Elucidating immunological characteristics of the adenoma-carcinoma sequence in colorectal cancer patients in South Korea using a bioinformatics approach.

Colorectal cancer (CRC) is one of the top five most common and life-threatening malignancies worldwide. Most CRC develops from advanced colorectal adenoma (ACA), a precancerous stage, through the adenoma-carcinoma sequence. However, its underlying mechanisms, including how the tumor microenvironment changes, remain elusive. Therefore, we conducted an integrative analysis comparing RNA-seq data collected from 40 ACA patients who visited Dongguk University Ilsan Hospital with normal adjacent colons and tumor samples from 18 CRC patients collected from a public database. Differential expression analysis identified 21 and 79 sequentially up- or down-regulated genes across the continuum, respectively. The functional centrality of the continuum genes was assessed through network analysis, identifying 11 up- and 13 down-regulated hub-genes. Subsequently, we validated the prognostic effects of hub-genes using the Kaplan-Meier survival analysis. To estimate the immunological transition of the adenoma-carcinoma sequence, single-cell deconvolution and immune repertoire analyses were conducted. Significant composition changes for innate immunity cells and decreased plasma B-cells with immunoglobulin diversity were observed, along with distinctive immunoglobulin recombination patterns. Taken together, we believe our findings suggest underlying transcriptional and immunological changes during the adenoma-carcinoma sequence, contributing to the further development of pre-diagnostic markers for CRC.

Continuity of care between dyslipidemia patients and multiple providers: A cohort study.

OBJECTIVE: This study aimed to investigate the impacts of continuity of care (COC) between patients and multiple providers, i.e., doctors and community pharmacists, on clinical and economic outcomes. METHODS: This is a retrospective cohort study and analyzed Korean national claims data for ambulatory care setting between 2007 and 2018. Patients with dyslipidemia newly diagnosed in 2008 were identified. COC between providers and patients was computed using the continuity of care index (COCI). Based on COCIs, the study patients were allocated to four groups: HM/HP, HM/LP, LM/HP, and LM/LP. Each symbol represents H for high, L for low, M for doctor, and P for pharmacist. The primary study outcome was the incidence of atherosclerotic cardiovascular disease (ASCVD). RESULTS: 126,710 patients were included. Percentages of patients in the four study groups were as follows: HM/HP 35%, HM/LP 19%, LM/HP 12%, and LM/LP 34%. During the seven-year outcome period, 8,337 patients (6.6%) developed an ASCVD, and percentages in the study groups were as follows; HM/HP 6.2%, HM/LP 6.3%, LM/HP 6.8%, and LM/LP 7.1%. After adjusting for confounding covariates, only the LM/LP group had a significantly higher risk of ASCVD than the reference group, HM/HP (aHR = 1.16 [95% confidence interval = 1.10~1.22]). The risk of inappropriate medication adherence gradually increased 1.03-fold in the HM/LP group, 1.67-fold in the LM/HP, and 2.26-fold in the LM/LP group versus the HM/HP group after adjusting for covariates. Disease-related costs were lower in the HM/HP and LM/HP groups. CONCLUSIONS: The study shows that patients with high relational care continuity with doctors and pharmacists achieved better clinical results and utilized health care less, resulting in reduced expenses. Further exploration for the group that exhibits an ongoing relationship solely with pharmacists is warranted.

Telocyte Recruitment During the Emergence of a Metaplastic Niche in the Stomach.

BACKGROUND & AIM: Telocytes, a recently identified type of sub-epithelial interstitial cell, have garnered attention for their potential roles in tissue homeostasis and repair. However, their contribution to gastric metaplasia remains unexplored. This study aimed to elucidate the role of telocytes in the development of metaplasia within the gastric environment. METHODS: To investigate the presence and behavior of telocytes during metaplastic transitions, we utilized both drug-induced acute injury models (using DMP-777 or L635) and a genetically engineered mouse model (Mist1-Kras). Lineage tracing via the Foxl1-CreERT2;R26R-tdTomato mouse model was used to track telocyte migratory dynamics. Immunofluorescence staining was used to identify telocyte markers and evaluate their correlation with metaplasia-related changes. RESULTS: We confirmed the existence of FOXL1+/PDGFRα+ double-positive telocytes in the stomach's isthmus region. As metaplasia developed, we observed a marked increase in the telocyte population. The distribution of telocytes expanded beyond the isthmus to encompass the entire gland and closely reflected the expansion of the proliferative cell zone. Rather than a general response to mucosal damage, the shift in telocyte distribution was associated with the establishment of a metaplastic cell niche at the gland base. Furthermore, lineage-tracing experiments highlighted the active recruitment of telocytes to the emerging metaplastic cell niche, and we observed expression of Wnt5a, Bmp4, and Bmp7 in PDGFRα+ telocytes. CONCLUSIONS: These results suggest that telocytes contribute to the evolution of a gastric metaplasia niche. The dynamic behavior of these stromal cells, their responsiveness to metaplastic changes, and potential association with Wnt5a, Bmp4, and Bmp7 signaling emphasize the significance of telocytes in tissue adaptation and repair.

Prioritizing susceptibility genes for the prognosis of male-pattern baldness with transcriptome-wide association study.

BACKGROUND: Male-pattern baldness (MPB) is the most common cause of hair loss in men. It can be categorized into three types: type 2 (T2), type 3 (T3), and type 4 (T4), with type 1 (T1) being considered normal. Although various MPB-associated genetic variants have been suggested, a comprehensive study for linking these variants to gene expression regulation has not been performed to the best of our knowledge. RESULTS: In this study, we prioritized MPB-related tissue panels using tissue-specific enrichment analysis and utilized single-tissue panels from genotype-tissue expression version 8, as well as cross-tissue panels from context-specific genetics. Through a transcriptome-wide association study and colocalization analysis, we identified 52, 75, and 144 MPB associations for T2, T3, and T4, respectively. To assess the causality of MPB genes, we performed a conditional and joint analysis, which revealed 10, 11, and 54 putative causality genes for T2, T3, and T4, respectively. Finally, we conducted drug repositioning and identified potential drug candidates that are connected to MPB-associated genes. CONCLUSIONS: Overall, through an integrative analysis of gene expression and genotype data, we have identified robust MPB susceptibility genes that may help uncover the underlying molecular mechanisms and the novel drug candidates that may alleviate MPB.

Amphiregulin Switches Progenitor Cell Fate for Lineage Commitment During Gastric Mucosal Regeneration.

BACKGROUND & AIMS: Isthmic progenitors, tissue-specific stem cells in the stomach corpus, maintain mucosal homeostasis by balancing between proliferation and differentiation to gastric epithelial lineages. The progenitor cells rapidly adopt an active state in response to mucosal injury. However, it remains unclear how the isthmic progenitor cell niche is controlled during the regeneration of damaged epithelium. METHODS: We recapitulated tissue recovery process after acute mucosal injury in the mouse stomach. Bromodeoxyuridine incorporation was used to trace newly generated cells during the injury and recovery phases. To define the epithelial lineage commitment process during recovery, we performed single-cell RNA-sequencing on epithelial cells from the mouse stomachs. We validated the effects of amphiregulin (AREG) on mucosal recovery, using recombinant AREG treatment or AREG-deficient mice. RESULTS: We determined that an epidermal growth factor receptor ligand, AREG, can control progenitor cell lineage commitment. Based on the identification of lineage-committed subpopulations in the corpus epithelium through single-cell RNA-sequencing and bromodeoxyuridine incorporation, we showed that isthmic progenitors mainly transition into short-lived surface cell lineages but are less frequently committed to long-lived parietal cell lineages in homeostasis. However, mucosal regeneration after damage directs the lineage commitment of isthmic progenitors towards parietal cell lineages. During recovery, AREG treatment promoted repopulation with parietal cells, while suppressing surface cell commitment of progenitors. In contrast, transforming growth factor-α did not alter parietal cell regeneration, but did induce expansion of surface cell populations. AREG deficiency impairs parietal cell regeneration but increases surface cell commitment. CONCLUSIONS: These data demonstrate that different epidermal growth factor receptor ligands can distinctly regulate isthmic progenitor-driven mucosal regeneration and lineage commitment.

The Fibroblast Landscape in Stomach Carcinogenesis.

Numerous recent studies using single cell RNA sequencing and spatial transcriptomics have shown the vast cell heterogeneity, including epithelial, immune, and stromal cells, present in the normal human stomach and at different stages of gastric carcinogenesis. Fibroblasts within the metaplastic and dysplastic mucosal stroma represent key contributors to the carcinogenic microenvironment in the stomach. The heterogeneity of fibroblast populations is present in the normal stomach, but plasticity within these populations underlies their alterations in association with both metaplasia and dysplasia. In this review, we summarize and discuss efforts over the past several years to study the fibroblast components in human stomach from normal to metaplasia, dysplasia, and cancer. In the stomach, myofibroblast populations increase during late phase carcinogenesis and are a source of matrix proteins. PDGFRA-expressing telocyte-like cells are present in normal stomach and expand during metaplasia and dysplasia in close proximity with epithelial lineages, likely providing support for both normal and metaplastic progenitor niches. The alterations in fibroblast transcriptional signatures across the stomach carcinogenesis process indicate that fibroblast populations are likely as plastic as epithelial populations during the evolution of carcinogenesis.

Anticancer Effects of α-Pinene in AGS Gastric Cancer Cells.

Gastric cancer is the fifth most common cancer globally and the third leading cause of cancer-related mortality. Existing treatment strategies for gastric cancer often present numerous side effects. Consequently, recent studies have shifted toward devising new treatments grounded in safer natural substances. α-Pinene, a natural terpene found in the essential oils of various plants, such as Lavender angustifolia and Satureja myrtifolia, displays antioxidant, antibiotic, and anticancer properties. Yet, its impact on gastric cancer remains unexplored. This research assessed the effects of α-pinene in vitro using a human gastric adenocarcinoma cell-line (AGS) human gastric cancer cells and in vivo via a xenograft mouse model. The survival rate of AGS cells treated with α-pinene was notably lower than that of the control group, as revealed by the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay. This decline in cell viability was linked to apoptosis, as verified by 4',6-diamidino-2-phenylindole and annexin V/propidium iodide staining. The α-pinene-treated group exhibited elevated cleaved-poly (ADP-ribose) polymerase and B cell lymphoma 2 (Bcl-2)-associated X (Bax) levels and reduced Bcl-2 levels compared with the control levels. Moreover, α-pinene triggered the activation of extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38 within the mitogen-activated protein kinase (MAPK) pathway. In the xenograft mouse model, α-pinene induced apoptosis through the MAPK pathway, devoid of toxicity. These findings position α-pinene as a promising natural therapeutic for gastric cancer.

Multifunctional Surface Treatment against Imperfections and Halide Segregation in Wide-Band Gap Perovskite Solar Cells.

Mixed-halide wide-band gap perovskites (WBPs) still suffer from losses due to imperfections within the absorber and the segregation of halide ions under external stimuli. Herein, we design a multifunctional passivator (MFP) by mixing bromide salt, formamidinium bromide (FABr) with a p-type self-assembled monolayer (SAM) to target the nonradiative recombination pathways. Photoluminescence measurement shows considerable suppression of nonradiative recombination rates after treatment with FABr. However, WBPs still remained susceptible to halide segregation for which the addition of 25% p-type SAM was effective to decelerate segregation. It is observed that FABr can act as a passivating agent of the donor impurities, shifting the Fermi-level (Ef) toward the mid-band gap, while p-type SAM could cause an overweight of Ef toward the valence band. Favorable band bending at the interface could prevent the funneling of carriers toward I-rich clusters. Instead, charge carriers funnel toward an integrated SAM, preventing the accumulation of polaron-induced strain on the lattice. Consequently, n-i-p structured devices with an optimal MFP treatment show an average open-circuit voltage (VOC) increase of about 20 mV and fill factor (FF) increase by 4% compared with the control samples. The unencapsulated devices retained 95% of their initial performance when stored at room temperature under 40% relative humidity for 2800 h.

Oncogenic Fatty Acid Metabolism Rewires Energy Supply Chain in Gastric Carcinogenesis.

BACKGROUND & AIMS: Gastric carcinogenesis develops within a sequential carcinogenic cascade from precancerous metaplasia to dysplasia and adenocarcinoma, and oncogenic gene activation can drive the process. Metabolic reprogramming is considered a key mechanism for cancer cell growth and proliferation. However, how metabolic changes contribute to the progression of metaplasia to dysplasia remains unclear. We have examined metabolic dynamics during gastric carcinogenesis using a novel mouse model that induces Kras activation in zymogen-secreting chief cells. METHODS: We generated a Gif-rtTA;TetO-Cre;KrasG12D (GCK) mouse model that continuously induces active Kras expression in chief cells after doxycycline treatment. Histologic examination and imaging mass spectrometry were performed in the GCK mouse stomachs at 2 to 14 weeks after doxycycline treatment. Mouse and human gastric organoids were used for metabolic enzyme inhibitor treatment. The GCK mice were treated with a stearoyl- coenzyme A desaturase (SCD) inhibitor to inhibit the fatty acid desaturation. Tissue microarrays were used to assess the SCD expression in human gastrointestinal cancers. RESULTS: The GCK mice developed metaplasia and high-grade dysplasia within 4 months. Metabolic reprogramming from glycolysis to fatty acid metabolism occurred during metaplasia progression to dysplasia. Altered fatty acid desaturation through SCD produces a novel eicosenoic acid, which fuels dysplastic cell hyperproliferation and survival. The SCD inhibitor killed both mouse and human dysplastic organoids and selectively targeted dysplastic cells in vivo. SCD was up-regulated during carcinogenesis in human gastrointestinal cancers. CONCLUSIONS: Active Kras expression only in gastric chief cells drives the full spectrum of gastric carcinogenesis. Also, oncogenic metabolic rewiring is an essential adaptation for high-energy demand in dysplastic cells.

Kaempferol induces apoptosis through the MAPK pathway and regulates JNK-mediated autophagy in MC-3 cells.

This study sought to determine the anticancer effect of kaempferol, a glycone-type flavonoid glycoside with various pharmacological benefits, on human oral cancer MC-3 cells. In vitro studies comprised a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, annexin V and propidium iodide staining, western blotting analysis, and acridine orange staining, while the in vivo studies entailed a xenograft model, hematoxylin and eosin staining, and TdT-mediated dUTP-biotin nick end labelling. In vitro, kaempferol reduced the rate of survival of MC-3 cells, mediated intrinsic apoptosis, increased the number of acidic vesicular organelles, and altered the expression of autophagy-related proteins. Further, treatment with the autophagy inhibitors revealed that the induced autophagy had a cytoprotective effect on apoptosis in kaempferol-treated MC-3 cells. Kaempferol also decreased the expression of phosphorylated extracellular signal-regulated kinase and increased that of phosphorylated c-Jun N-terminal kinase (p-JNK) and phosphorylated p38 kinase in MC-3 cells, suggesting the occurrence of mitogen-activated protein kinase-mediated apoptosis and JNK-mediated autophagy. In vivo, kaempferol reduced tumor growth inducing apoptosis and autophagy. These results showed that kaempferol has the potential use as an adjunctive agent in treating oral cancer.

High-Performance Indoor Perovskite Solar Cells by Self-Suppression of Intrinsic Defects via a Facile Solvent-Engineering Strategy.

Lead halide perovskite solar cells have been emerging as very promising candidates for applications in indoor photovoltaics. To maximize their indoor performance, it is of critical importance to suppress intrinsic defects of the perovskite active layer. Herein, a facile solvent-engineering strategy is developed for effective suppression of both surface and bulk defects in lead halide perovskite indoor solar cells, leading to a high efficiency of 35.99% under the indoor illumination of 1000 lux Cool-white light-emitting diodes. Replacing dimethylformamide (DMF) with N-methyl-2-pyrrolidone (NMP) in the perovskite precursor solvent significantly passivates the intrinsic defects within the thus-prepared perovskite films, prolongs the charge carrier lifetimes and reduces non-radiative charge recombination of the devices. Compared to the DMF, the much higher interaction energy between NMP and formamidinium iodide/lead halide contributes to the markedly improved quality of the perovskite thin films with reduced interfacial halide deficiency and non-radiative charge recombination, which in turn enhances the device performance. This work paves the way for developing efficient indoor perovskite solar cells for the increasing demand for power supplies of Internet-of-Things devices.

NIPBL::NACC1 Fusion Hepatic Carcinoma.

Several reports describing a rare primary liver tumor with histologic features reminiscent of follicular thyroid neoplasms have been published under a variety of descriptive terms including thyroid-like, solid tubulocystic, and cholangioblastic cholangiocarcinoma. Although these tumors are considered to represent histologic variants, they lack classic features of cholangiocarcinoma and have unique characteristics, namely immunoreactivity for inhibin and NIPBL::NACC1 fusions. The purpose of this study is to present clinicopathologic and molecular data for a large series of these tumors to better understand their pathogenesis. We identified 11 hepatic tumors with these features. Immunohistochemical and NACC1 and NIPBL fluorescence in situ hybridization assays were performed on all cases. Four cases had available material for whole-genome sequencing (WGS) analysis. Most patients were adult women (mean age: 42 y) who presented with abdominal pain and large hepatic masses (mean size: 14 cm). Ten patients had no known liver disease. Of the patients with follow-up information, 3/9 (33%) pursued aggressive behavior. All tumors were composed of bland cuboidal cells with follicular and solid/trabecular growth patterns in various combinations, were immunoreactive for inhibin, showed albumin mRNA by in situ hybridization, and harbored the NIPBL::NACC1 fusion by fluorescence in situ hybridization. WGS corroborated the presence of the fusion in all 4 tested cases, high tumor mutational burden in 2 cases, and over 30 structural variants per case in 3 sequenced tumors. The cases lacked mutations typical of conventional intrahepatic cholangiocarcinoma. In this report, we describe the largest series of primary inhibin-positive hepatic neoplasms harboring a NIPBL::NACC1 fusion and the first WGS analysis of these tumors. We propose to name this neoplasm NIPBL:NACC1 fusion hepatic carcinoma.

Targeting Stem Cells and Dysplastic Features With Dual MEK/ERK and STAT3 Suppression in Gastric Carcinogenesis.

BACKGROUNDS & AIMS: Precancerous metaplasia progression to dysplasia can increase the risk of gastric cancers. However, effective strategies to specifically target these precancerous lesions are currently lacking. To address this, we aimed to identify key signaling pathways that are upregulated during metaplasia progression and critical for stem cell survival and function in dysplasia. METHODS: To assess the response to chemotherapeutic drugs, we used metaplastic and dysplastic organoids derived from Mist1-Kras mice and 20 human precancerous organoid lines established from patients with gastric cancer. Phospho-antibody array analysis and single-cell RNA-sequencing were performed to identify target cell populations and signaling pathways affected by pyrvinium, a putative anticancer drug. Pyrvinium was administered to Mist1-Kras mice to evaluate drug effectiveness in vivo. RESULTS: Although pyrvinium treatment resulted in growth arrest in metaplastic organoids, it induced cell death in dysplastic organoids. Pyrvinium treatment significantly downregulated phosphorylation of ERK and signal transducer and activator of transcription 3 (STAT3) as well as STAT3-target genes. Single-cell RNA-sequencing data analyses revealed that pyrvinium specifically targeted CD133+/CD166+ stem cell populations, as well as proliferating cells in dysplastic organoids. Pyrvinium inhibited metaplasia progression and facilitated the restoration of normal oxyntic glands in Mist1-Kras mice. Furthermore, pyrvinium exhibited suppressive effects on the growth and survival of human organoids with dysplastic features, through simultaneous blocking of the MEK/ERK and STAT3 signaling pathways. CONCLUSIONS: Through its dual blockade of MEK/ERK and STAT3 signaling pathways, pyrvinium can effectively induce growth arrest in metaplasia and cell death in dysplasia. Therefore, our findings suggest that pyrvinium is a promising chemotherapeutic agent for reprogramming the precancerous milieu to prevent gastric cancer development.

Effect of nitro-conjugated linoleic acid on the inflammatory response of murine macrophages activated with lipopolysaccharide derived from Prevotella intermedia.

Nitro-conjugated linoleic acid (NO2-CLA) has been observed to manifest salutary signaling responses, including anti-inflammatory and antioxidant properties. Here, the authors have explored the influence and underlying mechanisms of NO2-CLA on the proinflammatory reaction of murine macrophages that were challenged with lipopolysaccharide (LPS) derived from Prevotella intermedia, a putative periodontopathic bacterium. Treatment of LPS-activated RAW264.7 cells with NO2-CLA notably dampened the secretion of iNOS-derived NO, IL-1ß and IL-6 as well as their gene expressions and significantly enhanced the markers for M2 macrophage polarization. NO2-CLA promoted the HO-1 expression in cells challenged with LPS, and tin protoporphyrin IX, an HO-1 inhibitor, significantly reversed the NO2-CLA-mediated attenuation of NO secretion, but not IL-1ß or IL-6. We found that cells treated with NO2-CLA significantly increased mRNA expression of PPAR-γ compared to control cells, and NO2-CLA significantly reverted the decrease in PPAR-γ mRNA caused by LPS. Nonetheless, antagonists to PPAR-γ were unable to reverse the NO2-CLA-mediated suppression of inflammatory mediators. In addition, NO2-CLA did not alter the p38 and JNK activation elicited by LPS. Both NF-κB reporter activity and IκB-α degradation caused by LPS were notably diminished by NO2-CLA. NO2-CLA was observed to interrupt the nuclear translocation and DNA binding of p50 subunits caused by LPS with no obvious alterations in p65 subunits. Further, NO2-CLA attenuated the phosphorylation of STAT1/3 elicited in response to LPS. We propose that NO2-CLA could be considered as a possible strategy for the therapy of periodontal disease, although additional researches are certainly required to confirm this.

Dynamic tuft cell expansion during gastric metaplasia and dysplasia.

Tuft cells are chemosensory cells associated with luminal homeostasis, immune response, and tumorigenesis in the gastrointestinal tract. We aimed to elucidate alterations in tuft cell populations during gastric atrophy and tumorigenesis in humans with correlative comparison to relevant mouse models. Tuft cell distribution was determined in human stomachs from organ donors and in gastric pathologies including Ménétrier's disease, Helicobacter pylori gastritis, intestinal metaplasia (IM), and gastric tumors. Tuft cell populations were examined in Lrig1-KrasG12D , Mist1-KrasG12D , and MT-TGFα mice. Tuft cells were evenly distributed throughout the entire normal human stomach, primarily concentrated in the isthmal region in the fundus. Ménétrier's disease stomach showed increased tuft cells. Similarly, Lrig1-Kras mice and mice overexpressing TGFα showed marked foveolar hyperplasia and expanded tuft cell populations. Human stomach with IM or dysplasia also showed increased tuft cell numbers. Similarly, Mist1-Kras mice had increased numbers of tuft cells during metaplasia and dysplasia development. In human gastric cancers, tuft cells were rarely observed, but showed positive associations with well-differentiated lesions. In mouse gastric cancer xenografts, tuft cells were restricted to dysplastic well-differentiated mucinous cysts and were lost in less differentiated cancers. Taken together, tuft cell populations increased in atrophic human gastric pathologies, metaplasia, and dysplasia, but were decreased in gastric cancers. Similar findings were observed in mouse models, suggesting that, while tuft cells are associated with precancerous pathologies, their loss is most associated with the progression to invasive cancer.

Hemoglobin Subunit Theta 1 Promotes Proliferation by Reducing Reactive Oxygen Species in Lung Adenocarcinoma.

Lung adenocarcinoma is a crucial contributor to cancer-related mortality; however, effective treatments remain challenging. The present study aimed to investigate the role of hemoglobin subunit theta 1 (HBQ1), an α subunit of hemoglobin whose expression has recently been reported in non-erythroid cells, in lung adenocarcinoma. Comparative analysis showed that HBQ1 expression was significantly higher in lung adenocarcinoma tissues compared to normal lung tissues. Moreover, high HBQ1 expression was correlated with unfavorable overall survival and progression-free survival in patients, highlighting its potential as a prognostic marker. Our functional experiments revealed that when overexpressed, HBQ1 acts as an oncogene, enhancing cell proliferation, whereas HBQ1 knockdown inhibits it. Additionally, HBQ1 exhibited antioxidant properties by reducing basal reactive oxygen species levels, playing a crucial role in lung adenocarcinoma progression. These findings emphasize the critical role of HBQ1 in driving tumor growth and progression in lung adenocarcinoma. Our in vivo studies further supported the role of HBQ1 in lung adenocarcinoma. HBQ1 knockdown resulted in the inhibition of lung adenocarcinoma growth, demonstrating the potential of HBQ1 as a therapeutic target. Our findings highlight the importance of HBQ1 in lung adenocarcinoma and suggest its potential as both a diagnostic marker and a molecular target for therapeutic interventions.

Meta-analysis of single-cell RNA-sequencing data for depicting the transcriptomic landscape of chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a respiratory disease characterized by airflow limitation and chronic inflammation of the lungs that is a leading cause of death worldwide. Since the complete pathological mechanisms at the single-cell level are not fully understood yet, an integrative approach to characterizing the single-cell-resolution landscape of COPD is required. To identify the cell types and mechanisms associated with the development of COPD, we conducted a meta-analysis using three single-cell RNA-sequencing datasets of COPD. Among the 154,011 cells from 16 COPD patients and 18 healthy subjects, 17 distinct cell types were observed. Of the 17 cell types, monocytes, mast cells, and alveolar type 2 cells (AT2 cells) were found to be etiologically implicated in COPD based on genetic and transcriptomic features. The most transcriptomically diversified states of the three etiological cell types showed significant enrichment in immune/inflammatory responses (monocytes and mast cells) and/or mitochondrial dysfunction (monocytes and AT2 cells). We then identified three chemical candidates that may potentially induce COPD by modulating gene expression patterns in the three etiological cell types. Overall, our study suggests the single-cell level mechanisms underlying the pathogenesis of COPD and may provide information on toxic compounds that could be potential risk factors for COPD.

Piperlongumine induces apoptosis via the MAPK pathway and ERK­mediated autophagy in human melanoma cells.

Piperlongumine (PL) is an amide alkaloid with diverse pharmacological effects against cancer, bronchitis and asthma; however, research on its efficacy against melanoma is lacking. The present study investigated the anticancer effects of PL on A375SM and A375P human melanoma cells. PL decreased the survival rate of A375SM and A375P cells, as shown by MTT assay, increase of apoptotic cells by DAPI staining. And PL induced apoptosis by decreasing the expression of the anti­apoptotic protein Bcl­2 and increasing that of the pro­apoptotic proteins cleaved­PARP and Bax. PL also induced apoptosis in A375SM and A375P cells via the MAPK pathway, increasing expression of the MAPK pathway proteins, phosphorylated­(p­ERK), p­JNK p­p38. These proteins were confirmed by western blot. In addition, A375SM and A375P cells treated with PL showed an increased number of acidic vesicular organelles by acridine orange staining. Also, autophagy induced by the expression of 1A/1B­light chain 3, Beclin 1and mTOR was investigated through western blot. When PL was applied following treatment with autophagy inhibitors 3­methyladenine and hydroxychloroquine, autophagy exhibited a cytoprotective effect against apoptosis in MTT assay. Pretreatment of A375P cells with the ERK inhibitor PD98059 and the JNK inhibitor SP600125 followed by treatment with PL confirmed that apoptosis and autophagy were mediated via the MAPK/ERK pathway by western blot. In summary, the present study provided empirical evidence supporting the anticancer effects of PL on human melanoma cells and indicated the potential of PL as a treatment for melanoma.

Piperine Induces Apoptosis and Autophagy in HSC-3 Human Oral Cancer Cells by Regulating PI3K Signaling Pathway.

Currently, therapies for treating oral cancer have various side effects; therefore, research on treatment methods employing natural substances is being conducted. This study aimed to investigate piperine-induced apoptosis and autophagy in HSC-3 human oral cancer cells and their effects on tumor growth in vivo. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay demonstrated that piperine reduced the viability of HSC-3 cells and 4',6-diamidino-2-phenylindole staining, annexin-V/propidium iodide staining, and analysis of apoptosis-related protein expression confirmed that piperine induces apoptosis in HSC-3 cells. Additionally, piperine-induced autophagy was confirmed by the observation of increased acidic vesicular organelles and autophagy marker proteins, demonstrating that autophagy in HSC-3 cells induces apoptosis. Mechanistically, piperine induced apoptosis and autophagy by inhibiting the phosphatidylinositol-3-kinase (PI3K)/protein kinase B/mammalian target of rapamycin pathway in HSC-3 cells. We also confirmed that piperine inhibits oral cancer tumor growth in vivo via antitumor effects related to apoptosis and PI3K signaling pathway inhibition. Therefore, we suggest that piperine can be considered a natural anticancer agent for human oral cancer.

Piperlongumine Induces Apoptosis and Cytoprotective Autophagy via the MAPK Signaling Pathway in Human Oral Cancer Cells.

Oral cancer is a malignant tumor that primarily affects areas such as the lips, tongue, buccal mucosa, salivary gland, and gingiva and has a very high malignancy. Piperlongumine (PL), isolated from long pepper (Piper longum L.), is a natural alkaloid with pharmacological effects, such as anti-inflammatory and anti-atherosclerotic effects. The effect and mechanism of PL in oral cancer cell lines has not been explored. Therefore, this study aimed to investigate the mechanism of anticancer effects of PL in the human oral cancer cell lines MC-3 and HSC-4 in vitro. This study demonstrated that PL inhibits cell proliferation by inducing apoptosis and autophagy in human oral cancer cell lines, which was confirmed by the levels of apoptosis- and autophagy-related proteins through Western blotting. Moreover, the pharmacological blockade of autophagy activation by hydroxychloroquine (HCQ), an autophagy inhibitor, significantly improved PL-induced apoptosis in MC-3 cells, suggesting a cytoprotective effect. In addition, activation of the mitogen-activated protein kinase (MAPK) signaling pathway contributed to PL-induced apoptosis. Collectively, the study suggested that combining an autophagy inhibitor with PL treatment can exert effective anticancer properties in oral cancer cells by inducing apoptosis and cytoprotective autophagy via the JNK-mediated MAPK pathway.