ObjectiveThe malaria parasites remodel the host erythrocyte structure by exporting parasite proteins that interact with the membrane skeleton proteins of red blood cells (RBCs), facilitating their intracellular survival and pathogenicity. Skeleton-binding protein 1 (SBP1) is a conserved exported protein across Plasmodium species. In Plasmodium falciparum, SBP1 has been reported to interact with erythrocyte membrane skeleton proteins 4.1R and spectrin, while its contribution to erythrocyte remodeling and parasite virulence in Plasmodium berghei (Pb) remains unclear. This study aims to determine whether PbSBP1 associates with the host cytoskeletal protein 4.1R and to investigate its role in the remodeling of host RBCs and the pathogenicity of Plasmodium berghei. MethodsIn Plasmodium berghei, the relationship between PbSBP1 and the erythrocyte cytoskeletal protein 4.1R was examined using co-immunoprecipitation. A Pbsbp1 gene knockout mutant of Plasmodium berghei (Pbsbp1∆) was generated based on the principle of double crossover homologous recombination. The deformability of erythrocytes infected with Pbsbp1∆ parasites was assessed using microfluidic methods. Microchannels with an array of cylindrical pillars were used to detect modifications in infected RBC deformability. The infected RBCs were squashed between the rows and recovered between the columns and the transit velocity (μm/s) of infected RBCs travelling through the microchannel was recorded. The component of the erythrocyte membrane skeleton junctional complex, tropomodulin (TMOD), was fluorescently labeled, and the cytoskeletal network of infected erythrocytes was imaged using super-resolution stochastic optical reconstruction microscopy (STORM) to analyze ultrastructural changes in the cytoskeleton of wild-type (WT) and Pbsbp1∆-infected erythrocytes. Actin-based junctional complexes were displayed as individual clusters by the labeled TMOD in the STORM images, and the cluster densities and distances between adjacent clusters of infected RBCs were calculated. Additionally, rodent malaria models (BALB/c mice) and experimental cerebral malaria models (C57BL/6 mice) were employed to monitor the growth of Pbsbp1∆ and WT parasites during the intraerythrocytic stage and their capacity to induce cerebral malaria in mice. ResultsPbSBP1 may participate in the remodeling of infected erythrocytes through direct or indirect interaction with the erythrocyte cytoskeletal protein 4.1R. Microfluidic assays revealed that the deformability of erythrocytes infected with Pbsbp1∆ parasites was significantly enhanced compared to those infected with WT parasites. STORM imaging further demonstrated that the ultrastructure of the erythrocyte cytoskeleton in Pbsbp1∆-infected cells was altered relative to that in WT-infected erythrocytes. The distances between nearest neighbors of clusters had a tendency to increase while the cluster densities were decreased in Pbsbp1∆-infected RBCs compared to WT-infected RBCs. Subsequent phenotypic analysis indicated that the growth rate of Pbsbp1∆ parasites during the intraerythrocytic stage was significantly slower than that of WT parasites, and their ability to induce cerebral malaria in mice was also attenuated. These findings suggest that PbSBP1 is involved in the remodeling of the erythrocyte membrane skeleton, likely through its direct or indirect interaction with protein 4.1R, thereby regulating the deformability of infected erythrocytes and influencing the pathogenicity of the blood-stage parasites. ConclusionThis study establishes a role for PbSBP1 in host erythrocyte remodeling and parasite virulence, providing new research strategies for the prevention and treatment of malaria.

Lianpo Yin was first recorded in the Revised Treatise on Cholera from Suixi Residence by WANG Mengying. It is composed of seven medicinal herbs： Coptidis Rhizoma， Magnoliae Officinalis Cortex， Sojae Semen Praeparatum， Acori Tatarinowii Rhizoma， Pinelliae Rhizoma， Gardeniae Fructus， and Phragmitis Rhizoma. As one of the classic prescriptions for clearing heat， resolving dampness， regulating Qi， and harmonizing the middle energizer， it has been included in the Catalogue of Ancient Classic Prescriptions （Second Batch： Han Chinese Medicine） published by the National Administration of Traditional Chinese Medicine in 2023. Lianpo Yin is primarily indicated for cholera caused by the accumulation of dampness-heat， and it can promote digestion and eliminate phlegm. By summarizing the ancient literature records， chemical constituents of individual herbs and the compound formula， pharmacological effects， and modern clinical applications of Lianpo Yin， this paper discovers that the understandings of most ancient physicians are consistent with the original text. The pathogenesis treated by this prescription is generally attributed to the accumulation of dampness-heat in the middle energizer and disrupted ascending and descending of Qi. The main chemical components of this prescription include coptisine， trigonelline， genistein， palmatine， berberine， honokiol， and magnolol. Lianpo Yin exhibits pharmacological effects such as anti-inflammatory activity， regulation of apoptosis， modulation of mitochondrial autophagy， regulation of the hypothalamic-pituitary-adrenal （HPA） axis， promotion of gastrointestinal motility， improvement of the gastric mucosal barrier， regulation of intestinal flora and their metabolites， and antimicrobial activity. In modern clinical practice， this prescription is mainly used to treat digestive system diseases such as chronic superficial gastritis and Helicobacter pylori （Hp）-associated gastritis. Additionally， it demonstrates significant therapeutic effects on various diseases affecting the nervous， respiratory， dermatological， and cardiovascular systems. This study provides a detailed review of the ancient literature records， chemical components， pharmacological effects， and clinical applications of Lianpo Yin and its modified formulas， aiming to offer references for the dosage form development and broader clinical application of this classic prescription.

To analyze the treatment strategy for a 78-year-old female patient with mismatch repair deficient (dMMR) gastric cancer who achieved long-term survival. After third-line chemotherapy failed, gene testing showed ARID1A p.Gln748fs, c.2733-1G＞T variation, with PD-L1 TPS 30%, CPS 60%. The nivolumab was employed, and two weeks later, the best response was partial response (PR). During the fourth-line immunotherapy maintenance treatment, progression of left adrenal metastasis was observed. The expression of human epidermal growth factor receptor-2 (HER-2) was positive, and the antibody drug conjugate disitamab vedotin (RC48) was chosen for treatment. After 10 months of treatment with nivolumab combined with RC48, the best efficacy was assessed as stable disease (SD), with a progression free survival (PFS) of up to 12 months. Radiotherapy was employed, and immunotherapy was maintained, allowing the patient to achieve a PFS of 18 months again. During immunotherapy, a clinical pharmacist developed a personalized pharmaceutical care plan for this patient. At the last follow-up, this patient achieved 78 months of long-term survival.

OBJECTIVE: Patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection frequently develop central nervous system damage, yet the mechanisms driving this pathology remain unclear. This study investigated the primary pathways and key factors underlying brain tissue damage induced by the SARS-CoV-2 beta variant (lineage B.1.351). METHODS: K18-hACE2 and C57BL/6 mice were intranasally infected with the SARS-CoV-2 beta variant. Viral replication, pathological phenotypes, and brain transcriptomes were analyzed. Gene Ontology (GO) analysis was performed to identify altered pathways. Expression changes of host genes were verified using reverse transcription-quantitative polymerase chain reaction and Western blot. RESULTS: Pathological alterations were observed in the lungs of both mouse strains. However, only K18-hACE2 mice exhibited elevated viral RNA loads and infectious titers in the brain at 3 days post-infection, accompanied by neuropathological injury and weight loss. GO analysis of infected K18-hACE2 brain tissue revealed significant dysregulation of genes associated with innate immunity and antiviral defense responses, including type I interferons, pro-inflammatory cytokines, Toll-like receptor signaling components, and interferon-stimulated genes. Neuroinflammation was evident, alongside activation of apoptotic and pyroptotic pathways. Furthermore, altered neural cell marker expression suggested viral-induced neuroglial activation, resulting in caspase 4 and lipocalin 2 release and disruption of neuronal molecular networks. CONCLUSION These findings elucidate mechanisms of neuropathogenicity associated with the SARS-CoV-2 beta variant and highlight therapeutic targets to mitigate COVID-19-related neurological dysfunction.
Animals ; COVID-19/genetics* ; Mice ; Brain/metabolism* ; Apoptosis ; Mice, Inbred C57BL ; SARS-CoV-2/physiology* ; Pyroptosis ; Gene Expression Profiling ; Transcriptome ; Male ; Female

Objective To explore the application effect of dexmedetomidine combined with ropivacaine for quadratus lumborum block at the lateral supra-arcuate ligament(QLB-LSAL) in open hepatocellular carcinoma resection.Methods A prospective study was conducted in 60 patients who underwent elective open hepatocellular carcinoma resection at Jining First People's Hospital. The patients were randomly divided into the compound group and the control group,with 30 cases in each group. Patients in the compound group received QLB-LSAL combined general anesthesia,and patients in the control group received simple general anesthesia. All patients underwent patient controlled intravenous analgesia (PCIA)postoperatively. The mean arterial pressure (MAP),heart rate (HR) and visual analogue scale (VAS) scores during rest and coughing at different time points were observed and compared between the two groups. The number of postoperative PCIA compressions,the dosage of sufentanil,the first postoperative exhaust time,the first postoperative ambulation time,the hospital stay and the occurrence of adverse reactions of the two groups were recorded. Results In the compound group,the HR and MAP were significantly lower than those of the control group at the time of skin incision (T2) and at the end of surgery (T3);the VAS scores during rest and coughing were significantly lower than those of the control group at the time of exiting the anesthesia recovery room and 6 hours and 12 hours after surgery;and the PCIA compression times were significantly less than those of the control group;the dosage of sufentanil was significantly lower than that in the control group 0 to 24 hours after surgery,and the dosage of sufentanil was higher than that in the control group 25 to 48 hours after surgery;the first postoperative ambulation time and the first postoperative exhaust time were significantly earlier than those in the control group;and the above differences were statistically significant(P<0.05). There was no significant difference in the HR or MAP at 5 minutes into the operating room (T0) and 5 minutes before skin incision (T1),VAS scores during rest and coughing 24 hours and 48 hours after surgery,hospital stay and incidence of adverse reactions between the two groups (P>0.05).Conclusion For patients with open hepatocellular carcinoma resection,dexmedetomidine combined with ropivazine for QLB-LSAL can provide more ideal postoperative analgesia,reduce perioperative opioid consumption,and have less impact on circulatory system,which is conducive to rapid postoperative recovery.

Objective:To evaluate the value of noninvasive assessment of the 13C-methacetin breath test (13C-MBT) based on infrared isotope spectrometry for liver function reserve in patients with nonalcoholic fatty liver disease (NAFLD). Methods:A total of 120 NAFLD patients met the diagnostic criteria,who admitted to Department of Liver Diseases of the First Affiliated Hospital of Xinjiang Medical University from January 2023 to January 2024,were prospectively selected. Patients were divided into three groups based on liver stiffness measurement (LSM) of FibroTouch:mild fibrosis group (LSM<7.0 kPa,n=40),moderate fibrosis group (7.0≤LSM<9.5 kPa) and severe fibrosis group (LSM≥9.5 kPa,n=40). Meanwhile,40 healthy subjects were selected as a healthy control group. All subjects underwent 13C-MBT and conventional liver function tests. The differences of 13C-MBT parameters and liver function indicators among various groups were compared,and the correlations between 13C-MBT parameters and the degree of liver fibrosis,and between liver function indexes and the degree of liver fibrosis were analyzed. Receiver operating characteristic (ROC) curve was used to evaluate the judgment ability of 13C-MBT parameters to the degree of liver fibrosis. Results:The 13C-MBT parameters in NAFLD patients were lower than those in healthy control group,and the differences were statistically significant (F=27.413,28.635,29.851,P<0.05). With the aggravation of liver fibrosis,13C-MBT parameters in NAFLD patients gradually decreased. The 13C-MBT parameters of severe fibrosis group were significantly lower than those in the mild and moderate fibrosis groups,with statistically significant differences (t=12.331,13.020,14.232,22.033,21.032,29.332,P<0.05),respectively. The 13C-MBT parameters were positively correlated with liver function indicators,and were negatively correlated with LSM,and the absolute values of the correlation coefficients were>0.5,all of them showed statistically significant differences (r=0.375,-0.875,P<0.05). The 13C-MBT parameters had higher sensitivity and specificity in judging the degree of liver fibrosis. Taking MVmax40 as an example,when the limit value was 9.5 kPa,the sensitivity was 86.3％,and the specificity was 83.8％,and the accuracy was 85.0％,and the area under curve (AUC) was 0.913. Conclusion:13C-MBT based on infrared isotope spectrometry is a non-invasive,safe,rapid and accurate detection method,which can reflect the liver function reserve and liver fibrosis degree of NAFLD patients,and has important clinical value for the diagnosis and treatment of NAFLD.

Objective To explore the application value of MRI diaphragmatic navigation technology combined with three dimensional liver acquisition with volume acceleration-flexible(3D LAVA-FLEX)sequence in abdominal enhanced imaging of infants and young children.Methods A retrospective analysis was conducted on imaging data of 84 infants and young children who underwent abdominal enhanced MRI examination in our hospital between January 2021 and December 2023.All 84 infants and young children initially underwent conventional dynamic contrast-enhanced 3D LAVA-FLEX sequence scanning;the delayed phase images obtained were included in the dynamic enhancement group.Subsequently,diaphragmatic navigation combined with 3D LAVA-FLEX sequence examination was implemented,and the obtained images were included in the diaphragm navigation group.Subjective scoring was performed for images in both groups,while the signal to noise ratio(SNR),contrast to noise ratio(CNR),and artifact quantification(AQ)were measured and compared between the two groups.Results The respiratory motion artifacts,the clarity of liver parenchyma enhancement,the clarity of liver vascular enhancement,the clarity of spleen parenchyma enhancement and the overall image quality score in the diaphragm navigation group were higher than those in the dynamic enhancement group,and the differences were statistically significant(P<0.05).There were statistically significant differences in SNR and AQ between the two groups of images(P<0.000 1),while there was no statistically significant difference in CNR between the two groups of images(P>0.05).Conclusion Diaphragmatic navigation technology combined with 3D LAVA-FLEX sequence imaging can improve the image quality of abdominal MRI enhanced imaging in infants and young children,and provide a reference for clinical diagnosis and treatment.

Aim To evaluate the role of the glucose transporter protein 1(GLUT1)-dependent glycolytic in the attenuation of oxygen-glucose deprivation-reoxygen-ation(OGD/R)injury in HK-2 cells by dexmedetomi-dine(Dex).Methods C57/BL6 mice were random-ly divided into three groups(n=6),namely,sham operation group(Sham group),renal ischemia reper-fusion group(I/R group)and Dex group(I/R+Dex group).Serum creatinine(Cr)and urea nitrogen(BUN)were measured,while the levels of key glyco-lytic enzymes HK2,PFKFB3 and GLUT1 were meas-ured.HK-2 cells were cultured and randomised into seven groups(n=6),which was treated with OGD/R,overexpression or interference with GLUT1,Dex and glycolysis inhibitor 2-DG.CCK-8 and LDH activi-ty were used to detect cellular damage.Glycolysis lev-els were detected by lactate and ECAR.The inflamma-tory level was reflected by qRT-PCR for IL-6 and TNF-α.qRT-PCR and Western blot were performed to de-tect the levels of GLUT1,HK2,and PFKFB3.Results Dex significantly ameliorated kidney injury and HK-2 cell injury(P＜0.05).Dex inhibited the OGD/R-induced rise in lactate and extracellular acidification rate(ECAR),as evidenced by suppression of the ex-pression of GLUT1,HK2 and PFKFB3(P＜0.05).In vitro experiments showed that GLUT1 knockdown sig-nificantly improved OGD/R-induced cellular damage.Lactate,ECAR,glycolysis-related mRNAs and pro-teins were inhibited by GLUT1 knockdown(P＜0.05).Significantly,there were no significant differ-ences in above indexes after Dex treatment based on GLUT1 knockdown.Overexpression of GLUT1 abroga-ted the protective effects of Dex,while reversing the inhibitory effects of Dex on the expression of GLUT1,HK2,and PFKFB3(P＜0.05).Conclusions Dexmedetomidine attenuates OGD/R induced injury in HK-2 cells by inhibiting GLUT1-dependent glycolysis.

This study predicts the quality markers(Q-markers) for the cough-relieving and phlegm-expelling effects of Kening Granules based on pharmacodynamics, plasma drug chemistry, network pharmacology, and pharmacokinetics. Strong ammonia solution spray and phenol red secretion assays were employed to evaluate the cough-relieving and phlegm-expelling effects of Kening Granules. Twentysix absorbed prototype components of Kening Granules were identified by ultra high performance liquid chromatography coupled with QExactive Plus quadrupole/Orbitrap high resolution mass spectrometry(UHPLC-Q-Exactive Plus Orbitrap HRMS). Through network pharmacology, 11 potential active components were screened out for the cough-relieving and phlegm-expelling effects of Kening Granules. The 11 components acted on 40 common targets such as IL6, TLR4, and STAT3, which mainly participated in PI3K/Akt, HIF-1, and EGFR signaling pathways. Pharmacokinetic quantitative analysis was performed for 7 prototype components. Three compounds including azelaic acid, caffeic acid, and vanillin were identified as Q-markers for the cough-relieving and phlegm-expelling effects of Kening Granules based on their effectiveness, transmissibility, and measurability. The results of this study are of great significance for clarifying the pharmacological substance basis, optimizing the quality standards, and promoting the clinical application of Kening Granules.
Drugs, Chinese Herbal/administration & dosage* ; Network Pharmacology ; Cough/blood* ; Male ; Humans ; Animals ; Rats ; Rats, Sprague-Dawley ; Biomarkers/blood* ; Quality Control ; Chromatography, High Pressure Liquid ; Antitussive Agents/chemistry*

This study employed bioinformatics to screen the feature genes related to efferocytosis in diabetic kidney disease(DKD) and explores traditional Chinese medicine(TCM) regulating these feature genes. The GSE96804 and GSE30528 datasets were integrated as the training set, and the intersection of differentially expressed genes and efferocytosis-related genes(ERGs) was identified as DKD-ERGs. Subsequently, correlation analysis, protein-protein interaction(PPI) network construction, enrichment analysis, and immune infiltration analysis were performed. Consensus clustering was conducted on DKD patients based on the expression levels of DKD-ERGs, and the expression levels, immune infiltration characteristics, and gene set variations between different subtypes were explored. Eight machine learning models were constructed and their prediction performance was evaluated. The best-performing model was evaluated by nomograms, calibration curves, and external datasets, followed by the identification of efferocytosis-related feature genes associated with DKD. Finally, potential TCMs that can regulate these feature genes were predicted. The results showed that the training set contained 640 differentially expressed genes, and after intersecting with ERGs, 12 DKD-ERGs were obtained, which demonstrated mutual regulation and immune modulation effects. Consensus clustering divided DKD into two subtypes, C1 and C2. The support vector machine(SVM) model had the best performance, predicting that growth arrest-specific protein 6(GAS6), S100 calcium-binding protein A9(S100A9), C-X3-C motif chemokine ligand 1(CX3CL1), 5'-nucleotidase(NT5E), and interleukin 33(IL33) were the feature genes of DKD. Potential TCMs with therapeutic effects included Astragali Radix, Trionycis Carapax, Sargassum, Rhei Radix et Rhizoma, Curcumae Radix, and Alismatis Rhizoma, which mainly function to clear heat, replenish deficiency, activate blood, resolve stasis, and promote urination and drain dampness. Molecular docking revealed that the key components of these TCMs, including β-sitosterol, quercetin, and sitosterol, exhibited good binding activity with the five target genes. These results indicated that efferocytosis played a crucial role in the development and progression of DKD. The feature genes closely related to both DKD and efferocytosis, such as GAS6, S100A9, CX3CL1, NT5E, and IL33, were identified. TCMs such as Astragali Radix, Trionycis Carapa, Sargassum, Rhei Radix et Rhizoma, Curcumae Radix, and Alismatis Rhizoma may provide a new therapeutic strategy for DKD by regulating efferocytosis.
Humans ; Computational Biology ; Diabetic Nephropathies/physiopathology* ; Protein Interaction Maps ; Medicine, Chinese Traditional ; Drugs, Chinese Herbal ; Phagocytosis/genetics* ; Efferocytosis