongs their half-lives and regulates liver fibrosis through Notch signal.

Lysyl oxidase (LOX) family members (LOX and LOXL1 to 4) are crucial copper-dependent enzymes responsible for cross-linking collagen and elastin. Previous studies have revealed that LOX and LOXL1 are the most dramatically dysregulated LOX isoforms during liver fibrosis. However, the crosstalk between them and the underlying mechanisms involved in the profibrotic behaviors of HSCs, as well as the progression of liver fibrosis, remain unclear. pCol9GFP-HS4,5Tg mice, Loxl1fl/flGfapCre mice, human HSC line, and primary HSCs were enrolled to study the dysregulation pattern, profibrotic roles, and the potential mechanisms of LOX and LOXL1 interaction involved in the myofibroblast-like transition of HSCs and liver fibrogenesis. LOX and LOXL1 were synergistically upregulated during liver fibrogenesis, irrespective of etiology, together orchestrating the profibrotic behaviors of HSCs. LOX and LOXL1 coregulated in HSCs, whereas LOXL1 dominated in the coregulation loop. Interestingly, the interaction between LOXL1 and LOX prolonged their half-lives, specifically enhancing the Notch signal-mediated myofibroblast-like transition of HSCs. Selective disruption of Loxl1 in Gfap+ HSCs deactivated the Notch signal, inhibited HSC activation, and relieved carbon tetrachloride-induced liver fibrosis. Our current study confirmed the synergistic roles and the underlying mechanisms of LOXL1 and LOX crosstalk in the profibrotic behaviors of HSCs and liver fibrosis progression, providing experimental evidence for further clear mechanism-based anti-LOXL1 strategy development in the therapy of liver fibrosis.

Cutaneous targets for topical pain medications in patients with neuropathic pain: individual differential expression of biomarkers supports the need for personalized medicine.

Numerous potential cutaneous targets exist for treating chronic pain with topically applied active pharmaceutical ingredients. This preliminary human skin tissue investigation was undertaken to characterize several key biomarkers in keratinocytes and provide proof-of-principle data to support clinical development of topical compounded formulations for peripheral neuropathic pain syndromes, such as postherpetic neuralgia (PHN). The study intended to identify objective biomarkers in PHN skin on a patient-by-patient personalized medicine platform. The totality of biopsy biomarker data can provide a tissue basis for directing individualized compounded topical preparations to optimize treatment efficacy. Referencing 5 of the most common actives used in topical pain relief formulations (ketamine, gabapentin, clonidine, baclofen, and lidocaine), and 3 well-established cutaneous mediators (ie, neuropeptides, cannabinoids, and vanilloids), comprehensive immunolabeling was used to quantify receptor biomarkers in skin biopsy samples taken from ipsilateral (pain) and contralateral (nonpain) dermatomes of patients with PHN. Epidermal keratinocyte labeling patterns were significantly different among the cohort for each biomarker, consistent with potential mechanisms of action among keratinocytes. Importantly, the total biomarker panel indicates that the enriched PHN cohort contains distinct subgroups. The heterogeneity of the cohort differences may explain studies that have not shown statistical group benefit from topically administered compounded therapies. Rather, the essential need for individual tissue biomarker evaluations is evident, particularly as a means to direct a more accurately targeted topical personalized medicine approach and generate positive clinical results.

Precision Education and Equity: A Participatory Framework to Advance Equitable Assessment.

Precision education (PE) may hold promise for the future of the field. Leveraging data and learning analytics to foster continuous improvement of individuals, programs, and organizations seems like a potential mechanism to advance both medical education and health care delivery systems toward a more equitable future. However, PE initiatives may also have unintended consequences and perpetuate inequities instead of ameliorating them. Although there have been some principles, ideas, and suggestions on how PE implementation may promote equity-particularly for the field of assessment-there is a lack of practical and evidence-informed guidance to support a more equitable and participatory approach to PE implementation. This paper provides actionable recommendations on how PE may advance equitable assessment. First, PE implementation must include democratizing access and ownership while enhancing literacy and transparency. Open and transparent access to both data and PE technology has the potential to enhance PE by fostering greater participation, rigor, and potential innovation. Transparency may also safeguard the use of assessment data for equitable purposes. Second, PE implementation must be cocreated with diverse learners. PE has the potential to empower learners if they are given an opportunity to participate in the development, application, and implementation of PE. Overall, a participatory approach to PE implementation has the potential to improve equitable assessment.