Local anesthetics (LAs), such as articaine (AT), exhibit limited efficacy in inflammatory environments, which constitutes a significant limitation in their clinical application within oral medicine. In our prior research, we developed AT-17, which demonstrated effective properties in chronic inflammatory conditions and appears to function as a novel oral LA that could address this challenge. In the present study, we further elucidated the beneficial effects of AT-17 in acute inflammation, particularly in oral acute inflammation, where mitochondrial-related apoptosis played a crucial role. Our findings indicated that AT-17 effectively inhibited lipopolysaccharide (LPS)-induced nerve cell apoptosis by ameliorating mitochondrial dysfunction in vitro. This process involved the inhibition of mitochondrial reactive oxygen species (mtROS) production and the subsequent activation of the NRF2 pathway. Most notably, improvements in mitochondria-related apoptosis were key contributors to AT-17's inhibition of voltage-gated sodium channels. Additionally, AT-17 was shown to reduce mtROS production in nerve cells through the Na⁺/NCLX/ETC signaling axis. In conclusion, we have developed a novel local anesthetic that exhibits pronounced anesthetic functionality under inflammatory conditions by enhancing mitochondria-related apoptosis. This advancement holds considerable promise for future drug development and deepening our understanding of the underlying mechanisms of action.

Microwave thermochemotherapy (MTC) has been applied to treat lip squamous cell carcinoma (LSCC), but a deeper understanding of its therapeutic mechanisms and molecular biology is needed. To address this, we used single-cell transcriptomics (scRNA-seq) and spatial transcriptomics (ST) to highlight the pivotal role of tumor-associated neutrophils (TANs) among tumor-infiltrating immune cells and their therapeutic response to MTC. MNDA⁺ TANs with anti-tumor activity (N1-phenotype) are found to be abundantly infiltrated by MTC with benefit of increased blood perfusion, and these TANs are characterized by enhanced cytotoxicity, ameliorated hypoxia, and upregulated IL1B, activating T&NK cells and fibroblasts via IL1B-IL1R. In this highly anti-tumor immunogenic and hypoxia-reversed microenvironment under MTC, fibroblasts accumulated in the tumor front (TF) can recruit N1-TANs via CXCL2-CXCR2 and clear N2-TANs (pro-tumor phenotype) via CXCL12-CXCR4, which results in the aggregation of N1-TANs and extracellular matrix (ECM) deposition. In addition, we construct an N1-TANs marker, MX2, which positively correlates with better prognosis in LSCC patients, and employ deep learning techniques to predict expression of MX2 from hematoxylin-eosin (H&E)-stained images so as to conveniently guide decision making in clinical practice. Collectively, our findings demonstrate that the N1-TANs/fibroblasts defense wall formed in response to MTC effectively combat LSCC.
Humans ; Neutrophils/metabolism* ; Single-Cell Analysis ; Lip Neoplasms/genetics* ; Hyperthermia, Induced/methods* ; Microwaves/therapeutic use* ; Transcriptome ; Carcinoma, Squamous Cell/immunology* ; Tumor Microenvironment

Neurodegenerative diseases(NDs)are a series of disorders characterized by varying degrees of cognitive and mobility impairment,with increasing incidence in recent years.Currently,the treatment of these diseases is mainly based on drug therapy,and there are no effective methods for reversing the course of the diseases.Corni Fructus has the efficacy of tonifying the liver and kidney,and astringency and arresting,which is effective to various types of NDs.This article summarized the pharmacological effects of Corni Fructus,including anti-inflammatory,anti-oxidative stress,regulation of mitochondrial function,modulation of autophagy,inhibition of neuronal apoptosis,and epigenetic modulation,and sorted out the research progress of Corni Fructus and its active components in the treatment of NDs,such as Alzheimer disease,Parkinson disease,multiple sclerosis,and so on,with a view to providing a reference for further research and clinical application of Corni Fructus in NDs.

OBJECTIVE To explore the possible molecular mechanism through which amygdala cell adhesion molecule-1(CADM1)is involved in acute sleep deprivation-induced anxiety.METHODS Sixteen 8-week-old C57BL/6J mice were randomly divided into the control group and para-chlorophe-nylalanine(PCPA)-induced acute sleep deprivation experimental group.The PCPA mice were intraperi-toneally injected with PCPA suspension(at a dose of 300 mg?kg-1)between 8∶00 and 9∶00 am for 2 consecutive days while the control mice were injected with the same dose of normal saline.The sleep latency and sleep duration of mice were detected via the righting reflex test.Anxiety-like behaviors were detected by the open field test and elevated plus maze test.The expression level of CADM1 in the mouse amygdala was detected by Western Blot and Immunofluorescence staining.The GeneNet-work database was used to analyze the association between Cadm1 genes and other genes in the mouse amygdala.The key candidate regulatory genes were screened,and the Cadm1-anxiety behavior phenotype network was constructed.The mRNA expression levels of the key candidate regulatory genes were analyzed via qPCR analysis.RESULTS Compared with the control mice,the sleep latency of PCPA mice was significantly prolonged(P<0.01)while the sleep duration was significantly shortened(P<0.01).The activity time and distance of PCPA mice in the open field center were significantly shorter than those of the control group(P<0.05).The elevated plus maze experiment showed that the percentage of the number of times PCPA mice entered the open arm and the percentage of residence time in the open arm were significantly lower than those of the control group(P<0.05).Western Blot and immuno-fluorescence staining showed that the expression of CADM1 protein in the amygdala from PCPA mice was down-regulated compared with the control mice(P<0.05).Based on gene-behavioral association network analysis,Cadm1 was significantly associated with 25 anxiety-like behavior-related genes.The enrichment analysis of Cadm1 co-expression genes showed that Cadm1 was associated with γ-amino-butyric acid GABAergic synaptic pathway(P=4.31e-09),and that the key genes were huntingtin associ-ated protein 1(Hap1)(r=0.705,P=1.09e-08)、inositol 1,4,5-triphosphate receptor type 1(Itpr1)(r=-0.751,P=3.34e-10)、gamma-aminobutyric acid type A receptor subunit delta(Gabrd)(r=-0.836,P=3.93e-14)、γ-aminobutyric acid A receptor β1 subunit gene(Gabrb1)(r=0.732,P=1.50e-09)and adrenoceptor alpha 2A(Adra2a)(r=0.759,P=1.73e-10).The results of qPCR analysis showed that the mRNA levels of Hap1(P<0.05)、Gabrb1 and Adra2a were significantly up-regulated(P<0.01)while those of Itpr1 and Gabrd were significantly down-regulated(P<0.01).CONCLUSION Acute sleep deprivation leads to down-regulation of Cadm1 expression in the amygdala,and induces anxiety-like behaviors by affecting the expression of GABAergic synaptic signaling pathways Hap1,Gabrb1,Adra2a,Itpr1 and Gabrd.

Neurodegenerative diseases(NDs)are a series of disorders characterized by varying degrees of cognitive and mobility impairment,with increasing incidence in recent years.Currently,the treatment of these diseases is mainly based on drug therapy,and there are no effective methods for reversing the course of the diseases.Corni Fructus has the efficacy of tonifying the liver and kidney,and astringency and arresting,which is effective to various types of NDs.This article summarized the pharmacological effects of Corni Fructus,including anti-inflammatory,anti-oxidative stress,regulation of mitochondrial function,modulation of autophagy,inhibition of neuronal apoptosis,and epigenetic modulation,and sorted out the research progress of Corni Fructus and its active components in the treatment of NDs,such as Alzheimer disease,Parkinson disease,multiple sclerosis,and so on,with a view to providing a reference for further research and clinical application of Corni Fructus in NDs.

OBJECTIVE To explore the possible molecular mechanism through which amygdala cell adhesion molecule-1(CADM1)is involved in acute sleep deprivation-induced anxiety.METHODS Sixteen 8-week-old C57BL/6J mice were randomly divided into the control group and para-chlorophe-nylalanine(PCPA)-induced acute sleep deprivation experimental group.The PCPA mice were intraperi-toneally injected with PCPA suspension(at a dose of 300 mg?kg-1)between 8∶00 and 9∶00 am for 2 consecutive days while the control mice were injected with the same dose of normal saline.The sleep latency and sleep duration of mice were detected via the righting reflex test.Anxiety-like behaviors were detected by the open field test and elevated plus maze test.The expression level of CADM1 in the mouse amygdala was detected by Western Blot and Immunofluorescence staining.The GeneNet-work database was used to analyze the association between Cadm1 genes and other genes in the mouse amygdala.The key candidate regulatory genes were screened,and the Cadm1-anxiety behavior phenotype network was constructed.The mRNA expression levels of the key candidate regulatory genes were analyzed via qPCR analysis.RESULTS Compared with the control mice,the sleep latency of PCPA mice was significantly prolonged(P<0.01)while the sleep duration was significantly shortened(P<0.01).The activity time and distance of PCPA mice in the open field center were significantly shorter than those of the control group(P<0.05).The elevated plus maze experiment showed that the percentage of the number of times PCPA mice entered the open arm and the percentage of residence time in the open arm were significantly lower than those of the control group(P<0.05).Western Blot and immuno-fluorescence staining showed that the expression of CADM1 protein in the amygdala from PCPA mice was down-regulated compared with the control mice(P<0.05).Based on gene-behavioral association network analysis,Cadm1 was significantly associated with 25 anxiety-like behavior-related genes.The enrichment analysis of Cadm1 co-expression genes showed that Cadm1 was associated with γ-amino-butyric acid GABAergic synaptic pathway(P=4.31e-09),and that the key genes were huntingtin associ-ated protein 1(Hap1)(r=0.705,P=1.09e-08)、inositol 1,4,5-triphosphate receptor type 1(Itpr1)(r=-0.751,P=3.34e-10)、gamma-aminobutyric acid type A receptor subunit delta(Gabrd)(r=-0.836,P=3.93e-14)、γ-aminobutyric acid A receptor β1 subunit gene(Gabrb1)(r=0.732,P=1.50e-09)and adrenoceptor alpha 2A(Adra2a)(r=0.759,P=1.73e-10).The results of qPCR analysis showed that the mRNA levels of Hap1(P<0.05)、Gabrb1 and Adra2a were significantly up-regulated(P<0.01)while those of Itpr1 and Gabrd were significantly down-regulated(P<0.01).CONCLUSION Acute sleep deprivation leads to down-regulation of Cadm1 expression in the amygdala,and induces anxiety-like behaviors by affecting the expression of GABAergic synaptic signaling pathways Hap1,Gabrb1,Adra2a,Itpr1 and Gabrd.

ObjectiveTo study the effect of modified Erchentang on the expression of key molecules in the high mobility group Box 1 protein （HMGB1）/receptor for advanced glycation endproduct （RAGE）/nuclear factor-κB （NF-κB） signaling pathway in bronchioles of rats with chronic obstructive pulmonary disease （COPD）， to explore the mechanism of modified Erchentang against bronchiolar inflammation of COPD rats via HMGB1/RAGE/NF-κB signaling pathway. MethodSixty SD rats were randomly divided into normal group， model group， modified Erchentang low-， medium- and high-dose groups （5， 10， 20 g·kg^-1·d^-1） and ethyl pyruvate （HMGB1 inhibitor） group， with 10 in each group. The COPD rat model was prepared by cigarette smoke combined with tracheal injection of lipopolysaccharide （LPS）. After modeling， the modified Erchentang groups were given corresponding drugs （ig） and Ringer's solution （4 mL， ip）， while the EP group was treated with equal volume of normal saline （ig） and EP （0.04 g·kg^-1·d^-1， ip）. The normal group and the model group received equal volume of normal saline （ig） and Ringer's solution （ip） for 21 consecutive days. The contents of HMGB1， chemokine （C-X-C motif） ligand 1 （CXCL1）， CXCL2 and monocyte chemotactic protein-1 （MCP-1） in bronchoalveolar lavage fluid （BALF） were detected by enzyme-linked immunosorbent assay （ELISA）. The mRNA expressions of HMGB1， RAGE and NF-κB p65 were determined by Real-time polymerase chain reaction （Real-time PCR）， and the protein expressions of HMGB1， RAGE， p-NF-κB p65， and alpha-smooth muscle actin （α-SMA） in bronchioles tissue of rats were determined by immunohistochemistry （IHC）. ResultCompared with the conditions in the normal group， the forced vital capacity （FVC）， forced expiratory volume in the first second （FEV1） and FEV1/FVC in the model group were decreased （P<0.01） while the contents of HMGB1， CXCL1， CXCL2 and MCP-1 in BALF were increased （P<0.01）. And the model group presented higher mRNA expressions of HMGB1， RAGE and NF-κB p65 （P<0.01） and protein expressions of HMGB1， RAGE， p-NF-κB p65 and α-SMA （P<0.05， P<0.01） than the normal group. Compared with the model group， the modified Erchentang medium- and high-dose groups had increased FEV1/FVC （P<0.05， P<0.01）， lowered contents of HMGB1， CXCL1， CXCL2 and MCP-1 in BALF （P<0.05， P<0.05）， and reduced mRNA expressions of HMGB1， RAGE and NF-κB p65 （P<0.05， P<0.01） and protein expressions of HMGB1， RAGE， p-NF-κB p65 and α-SMA （P<0.05， P<0.01）. ConclusionModified Erchentang can resist bronchiolar inflammation of COPD rats. The mechanism may be related to down-regulating the mRNA expressiona of HMGB1 and RAGE， inhibiting the activity of NF-κB， and reducing the release of HMGB1， CXCL1， CXCL2 and MCP-1， thus suppressing the inflammatory injury and abnormal repair of bronchioles.

ObjectiveTo observe the effect of modified Erchentang on the expression of key molecules in the Jagged1/Notch1/Hes1 signaling pathway in lung tissues of rats with chronic obstructive pulmonary disease （COPD） and explore its anti-inflammatory effect and molecular mechanism on COPD through the Jagged1/Notch1/Hes1 signaling pathway. MethodSixty SD rats were randomly divided into normal group， model group， low-， medium-， and high-dose modified Erchentang groups （5， 10， 20 g·kg^-1）， and γ-secretase inhibitor DAPT group （0.02 g·kg^-1）， with 10 rats in each group. The COPD model was induced in rats by cigarette smoking combined with intratracheal instillation of lipopolysaccharide （LPS）. Rats were treated with corresponding drugs by gavage， while those in the normal group and the model group were treated with the same amount of normal saline by gavage. The serum levels of Notch1， soluble intercellular adhesion molecule-1 （sICAM-1）， activated leukocyte cell adhesion molecule （ALCAM）， and soluble vascular adhesion molecule-1 （sVCAM-1） were detected by enzyme-linked immunosorbent assay （ELISA）. The mRNA expression of Jagged1， Notch1， and Hes1 was detected by Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR）. The protein expression of Jagged1， Notch1， Notch1 intracellular domain （NICD1）， and Hes1 in lung tissues of rats was detected by immunohistochemistry （IHC）. ResultCompared with the normal group， the model group showed increased serum content of Notch1， sICAM-1， ALCAM， and sVCAM-1 （P<0.01）， increased mRNA expression of Jagged1， Notch1， and Hes1 in lung tissues （P<0.01）， and increased protein expression of Jagged1， Notch1， NICD1， and Hes1 （P<0.01）. Compared with the model group， the medium- and high-dose modified Erchentang groups and the DAPT group showed decreased serum content of Notch1， sICAM-1， ALCAM， and sVCAM-1 （P<0.05， P<0.05）， down-regulated mRNA expression of Jagged1， Notch1， and Hes1 （P<0.05， P<0.01）， and reduced protein expression of Jagged1， Notch1， NICD1， and Hes1（P<0.05， P<0.01）. ConclusionModified Erchentang may inhibit the inflammatory response in the lung of COPD rats， and its mechanism may be related to the resistance of inflammatory injury in the lung by decreasing the mRNA expression of Jagged1， Notch1， and Hes1 and inhibiting the release of Notch1， sICAM-1， ALCAM， and sVCAM-1.

Objective:To explore the safety of nirmatrelvir/ritonavir (Paxlovid) in the treatment of coronavirus disease 2019 (COVID-19).Methods:Medical records of adult patients with COVID-19 who were hospitalized and treated with Paxlovid in Beijing Ditan Hospital, Capital Medical University between March 23 and May 31, 2022 were collected through the hospital electronic medical record system. The occurrence (time of occurrence, clinical manifestations, severity, etc.) and outcomes of adverse reactions were analyzed retrospectively and the clinical characteristics of patients with or without adverse reactions were compared. Paxlovid was administered orally with nirmatrelvir 300 mg and ritonavir 100 mg every 12 hours for 5 consecutive days.Results:Three hundred and sixty-four patients were entered in the analysis, including 200 males (54.9%) and 164 females (45.1%), with a median age of 60 (19, 92) years. The incidence of adverse reactions of Paxlovid was 13.2% (48/364), and the adverse reactions occurred 1 to 7 days after taking Paxlovid. Among the 48 patients, 37 patients had digestive system symptoms (mainly manifested as diarrhea in 17 patients, bitter mouth in 14 patients, etc.), 7 patients had nervous system symptoms (dizziness in 5 patients, headache in 2 patients), 4 patients had respiratory system symptoms (pharyngalgia in 3 patients, pharyngeal itching in 1 patient), 2 patients had kidney injury, 1 patient had elevated blood uric acid, 1 patient had myalgia, and 1 patient had rash. Of them, 2 patients had digestive and neurological symptoms at the same time, 1 patient had digestive and respiratory symptoms at the same time, and 1 patient had digestive, neurological, and respiratory symptoms at the same time. The severity of adverse reactions was grade 1 in 33 patients (68.8%) and grade 2 in 15 patients (31.2%), and no serious adverse reactions of grade 3 and above occurred. All patients completed 5 days of treatment except 1 patient who discontinued the drug because of intolerance to grade 2 digestive symptoms (nausea and bitter mouth). There were no significant differences in gender, age, body mass index, smoking status, underlying diseases, and COVID-19 clinical classification between the patients with and without adverse reactions (all P>0.05). Conclusions:Paxlovid has a good safety in the treatment of COVID-19. The main adverse reaction is digestive system symptoms, mainly diarrhea and bitter mouth. Most of the symptoms are mild and the patient′s tolerance is good.

Objective:To explore the safety of nirmatrelvir/ritonavir (Paxlovid) in the treatment of coronavirus disease 2019 (COVID-19).Methods:Medical records of adult patients with COVID-19 who were hospitalized and treated with Paxlovid in Beijing Ditan Hospital, Capital Medical University between March 23 and May 31, 2022 were collected through the hospital electronic medical record system. The occurrence (time of occurrence, clinical manifestations, severity, etc.) and outcomes of adverse reactions were analyzed retrospectively and the clinical characteristics of patients with or without adverse reactions were compared. Paxlovid was administered orally with nirmatrelvir 300 mg and ritonavir 100 mg every 12 hours for 5 consecutive days.Results:Three hundred and sixty-four patients were entered in the analysis, including 200 males (54.9%) and 164 females (45.1%), with a median age of 60 (19, 92) years. The incidence of adverse reactions of Paxlovid was 13.2% (48/364), and the adverse reactions occurred 1 to 7 days after taking Paxlovid. Among the 48 patients, 37 patients had digestive system symptoms (mainly manifested as diarrhea in 17 patients, bitter mouth in 14 patients, etc.), 7 patients had nervous system symptoms (dizziness in 5 patients, headache in 2 patients), 4 patients had respiratory system symptoms (pharyngalgia in 3 patients, pharyngeal itching in 1 patient), 2 patients had kidney injury, 1 patient had elevated blood uric acid, 1 patient had myalgia, and 1 patient had rash. Of them, 2 patients had digestive and neurological symptoms at the same time, 1 patient had digestive and respiratory symptoms at the same time, and 1 patient had digestive, neurological, and respiratory symptoms at the same time. The severity of adverse reactions was grade 1 in 33 patients (68.8%) and grade 2 in 15 patients (31.2%), and no serious adverse reactions of grade 3 and above occurred. All patients completed 5 days of treatment except 1 patient who discontinued the drug because of intolerance to grade 2 digestive symptoms (nausea and bitter mouth). There were no significant differences in gender, age, body mass index, smoking status, underlying diseases, and COVID-19 clinical classification between the patients with and without adverse reactions (all P>0.05). Conclusions:Paxlovid has a good safety in the treatment of COVID-19. The main adverse reaction is digestive system symptoms, mainly diarrhea and bitter mouth. Most of the symptoms are mild and the patient′s tolerance is good.