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Skin wounds, leading to infections and death, have a huge negative impact on healthcare systems around the world. Antibacterial therapy and the suppression of excessive inflammation help wounds heal. To date, the application of wound dressings, biologics and biomaterials (hydrogels, epidermal growth factor, stem cells, etc.) is limited due to their difficult and expensive preparation process. Cinnamomum burmannii (Nees & T. Nees) Blume is an herb in traditional medicine, and its essential oil is rich in D-borneol, with antibacterial and anti-inflammatory effects. However, it is not clear whether Cinnamomum burmannii essential oil has the function of promoting wound healing. This study analyzed 32 main components and their relative contents of essential oil using GC-MS. Then, network pharmacology was used to predict the possible targets of this essential oil in wound healing. We first proved this essential oil's effects in vitro and in vivo. Cinnamomum burmannii essential oil could not only promote the proliferation and migration of skin stromal cells, but also promote M2-type polarization of macrophages while inhibiting the expression of pro-inflammatory cytokines. This study explored the possible mechanism by which Cinnamomum burmannii essential oil promotes wound healing, providing a cheap and effective strategy for promoting wound healing.
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Cinnamomum , Óleos Voláteis , Pele , Cicatrização , Cinnamomum/química , Óleos Voláteis/química , Óleos Voláteis/farmacologia , Cicatrização/efeitos dos fármacos , Cromatografia Gasosa-Espectrometria de Massas , Proliferação de Células/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Pele/citologia , Pele/efeitos dos fármacos , Pele/lesões , Pele/microbiologia , Células Estromais/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Animais , Camundongos , Humanos , Células RAW 264.7 , Células HaCaTRESUMO
BACKGROUND: High-resolution esophageal manometry (HREM) is the gold standard test for esophageal motility disorders. Nasopharyngeal airway-assisted insertion of the HREM catheter is a suggested salvage technique for failure from the inability to pass the catheter through the upper esophageal sphincter (UES). It has not been demonstrated that the nasopharyngeal airway improves procedural success rate. METHODS: Patients undergoing HREM between March 2019 and March 2023 were evaluated. Chart review was conducted for patient factors and procedural success rates before and after use of nasopharyngeal airway. Patients from March 2019 to May 2021 did not have nasopharyngeal airway available and were compared to patients from May 2021 to March 2023 who had the nasopharyngeal airway available. KEY RESULTS: In total, 523 HREM studies were conducted; 234 occurred prior to nasopharyngeal airway availability, and 289 occurred with nasopharyngeal airway availability. There was no difference in HREM catheter UES intubation rates between periods when a nasopharyngeal airway attempt was considered procedural failure (85% vs. 85%, p = 0.9). Nasopharyngeal airway use after UES intubation failure lead to improved UES intubation rates (94% vs. 85%, p < 0.01). Thirty-six patients that failed HREM catheter UES intubation had the procedure reattempted with a nasopharyngeal airway, 30 (83%) of which were successful. The nasopharyngeal airway assisted catheter UES intubation for failures attributed to nasal pain and hypersensitivity, gagging, coughing, and pharyngeal coiling. CONCLUSIONS & INFERENCES: Utilization of the nasopharyngeal airway increased rates of UES intubation. When HREM catheter placement through the UES fails, placement of a nasopharyngeal airway can be trialed to overcome patient procedural intolerance.
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Transtornos da Motilidade Esofágica , Manometria , Humanos , Manometria/métodos , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Transtornos da Motilidade Esofágica/diagnóstico , Transtornos da Motilidade Esofágica/terapia , Idoso , Nasofaringe , Catéteres , Estudos Retrospectivos , Esfíncter Esofágico Superior/fisiologiaRESUMO
BACKGROUND: Hypercontractile esophagus (HE) is a disorder of increased esophageal body contractile strength on high-resolution esophageal manometry (HREM). Compartmentalized pressurization (CP) is a pattern with an isobaric contour of >30 mmHg extending from the contractile front to the lower esophageal sphincter on HREM. The relevance of CP to HE has yet to be explored. METHODS: A retrospective review was performed on 830 HREM studies of patients to identify HE. HE patients' CP status and symptoms by Eckardt score (ES) were reviewed. Diagnoses were made using Chicago Classification (CC) v4.0. KEY RESULTS: Forty-seven patients (5.6%) were identified as having HE by CCv3, 30 (3.6%) of which had HE by CCv4. 11/30 HE patients had CP, and 19/30 did not. CP was associated with chronic opioid use (36.4% vs. 5.3% p = 0.047). Presenting ES was greater for HE patients with CP (7 vs. 4). Seven HE patients with CP and 11 without CP were managed medically. ES after medical therapy was higher in HE patients with CP compared to those without CP (9 vs. 0). No HE patients with CP responded to medical therapy. Kaplan-Meier analysis demonstrated significance of this association over time. 83% of all HE patients had all-cause symptom remission. CONCLUSIONS & INFERENCES: HE patients with CP are associated with a higher presenting ES. HE patients with CP do not respond to medical therapy, while HE patients without CP frequently do respond. CP in HE may have prognostic value in determination of treatment strategy for patients with HE.
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Transtornos da Motilidade Esofágica , Humanos , Transtornos da Motilidade Esofágica/diagnóstico , Transtornos da Motilidade Esofágica/complicações , Prognóstico , Manometria , Estudos RetrospectivosRESUMO
M3 muscarinic receptors (M3R) modulate ß-catenin signaling and colon neoplasia. CDC42/RAC guanine nucleotide exchange factor, ßPix, binds to ß-catenin in colon cancer cells, augmenting ß-catenin transcriptional activity. Using in silico, in vitro, and in vivo approaches, we explored whether these actions are regulated by M3R. At the invasive fronts of murine and human colon cancers, we detected co-localized nuclear expression of ßPix and ß-catenin in stem cells overexpressing M3R. Using immunohistochemistry, immunoprecipitation, proximity ligand, and fluorescent cell sorting assays in human tissues and established and primary human colon cancer cell cultures, we detected time-dependent M3R agonist-induced cytoplasmic and nuclear association of ßPix with ß-catenin. ßPix knockdown attenuated M3R agonist-induced human colon cancer cell proliferation, migration, invasion, and expression of PTGS2, the gene encoding cyclooxygenase-2, a key player in colon neoplasia. Overexpressing ßPix dose-dependently augmented ß-catenin binding to the transcription factor TCF4. In a murine model of sporadic colon cancer, advanced neoplasia was attenuated in conditional knockout mice with intestinal epithelial cell deficiency of ßPix. Expression levels of ß-catenin target genes and proteins relevant to colon neoplasia, including c-Myc and Ptgs2, were reduced in colon tumors from ßPix-deficient conditional knockout mice. Targeting the M3R/ßPix/ß-catenin axis may have therapeutic potential.
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Neoplasias do Colo , beta Catenina , Camundongos , Humanos , Animais , beta Catenina/metabolismo , Ciclo-Oxigenase 2/metabolismo , Neoplasias do Colo/patologia , Fatores de Troca de Nucleotídeo Guanina Rho/metabolismo , Receptores Muscarínicos/metabolismo , Camundongos Knockout , Regulação Neoplásica da Expressão GênicaRESUMO
M3 muscarinic receptor (M3R) activation stimulates colon cancer cell proliferation, migration, and invasion; M3R expression is augmented in colon cancer and ablating M3R expression in mice attenuates colon neoplasia. Several lines of investigation suggest that in contrast to these pro-neoplastic effects of M3R, M1R plays an opposite role, protecting colon epithelial cells against neoplastic transformation. To pursue these intriguing findings, we examined the relative expression of M1R versus M3R in progressive stages of colon neoplasia and the effect of treating colon cancer cells with selective M1R agonists. We detected divergent expression of M1R and M3R in progressive colon neoplasia, from aberrant crypt foci to adenomas, primary colon cancers, and colon cancer metastases. Treating three human colon cancer cell lines with two selective M1R agonists, we found that in contrast to the effects of M3R activation, selective activation of M1R reversibly inhibited cell proliferation. Moreover, these effects were diminished by pre-incubating cells with a selective M1R inhibitor. Mechanistic insights were gained using selective chemical inhibitors of post-muscarinic receptor signaling molecules and immunoblotting to demonstrate M1R-dependent changes in the activation (phosphorylation) of key downstream kinases, EGFR, ERK1/2, and p38 MAPK. We did not detect a role for drug toxicity, cellular senescence, or apoptosis in mediating M1R agonist-induced attenuated cell proliferation. Lastly, adding M1R-selective agonists to colon cancer cells augmented the anti-proliferative effects of conventional chemotherapeutic agents. Collectively, these results suggest that selective M1R agonism for advanced colon cancer, alone or in combination with conventional chemotherapy, is a therapeutic strategy worth exploring.
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Cancer is one of the most lethal diseases in human society, and its incidence is gradually increasing. However, the current tumor treatment often meets the problem of poor efficacy and big side effects. The unique physical and chemical properties of nanomaterials can target the delivery of drugs to tumors, which can improve the therapeutic effect while reducing the damage of drugs to normal cells. This makes nanomaterials become a hot topic in the field of biomedicine. This review summarizes the recent progress of nanomaterials in tumor targeted therapy.
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Gastric pneumatosis, an uncommon radiologic finding characterized by the presence of gas within the gastric wall, presents a diagnostic challenge due to its association with both benign gastric emphysema and more severe emphysematous gastritis. The contrasting outcomes and management approaches for these conditions underscore the necessity for accurate diagnosis and appropriate intervention. We present a case of a 29-year-old female with a medical history significant for type 1 diabetes mellitus who presented with abdominal pain, nausea, and vomiting. Initial evaluation revealed elevated blood glucose levels, an anion gap metabolic acidosis, and evidence of gastric pneumatosis on imaging. The patient was managed with aggressive fluid resuscitation and intravenous insulin therapy per diabetic ketoacidosis protocol. General surgery evaluation ruled out the need for acute surgical intervention and attributed the gastric pneumatosis to increased intragastric pressures from prolonged vomiting. The patient was managed with conservative measures, including nasogastric tube decompression and antibiotics. Over the course of a few days, the patient showed signs of clinical and radiologic improvement, with a resolution of symptoms. This case highlights the importance of accurate diagnosis and appropriate management strategies tailored to the underlying pathology to optimize patient outcomes in cases of gastric pneumatosis.
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Despite colorectal cancer remaining a leading worldwide cause of cancer-related death, there remains a paucity of effective treatments for advanced disease. The molecular mechanisms underlying the development of colorectal cancer include altered cell signaling and cell cycle regulation that may result from epigenetic modifications of gene expression and function. Acting as important transcriptional regulators of normal biological processes, zinc finger proteins also play key roles in regulating the cellular mechanisms underlying colorectal neoplasia. These actions impact cell differentiation and proliferation, epithelial-mesenchymal transition, apoptosis, homeostasis, senescence, and maintenance of stemness. With the goal of highlighting promising points of therapeutic intervention, we review the oncogenic and tumor suppressor roles of zinc finger proteins with respect to colorectal cancer tumorigenesis and progression.
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Transformação Celular Neoplásica , Neoplasias Colorretais , Humanos , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Carcinogênese/genética , Neoplasias Colorretais/patologia , Dedos de Zinco , Transição Epitelial-Mesenquimal/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão GênicaRESUMO
BACKGROUND: Esophagogastric junction outflow obstruction (EGJOO) is an esophageal motility disorder characterized by a lack of relaxation of the esophagogastric junction (EGJ), with preserved esophageal body peristalsis. We propose new terminology for the coexistence of EGJOO with hypercontractile esophagus and distal esophageal spasm as a major mixed motility disorder (MMMD), and normal peristalsis or a minor disorder of peristalsis such as ineffective esophageal motility with EGJOO as isolated or ineffective EGJOO (IEGJOO). METHODS: We reviewed prior diagnoses of EGJOO, stratified diagnoses as IEGJOO or MMMD, and compared their symptomatic presentations, high-resolution manometry (HRM) and endoluminal functional lumen imaging probe (EndoFLIP) metrics, and treatment responses at 2-6 months of follow-up. RESULTS: Out of a total of 821 patients, 142 met CCv3 criteria for EGJOO. Twenty-two were confirmed by CCv4 and EndoFLIP as having EGJOO and were clinically managed. Thirteen had MMMD, and nine had IEGJOO. Groups had no difference in demographic data or presenting symptoms by Eckardt score (ES). HRM showed MMMD had greater distal contractile integral, frequency of hypercontractile swallows, and frequency of spastic swallows, and greater DI by EndoFLIP. Patients with MMMD showed greater reduction in symptoms after LES-directed intervention when measured by ES compared with IEGJOO (7.2 vs. 4.0). CONCLUSION: Patients with MMMD and IEGJOO present similarly. Detectable differences in HRM portend different responses to endoscopic therapy. Because patients with MMMD have greater short-term prognosis, they should be considered a different diagnostic classification to guide therapy.
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Transtornos da Motilidade Esofágica , Gastropatias , Humanos , Benchmarking , Junção Esofagogástrica , Manometria , Contração MuscularRESUMO
Long non-coding RNAs (lncRNAs) have been to regulate tumor progression and therapy resistance through various molecular mechanisms. In this study, we investigated the role of lncRNAs in nasopharyngeal carcinoma (NPC) and the underlying mechanism. Using lncRNA arrays to analyze the lncRNA profiles of the NPC and para-tumor tissues, we detected the novel lnc-MRPL39-2:1, which was validated by in situ hybridization and by the 5' and 3' rapid amplification of the cDNA ends. Further, its role in NPC cell growth and metastasis was verified in vitro and in vivo. The researchers conducted the RNA pull-down assays, mass spectrometry (MS), dual-luciferase reporter assays, RNA immunoprecipitation (RIP) assays, and the MS2-RIP assays were then used to identify the lnc-MRPL39-2:1-interacting proteins and miRNAs. We found that lnc-MRPL39-2:1, which was highly expressed in in NPC tissues, was related to a poor prognosis in NPC patients. Furthermore, lnc-MRPL39-2:1 was shown to induce the growth and invasion of NPC by interacting directly with the Hu-antigen R (HuR) to upregulate ß-catenin expression both in vivo and in vitro. Lnc-MRPL39-2:1 expression was also suppressed by microRNA (miR)-329. Thus, these findings indicate that lnc-MRPL39-2:1 is essential in NPC tumorigenesis and metastasis and highlight its potential as a prognostic marker and therapeutic target for NPC.
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MicroRNAs , Neoplasias Nasofaríngeas , RNA Longo não Codificante , Humanos , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Mensageiro , beta Catenina/genética , beta Catenina/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Proliferação de Células/genética , Neoplasias Nasofaríngeas/metabolismo , Linhagem Celular TumoralRESUMO
OBJECTIVES: Metabolic reprogramming is not only an essential hallmark in the progression of head and neck squamous cell carcinoma (HNSCC), but also an important regulator of cancer cell adaptation to tumor microenvironment (TME). However, the potential mechanism of metabolic reprogramming in TME of HNSCC is still unknown. METHODS: The head and neck squamous cell carcinoma with survival information were obtained the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The metabolic-related genes were identified by differential analysis and survival analysis. Univariate and multivariate Cox regression analyses were applied to determine an overall estimate of metabolic-related risk signature and related clinical parameters. The sensitivity and specificity of the risk signature were evaluated by time-dependent receiver operation characteristic (ROC) curves. TME immune cell infiltration mediated by metabolic-related genes was explored by gene set enrichment analysis (GSEA) and correlation analysis. RESULTS: Seven metabolic-related genes (SMS, MTHFD2, HPRT1, DNMT1, PYGL, ADA, and P4HA1) were identified to develop a metabolic-related risk signature. The low-risk group had a better overall survival compared to that of the high-risk group in the TCGA and GSE65858 cohorts. The AUCs for 1-, 3-, and 5-year overall survival were 0.646 vs. 0.673, 0.694 vs. 0.639, and 0.673 vs. 0.573, respectively. The AUC vale of risk score was 0.727 vs. 0.673. The low-risk group was associated with immune cell infiltration in the TME. CONCLUSIONS: The metabolic-related risk signature were constructed and validated, which could involve in regulating the immune cell infiltration in the TME and act as an independent biomarker that predicted the prognosis of HNSCC.
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Neoplasias de Cabeça e Pescoço , Hipoxantina Fosforribosiltransferase , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Fatores de Risco , Neoplasias de Cabeça e Pescoço/genética , Microambiente Tumoral/genéticaRESUMO
BACKGROUND AND AIMS: Jackhammer esophagus (JE) is a rare hypercontractile motility disorder often associated with dysphagia, regurgitation, and chest pain. In patients with clinically relevant symptoms, treatment options aim to decrease esophageal contractions. Medical, endoscopic and surgical therapies have limited long-term efficacy. The advent of peroral endoscopic myotomy (POEM) has evolved as a minimally invasive treatment option. Yet data regarding JE is scare. As such we aimed to investigate the clinical efficacy of JE. PATIENTS AND METHODS: This was a single center retrospective study of consecutive adult patients undergoing POEM for JE from April 2018 to September 2021. All procedures were conducted by a single endoscopist. Primary outcome was clinical success, defined as Eckardt score (ES) ≤3 following the procedure. RESULTS: A total of 13 patients (mean age 58, 7 females) underwent POEM with a mean duration of symptoms of 42.6 months. Preprocedure mean ES was 8.92. Nine patients were treatment naive. Pre-POEM endoluminal functional luminal imaging probe (n=10) demonstrated a distensibility index of 0.34. The average length of follow-up after POEM was 15.8 months.There was a 92.3% (12/13) clinical success rate, with a mean post-POEM ES of 1.53. One patient's ES improved from 12 to 1 after POEM; however, 2.5 years later she developed recurrent symptoms (ES 10). Only 1 patient had endoscopic evidence of Los Angeles grade A esophagitis. One year after POEM, 5 patients had gastroesophageal reflux disease symptoms, but only 2 required acid suppression therapy. CONCLUSION: POEM is an effective treatment modality with long-term efficacy. Larger, prospective studies are needed to validate these findings.
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Acalasia Esofágica , Miotomia , Cirurgia Endoscópica por Orifício Natural , Adulto , Feminino , Humanos , Estudos Retrospectivos , Esôfago , Acalasia Esofágica/cirurgia , Resultado do Tratamento , Miotomia/métodos , Esfíncter Esofágico Inferior/cirurgiaRESUMO
Background: Recent studies have identified that RNA 5-methylcytosine (m5C) is a wide-spread epigenetic modification in tumorigenesis. However, the clinical and immunotherapeutic values of m5C regulator NOP2 in 33 cancers remain unclear. Methods: The mRNA expression data and clinical data of 33 cancers were downloaded from The Cancer Genome Atlas (TCGA) database. The immunotherapy data including GSE67501, GSE78220, GSE35640, and IMvigor210 were downloaded from the Gene Expression Omnibus (GEO) database and the website based on the Creative Commons 3.0 license (http://research-pub.Gene.com/imvigor210corebiologies). The expression, survival, clinical parameters, tumor mutation burden (TMB), microsatellite instability (MSI), and tumor microenvironment (TME) were evaluated. Finally, the relationship between NOP2 and immunotherapy response was further explored. Results: NOP2 was significantly upregulated in most cancers, and high NOP2 expression was associated with poor prognosis. TMB, MSI, and NOP2 activities were involved in the dysregulation of NOP2. NOP2 was closely associated with immune cell infiltration, immune modulators, and immunotherapeutic inactivation. Conclusions: We comprehensively explored the clinical and immunotherapeutic values of NOP2 in cancers, providing evidence regarding the function of NOP2 and its role in clinical treatment.
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Two decades after the rapid expansion of photovoltaics, the number of solar panels reaching end-of-life is increasing. While precious metals such as silver and copper are usually recycled, silicon, which makes up the bulk of a solar cells, goes to landfills. This is due to the defect- and impurity-sensitive nature in most silicon-based technologies, rendering it uneconomical to purify waste silicon. Thermoelectrics represents a rare class of material in which defects and impurities can be engineered to enhance the performance. This is because of the majority-carrier nature, making it defect- and impurity-tolerant. Here, the upcycling of silicon from photovoltaic (PV) waste into thermoelectrics is enabled. This is done by doping 1% Ge and 4% P, which results in a figure of merit (zT) of 0.45 at 873 K, the highest among silicon-based thermoelectrics. The work represents an important piece of the puzzle in realizing a circular economy for photovoltaics and electronic waste.
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Transtornos da Motilidade Esofágica , Catéteres , Impedância Elétrica , Humanos , ManometriaRESUMO
Based on the method of non-equilibrium Green's function, we investigate the thermal transport and thermoelectric properties of graphenylene nanoribbons (GRNRs) with different width and chirality. The results show that the thermoelectric (TE) performance of GRNRs significantly increases with decreasing ribbon width, which stems from the reduction of thermal conductance. In addition, by changing the ribbon width and chirality, the figure of merit (ZT) can be controllably manipulated and maximized up to 0.45 at room temperature. Moreover, it is found that theZTvalue of GRNRs with branched structure can reach 1.8 at 300 K and 3.4 at 800 K owing to the phonon local resonance. Our findings here are of great importance for thermoelectric applications of GRNRs.
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The role played by the key tumor suppressor gene p53 and the implications of p53 mutations for the development and progression of neoplasia continue to expand. This review focuses on colorectal cancer and the regulators of p53 expression and activity identified over the past decade. These newly recognized regulatory mechanisms include (1) direct regulation of mouse double minute 2 homolog (MDM2), an E3 ubiquitin-protein ligase; (2) modulation of the MDM2-p53 interaction; (3) MDM2-independent p53 degradation; and (4) inhibition of p53 nuclear translocation. We positioned these regulatory mechanisms in the context of p53 missense mutations, which not only evade canonical p53 degradation machinery but also exhibit gain-of-function phenotypes that enhance tumor survival and metastasis. Lastly, we discuss current and potential therapeutic strategies directed against p53 mutant-bearing tumors.
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Sustained proliferative signaling and resisting cell death are hallmarks of cancer. Zinc finger protein 277 (ZNF277; murine Zfp277), a transcription factor regulating cellular senescence, is overexpressed in colon cancer, but its actions in intestinal homeostasis and neoplasia are unclear. Using human and murine intestine, human colon cancer cells, and ApcMin/+ mice with dysregulated ß-catenin signaling and exuberant intestinal neoplasia, we explored the actions of ZNF277/Zfp277 and defined the underlying mechanisms. In normal human and murine intestine, ZNF277/Zfp277 was expressed uniquely in early stem cell progenitors, undifferentiated transit-amplifying cells (TACs). Zfp277 was overexpressed in the ApcMin/+ mouse colon, implicating ZNF277/Zfp277 as a transcriptional target of ß-catenin signaling. We confirmed this by showing ß-catenin knockdown reduced ZNF277 expression and, using chromatin IP, identified 2 ß-catenin binding sites in the ZNF277 promoter. Zfp277 deficiency attenuated intestinal epithelial cell proliferation and tumor formation, and it strikingly prolonged ApcMin/+ mouse survival. RNA-Seq and PCR analyses revealed that Zfp277 modulates expression of genes in key cancer pathways, including ß-catenin signaling, the HOXD family that regulates development, and p21WAF1, a cell cycle inhibitor and tumor suppressor. In both human colon cancer cells and the murine colon, ZNF277/Zfp277 deficiency induced p21WAF1 expression and promoted senescence. Our findings identify ZNF277/Zfp277 as both a TAC marker and colon cancer oncogene that regulates cellular proliferation and senescence, in part by repressing p21WAF1 expression.
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Colo/metabolismo , Neoplasias do Colo/genética , Proteínas de Ligação a DNA/genética , Regulação Neoplásica da Expressão Gênica , Mucosa Intestinal/metabolismo , Neoplasias Experimentais , Dedos de Zinco/genética , Animais , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Proliferação de Células , Colo/patologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Proteínas de Ligação a DNA/biossíntese , Humanos , Mucosa Intestinal/patologia , Camundongos , Regiões Promotoras Genéticas , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Fatores de Transcrição , Via de Sinalização Wnt/genéticaRESUMO
Cancers arising from gastrointestinal epithelial cells are common, aggressive, and difficult to treat. Progress in this area resulted from recognizing that the biological behavior of these cancers is highly dependent on bioactive molecules released by neurocrine, paracrine, and autocrine mechanisms within the tumor microenvironment. For many decades after its discovery as a neurotransmitter, acetylcholine was thought to be synthesized and released uniquely from neurons and considered the sole physiological ligand for muscarinic receptor subtypes, which were believed to have similar or redundant actions. In the intervening years, we learned this former dogma is not tenable. (1) Acetylcholine is not produced and released only by neurons. The cellular machinery required to synthesize and release acetylcholine is present in immune, cancer, and other cells, as well as in lower organisms (e.g., bacteria) that inhabit the gut. (2) Acetylcholine is not the sole physiological activator of muscarinic receptors. For example, selected bile acids can modulate muscarinic receptor function. (3) Muscarinic receptor subtypes anticipated to have overlapping functions based on similar G protein coupling and downstream signaling may have unexpectedly diverse actions. Here, we review the relevant research findings supporting these conclusions and discuss how the complexity of muscarinic receptor biology impacts health and disease, focusing on their role in the initiation and progression of gastric, pancreatic, and colon cancers.
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Neoplasias do Colo/metabolismo , Neoplasias Pancreáticas/metabolismo , Receptores Muscarínicos/metabolismo , Neoplasias Gástricas/metabolismo , Acetilcolina/metabolismo , Ácidos e Sais Biliares/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Transdução de Sinais , Microambiente TumoralRESUMO
Despite structural similarity, the five subtypes comprising the cholinergic muscarinic family of G protein-coupled receptors regulate remarkably diverse biological functions. This mini review focuses on the closely related and commonly co-expressed M1R and M3R muscarinic acetylcholine receptor subtypes encoded respectively by CHRM1 and CHRM3. Activated M1R and M3R signal via Gq and downstream initiate phospholipid turnover, changes in cell calcium levels, and activation of protein kinases that alter gene transcription and ultimately cell function. The unexpectedly divergent effects of M1R and M3R activation, despite similar receptor structure, distribution, and signaling, are puzzling. To explore this conundrum, we focus on the gastrointestinal (GI) tract and liver because abundant data identify opposing effects of M1R and M3R activation on the progression of gastric, pancreatic, and colon cancer, and liver injury and fibrosis. Whereas M3R activation promotes GI neoplasia, M1R activation appears protective. In contrast, in murine liver injury models, M3R activation promotes and M1R activation mitigates liver fibrosis. We analyze these findings critically, consider their therapeutic implications, and review the pharmacology and availability for research and therapeutics of M1R and M3R-selective agonists and antagonists. We conclude by considering gaps in knowledge and other factors that hinder the application of these drugs and the development of new agents to treat GI and liver diseases.