The transcription factor Foxp1 is a critical negative regulator of the differentiation of follicular helper T cells.

CD4(+) follicular helper T cells (T(FH) cells) are essential for germinal center (GC) responses and long-lived antibody responses. Here we report that naive CD4(+) T cells deficient in the transcription factor Foxp1 'preferentially' differentiated into T(FH) cells, which resulted in substantially enhanced GC and antibody responses. We found that Foxp1 used both constitutive Foxp1A and Foxp1D induced by stimulation of the T cell antigen receptor (TCR) to inhibit the generation of T(FH) cells. Mechanistically, Foxp1 directly and negatively regulated interleukin 21 (IL-21); Foxp1 also dampened expression of the costimulatory molecule ICOS and its downstream signaling at early stages of T cell activation, which rendered Foxp1-deficient CD4(+) T cells partially resistant to blockade of the ICOS ligand (ICOSL) during T(FH) cell development. Our findings demonstrate that Foxp1 is a critical negative regulator of T(FH) cell differentiation.

Colloidal Synthesis of Carbon Dot-ZnSe Nanoplatelet Van der Waals Heterostructures for Boosting Photocatalytic Generation of Methanol-Storable Hydrogen.

Methanol is not only a promising liquid hydrogen carrier but also an important feedstock chemical for chemical synthesis. Catalyst design is vital for enabling the reactions to occur under ambient conditions. This study reports a new class of van der Waals heterojunction photocatalyst, which is synthesized by hot-injection method, whereby carbon dots (CDs) are grown in situ on ZnSe nanoplatelets (NPLs), i.e., metal chalcogenide quantum wells. The resultant organic-inorganic hybrid nanoparticles, CD-NPLs, are able to perform methanol dehydrogenation through CH splitting. The heterostructure has enabled light-induced charge transfer from the CDs into the NPLs occurring on a sub-nanosecond timescale, with charges remaining separated across the CD-NPLs heterostructure for longer than 500 ns. This resulted in significantly heightened H2 production rate of 107 µmole·g-1·h-1 and enhanced photocurrent density up to 34 µA cm-2 at 1 V bias potential. EPR and NMR analyses confirmed the occurrence of α-CH splitting and CC coupling. The novel CD-based organic-inorganic semiconductor heterojunction is poised to enable the discovery of a host of new nano-hybrid photocatalysts with full tunability in the band structure, charge transfer, and divergent surface chemistry for guiding photoredox pathways and accelerating reaction rates.

Reconstruction of Radio Environment Map Based on Multi-Source Domain Adaptive of Graph Neural Network for Regression.

The graph neural network (GNN) has shown outstanding performance in processing unstructured data. However, the downstream task performance of GNN strongly depends on the accuracy of data graph structural features and, as a type of deep learning (DL) model, the size of the training dataset is equally crucial to its performance. This paper is based on graph neural networks to predict and complete the target radio environment map (REM) through multiple complete REMs and sparse spectrum monitoring data in the target domain. Due to the complexity of radio wave propagation in space, it is difficult to accurately and explicitly construct the spatial graph structure of the spectral data. In response to the two above issues, we propose a multi-source domain adaptive of GNN for regression (GNN-MDAR) model, which includes two key modules: (1) graph structure alignment modules are used to capture and learn graph structure information shared by cross-domain radio propagation and extract reliable graph structure information for downstream reference signal receiving power (RSRP) prediction task; and (2) a spatial distribution matching module is used to reduce the feature distribution mismatch across spatial grids and improve the model's ability to remain domain invariant. Based on the measured REMs dataset, the comparative results of simulation experiments show that the GNN-MDAR outperforms the other four benchmark methods in accuracy when there is less RSRP label data in the target domain.

Joint Multidimensional Pattern for Spectrum Prediction Using GNN.

In general, judging the use/idle state of the wireless spectrum is the foundation for cognitive radio users (secondary users, SUs) to access limited spectrum resources efficiently. Rich information can be mined by the inherent correlation of electromagnetic spectrum data from SUs in time, frequency, space, and other dimensions. Therefore, how to efficiently use the spectrum status of each SU implementation of reception multidimensional combination forecasting is the core of this paper. In this paper, we propose a deep-learning hybrid model called TensorGCN-LSTM based on the tensor data structure. The model treats SUs deployed at different spatial locations under the same frequency, and the spectrum status of SUs themselves under different frequencies in the task area as nodes and constructs two types of graph structures. Graph convolutional operations are used to sequentially extract corresponding spatial-domain and frequency-domain features from the two types of graph structures. Then, the long short-term memory (LSTM) model is used to fuse the spatial, frequency, and temporal features of the cognitive radio environment data. Finally, the prediction task of the spectrum distribution situation is accomplished through fully connected layers. Specifically, the model constructs a tensor graph based on the spatial similarity of SUs' locations and the frequency correlation between different frequency signals received by SUs, which describes the electromagnetic wave's dependency relationship in spatial and frequency domains. LSTM is used to capture the electromagnetic wave's dependency relationship in the temporal domain. To evaluate the effectiveness of the model, we conducted ablation experiments on LSTM, GCN, GC-LSTM, and TensorGCN-LSTM models using simulated data. The experimental results showed that our model achieves better prediction performance in RMSE, and the correlation coefficient R2 of 0.8753 also confirms the feasibility of the model.

Prognostic significance of prognostic nutritional index and systemic immune-inflammation index in patients after curative breast cancer resection: a retrospective cohort study.

BACKGROUND: Nutritional status and inflammation are closely associated with poor outcome in malignant tumors. However, the prognostic impact of postoperative in these variables on breast cancer (BC) remains inconclusive. We aimed to determine whether prognostic nutritional index (PNI), systemic immune-inflammation index (SII), neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) affect two long-term outcomes among patients after curative resection of BC. METHODS: We retrospectively reviewed 508 patients with BC treated with curative surgery between February 5, 2013 and May 26, 2020. All patients were divided into 3 groups based on tertiles (T1-T3) of PNI, SII, NLR, and PLR. The effects of four indexes on disease-free survival (DFS) and overall survival (OS) have been evaluated using Cox proportional hazards models and Kaplan-Meier method. RESULTS: Compared with PNI-lowest cases, patients with highest PNI showed significantly longer DFS (multivariate adjusted hazard ratio [HR] = 0.37, 95% confident interval [CI] 0.19-0.70, P for trend = 0.002), whereas higher PLR seemed to be marginally associated with poorer DFS (P for trend = 0.086 and 0.074, respectively). Subgroup analyses indicate the potential modification effects of family history of BC and radiotherapy on the prognosis value of PNI to DFS in BC patients (P for interaction = 0.004 and 0.025, respectively). In addition, the levels of three inflammatory indices, namely SII, NLR, and PLR might be positively related with increased age at diagnosis (all P for trend < 0.001). CONCLUSIONS: A high PNI was associated with better DFS, supporting its roles as prognostic parameters for patients with BC. The nutritional status and systemic immune may exert great effects on patient prognosis. Further studies are warrant to explore the prognosis value of PLR.

MAPK/ERK Pathway as a Central Regulator in Vertebrate Organ Regeneration.

Damage to organs by trauma, infection, diseases, congenital defects, aging, and other injuries causes organ malfunction and is life-threatening under serious conditions. Some of the lower order vertebrates such as zebrafish, salamanders, and chicks possess superior organ regenerative capacity over mammals. The extracellular signal-regulated kinases 1 and 2 (ERK1/2), as key members of the mitogen-activated protein kinase (MAPK) family, are serine/threonine protein kinases that are phylogenetically conserved among vertebrate taxa. MAPK/ERK signaling is an irreplaceable player participating in diverse biological activities through phosphorylating a broad variety of substrates in the cytoplasm as well as inside the nucleus. Current evidence supports a central role of the MAPK/ERK pathway during organ regeneration processes. MAPK/ERK signaling is rapidly excited in response to injury stimuli and coordinates essential pro-regenerative cellular events including cell survival, cell fate turnover, migration, proliferation, growth, and transcriptional and translational activities. In this literature review, we recapitulated the multifaceted MAPK/ERK signaling regulations, its dynamic spatio-temporal activities, and the profound roles during multiple organ regeneration, including appendages, heart, liver, eye, and peripheral/central nervous system, illuminating the possibility of MAPK/ERK signaling as a critical mechanism underlying the vastly differential regenerative capacities among vertebrate species, as well as its potential applications in tissue engineering and regenerative medicine.

Hsa_circ_0102171 aggravates the progression of cervical cancer through targeting miR-4465/CREBRF axis.

Cervical cancer (CC) has caused numerous cancer-related deaths in women. Recent years, circular RNAs have been reported as vital factors in CC tumorigenesis. Our current study focused on the role of hsa_circ_0102171 (called circ_0102171 subsequently) in CC. At first, we applied reverse transcription polymerase chain reaction to detect the expression of circ_0102171 in CC tissues and cells. Subsequently, we silenced circ_0102171 to conduct loss-of-function assays, including cell counting kit-8 assay, 5-ethynyl-2'-deoxyuridine staining, Transwell assay, and flow cytometry analysis. Interestingly, we discovered that circ_0102171 expressed at a high level in CC tissues and cells. Functionally, silencing circ_0102171 prohibited cell proliferation, migration and invasion, and strengthened cell apoptosis in CC in vitro. Mechanistic investigations revealed that circ_0102171 could act as a sponge for miR-4465. Gain-of-function assays demonstrated that miR-4465 hindered the growth and migration of CC cells. Moreover, circ_0102171 enhanced the level of CREB3 regulatory factor (CREBRF) which was the downstream target of miR-4465. Rescue assays suggested that CREBRF and miR-4465 could involve in circ_0102171-mediated CC progression. Finally, in vivo data supported that silencing circ_0102171 hindered CC cell growth. In conclusion, circ_0102171 aggravates CC progression via targeting miR-4465/CREBRF axis.

LINC02535 co-functions with PCBP2 to regulate DNA damage repair in cervical cancer by stabilizing RRM1 mRNA.

Cervical cancer (CC) is one of the commonest malignant cancers among women with high morbidity and mortality. Despite encouraging advances had been found in diagnostic and therapeutic strategies, effective therapeutic strategy and further exploration of the mechanism underlying in CC is still needed. We searched The Cancer Genome Atlas database and found that long noncoding RNA LINC02535 was highly expressed in CC. LINC02535 has not been studied in CC, and its molecular regulation mechanism remains unknown. Based on starBase database, LINC02535 could potentially bind poly (rC) binding protein 2 (PCBP2). In the present study, we discovered a significant increase of the LINC02535 and PCBP2 expression in CC tissues and cells as compared with the adjacent normal tissues and normal cervical epithelial cells. LINC02535 and PCBP2 can bind with each other and were colocated in cytoplasm. LINC02535 and PCBP2 promoted cell proliferation, migration, invasion, and suppressed apoptosis in CC. LINC02535 and PCBP2 facilitated the repair of DNA damage to promote CC progression. LINC02535 cooperated with PCBP2 to enhance the stability of RRM1 messenger RNA (mRNA). RRM1 promoted the repair of DNA damage and epithelial-to-mesenchymal transition (EMT) process in CC cells. LINC02535 regulated tumorigenesis in vivo. In conclusion, LINC02535 cooperated with PCBP2, regulated stability of RRM1 mRNA to promote cell proliferation and EMT process in CC cells by facilitating the repair of DNA damage, providing a potential biomarker for CC.

Regulation of Tcrb recombination ordering by c-Fos-dependent RAG deposition.

Antigen receptor variable-(diversity)-joining (V(D)J) recombination at the locus encoding the T cell antigen receptor-beta (Tcrb) is ordered, with D(beta)-to-J(beta) assembly preceding V(beta)-to-DJ(beta) joining. The molecular mechanism underlying this 'preferred' order of rearrangement remains unclear. Here we show that the D(beta) 23-base pair recombination signal sequence (D(beta) 23-RSS) contains a specific AP-1 transcription factor-binding site bound by AP-1 and its component c-Fos expressed at a specific stage. Cell-based recombination assays suggested that c-Fos interacted directly with the RAG recombinase and enhanced its deposition to D(beta) 23-RSSs, thus conferring the priority of DJ(beta) recombination. Loss of c-Fos decreased Tcrb recombination efficiency and disrupted recombination ordering in vivo. Our results show an unexpected function for c-Fos as a direct regulator of Tcrb recombination, rather than its usual function as a transcription regulator, and provide new insight into the mechanisms of recombination ordering.

Role of hematological parameters in the diagnosis of influenza virus infection in patients with respiratory tract infection symptoms.

BACKGROUND: The differential diagnoses of patients hospitalized for respiratory infections due to influenza virus vs other pathogens are challenging. Our study investigated whether hematological parameters such as neutrophil (N), lymphocyte (L), platelet (PLT), and neutrophil-to-lymphocyte ratio (NLR) contributed in diagnosing influenza virus infections and in discriminating other respiratory infections. METHODS: We retrospectively analyzed the laboratory characteristics of 307 patients with respiratory infections caused by influenza/non-influenza virus and bacteria. The diagnostic abilities of hematological indexes were evaluated in the patients compared with 100 healthy people. RESULTS: The hematological parameters in patients with influenza virus infection were dramatically altered compared with those in the controls. Additionally, among the systemic inflammatory markers, the sensitivity of NLR for influenza detection was higher than that of N and L. PLT was significantly lower in influenza virus-positive infection than in influenza virus-negative infection. Moreover, when patients with influenza virus infection were cured, PLT returned to a normal level. The red blood cell (RBC) and hemoglobin (Hb) levels of influenza virus infection were higher than those of bacterial infection. Compared with traditional N and L, NLR and platelet-to-neutrophil (PNR) showed greater significance between influenza virus and bacterial infection (P < .01). CONCLUSION: Neutrophil-to-lymphocyte ratio with high sensitivity is a preferable diagnostic tool to screen influenza virus-infected patients than N and L. PLT accounts in the differential diagnoses of respiratory infections due to influenza virus and other pathogens among patients. In addition, RBC, Hb, NLR, and PNR can significantly differentiate between influenza virus infections and bacterial infections.

Antigen-Specific T Cell Analysis Reveals That Active Immune Responses to ß Cell Antigens Are Focused on a Unique Set of Epitopes.

CD38 is an activation marker that is present on recently activated T cells, but absent on resting memory T cells. In this study, we show that CD45RO+CD38+ ß cell Ag-specific CD4+ T cells were present at higher frequencies in type 1 diabetes subjects compared with those in healthy subjects. These results imply an ongoing ß cell immunity years after onset of diabetes and suggest these activated T cells have an active role in the disease process. The Ag specificities of these activated T cells were determined by a novel CD154 T cell epitope mapping assay. Although each patient usually had a unique set of epitopes recognized by these T cells, two epitopes, DR0401-restricted modified preproinsulin peptide 78-90K88S and zinc transport 8 266-285, were repeatedly identified in multiple subjects. Identifying these T cells and their specific antigenic epitopes might provide immunotherapeutic targets for personalized therapies.

The effect of vitamin D auxiliary rehabilitation therapy in children with cerebral palsy and language dysfunction.

BACKGROUND: The aim of the present study was to observe the clinical efficacy of vitamin D auxiliary rehabilitation therapy in children with cerebral palsy and language dysfunction. METHODS: Eighty-two cases of children with cerebral palsy and language dysfunction in our hospital from March 2011 to June 2014 were selected for this study. They were divided into two groups: the rehabilitation treatment group (simple group, N.=39) and the vitamin D auxiliary rehabilitation therapy group (combination group, N.=43). After three months of treatment, language development, Gesell Child Development Scale, Bayley Infant Development Scale score and vitamin D and calcium levels were compared. RESULTS: The language development, Gesell Child Development Scale, Bayley Infant Development Scale score and vitamin D and calcium levels for two of the groups, after treatment, are improved compared to before treatment. The difference was statistically significant (P<0.05). The total efficiency of the language development in the combination group was obviously higher than the simple group. The difference was significant (95.3% vs. 74.4%, χ2=2.486, P=0.032). The Gesell Child Development Scale improved in the combination group compared to the simple group. The difference was statistically significant (70.4±11.3 vs. 53.3±10.5, t=3.127, P=0.026). The proportion of normal children was significantly higher than the rehabilitation treatment group, and the difference was statistically significant (30.2% vs. 20.5%, χ2=3.016, P=0.029). In the combination group, the vitamin D and calcium levels were statistically increased compared to the rehabilitation treatment group. It had statistical differences between the two groups (P<0.05). CONCLUSIONS: Vitamin D auxiliary rehabilitation therapy could improve the language function and the language development status in children with cerebral palsy and language dysfunction.

Nomogram for Predicting Survival in Locally Advanced Cervical Cancer with Concurrent Chemoradiotherapy plus or Not Adjuvant Chemotherapy: A Retrospective Analysis Based on 2018 FIGO Staging.

Background: The comprehensive treatment mode of combining concurrent chemoradiotherapy (CCRT) with adjuvant chemotherapy (AC) is a commonly used mainstream model in the clinical practice of locally advanced cervical cancer (LACC). However, the necessity for AC after CCRT lacks sufficient evidence-based medical support. This study constructs a predictive model for the survival time dependence of CCRT ± AC for LACC based on the 2018 International Federation of Gynecology and Obstetrics (FIGO) staging with internal validation, the prognosis was assessed with intensity-modulated radiotherapy (IMRT) and concurrent cisplatin, and provides guidance for future stratified treatment. Materials and Methods: The retrospective analysis included 482 patients with LACC who CCRT from January 2016 to January 2023. Patients who used the 2009 FIGO staging were all standardized for the 2018 FIGO staging. The 482 patients with LACC were divided into a training set (n = 290) and a validation set (n = 192) at a ratio of 6:4. COX multivariate regression model and LASSO regression were used to screen for independent prognostic factors affecting progression-free survival (PFS) and overall survival (OS), and a nomogram clinical prediction model was constructed based on these factors. Evaluate the effectiveness of the model through the receiver operating characteristic curve, calibration curve, decision curve, risk heat map, and survival curves for risk stratification. Results: The PFS and OS independent prognostic risk factors affecting the 2018 FIGO staging of LACC during CCRT were validated to be similar to the 2009 FIGO staging prediction model reported in previous literature. In the training cohort, area under the curve (AUC) values at 1, 3, and 5 years were 0.941, 0.882, and 0.885 for PFS, and 0.946, 0.946, and 0.969 for OS, respectively. When applied to a test cohort, the model also showed accurate prediction result (AUC at 1, 3, and 5 years were 0.869, 0.891, and 0.899 for PFS, and 0.891, 0.941 and 0.878 for OS, respectively). Subgroup analysis suggests that patients with LACC, adenocarcinoma, stage IVA, pelvic lymph node metastasis, pretreatment hemoglobin ≤100 g/l and residual tumor diameter >2 cm, who received CCRT in the 2018 FIGO stage, may benefit more from adjuvant chemtherapy. Conclusions: Based on the 2018 FIGO staging, a nomogram prediction model for PFS and OS in patients with LACC undergoing CCRT was developed. The model, established by combining weighted clinical and pathological factors, can provide more personalized treatment predictions in clinical practice. For patients with high-risk factors such as residual tumor diameter > 2 cm after CCRT for LACC, AC may bring benefits.

Activation of APE1 modulates Nrf2 protected against acute liver injury by inhibit hepatocyte ferroptosis and promote hepatocyte autophagy.

BACKGROUND: Apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1) plays a crucial role in DNA base excision repair, cell apoptosis, cell signaling, and the regulation of transcription factors through redox modulation and the control of reactive oxygen species (ROS). However, the connection between APE1 and acute liver injury (ALI) remains enigmatic. This study aims to unravel the molecular mechanisms underlying ALI and shed light on the role of APE1 in this context. METHOD: We induced acute liver injury (ALI) in mice by lipopolysaccharide/D-galactosamine (LPS/GalN) and intervened with the APE1 inhibitor E3330. We examined the expression of APE1 in ALI mice and ALI patient tissues after E3330 intervention, Additionally, we measured hepatic oxidative stress, ferroptosis, and autophagy marker proteins and genes. In establishing an AML-12 liver cell injury model, we utilized the Nrf2 activator tert-butylhydroquinone (TBHQ) as an intervention and examined APE1, Nrf2, ferroptosis-related proteins, and autophagy marker proteins and mRNA. RESULTS: Both ALI patients and ALI mice exhibited reduced APE1 expression levels. After E3330 intervention, there was a significant exacerbation of liver injury, oxidative stress, and a reduction in the expression of proteins, including GPX4, X-CT, ATG3, ATG5, and LC3 (LC3I/II). Consistent results were also observed in AML-12 cells. With TBHQ intervention, Nrf2 expression increased, along with the expression of proteins associated with iron death and autophagy. Mechanistically, APE1 activation regulates Nrf2 to inhibit ferroptosis and promote autophagy in hepatocytes. CONCLUSION: The data suggest that APE1 is a pivotal player in ALI, closely linked to its regulation of Nrf2. Strategies involving APE1 activation to modulate Nrf2, thereby inhibiting hepatocyte ferroptosis and promoting autophagy, may represent innovative therapeutic approaches for ALI. Additionally, tert-butylhydroquinone (TBHQ) holds significant promise in the treatment of acute liver injury.

[Effects of qingyang toujie mixture in combination with prednisone tablet on Th1/Th2 cytokines in patients suffering from systemic lupus erythematosus].

OBJECTIVE: To research the effects of Qingyang Toujie Mixture (QTM) in combination with prednisone tablet on the balance of Th1 and Th2 (Th1/Th2) of systemic lupus erythematosus (SLE) patients of yin deficiency syndrome (YDS). METHODS: Totally 42 patients with SLE were recruited from clinics of internal medicine and hospitalization department of First Hospital Affiliated to Guangzhou University of Traditional Chinese Medicine from August 2009 to March 2011. They were randomly assigned to the treatment group (22 cases) and the control group (20 cases) according to the random digit table. Another 12 healthy subjects were recruited as the healthy control group from employees of First Hospital Affiliated to Guangzhou University of Traditional Chinese Medicine and healthy students in physical examinations. All patients took prednisone tablet. The dosage was adjusted according to the severity of SLE activity index and the condition: 40 -60 mg per day for severe active stage; 20-40 mg per day for moderate active stage; 15 -20 mg per day for light active stage; and less than 15 mg per day for those in the stable stage, respectively. When patients' condition had been stabilized for 1 to 2 weeks, the dosage was gradually reduced according to the method of hormone reduction. In case of the recurrence of symptoms or when complicated with lupus nephritis or lupus encephalitis uncontrollable, standard shock therapy with Cyclophosphamide Injection (0.5-1 g/m2 body surface area, intravenous dripping, once every 4 weeks) was performed. Patients in the treatment group took QTM additionally, one dose daily, taken in two portions, once in the morning and once in the evening. Those in the control group took placebos additionally, one dose daily, taken in two portions, once in the morning and once in the evening. The therapeutic course was 6 months for all. No measure was taken for those in the healthy control group. Venous blood was withdrawal before and after treatment. Th1 cytokines (IFN-gamma, IL-12) and Th2 cytokines (IL-10, IL-4) were detected by ELISA. RESULTS: Compared with the healthy control group, the serum Th1 cytokines such as IL-12 and IFN-gamma, Th2 cytokines such as IL-10 and IL-4 increased, the Th1/Th2 ratios such as IFN-gamma/IL-4 and IL-12/IL-10 decreased in the treatment group and the control group before treatment (P < 0.01). Compared with before treatment in the same group, the serum Th1 cytokines such as IL-12 and IFN-gamma decreased, the serum Th2 cytokines such as IL-10 and IL-4 decreased, the ratios of Th1/Th2 cytokines such as IFN-gamma/IL-4 and IL-12/IL-10 increased in the treatment group (all P < 0.05). Compared with the control group after treatment, IL-4 decreased, and the ratio of IFN-gamma/IL-4 increased in the treatment group (P < 0.05). Fewer patients suffered from adverse reactions in the treatment group than in the control group (P < 0.01). CONCLUSION: QTM in combination with prednisone tablet was effective to improve the balance of Th1/Th2 cytokines, and alleviate the toxic and adverse reactions of hormone or immune inhibitors.

Lactoferrin modification of berberine nanoliposomes enhances the neuroprotective effects in a mouse model of Alzheimer's disease.

Previous studies have shown that berberine has neuroprotective effects against Alzheimer's disease, including antagonizing tau phosphorylation, and inhibiting acetylcholinesterase activity and neural cell apoptosis. However, its low bioavailability and adverse reactions with conventional administration limit its clinical application. In this study, we prepared berberine nanoliposomes using liposomes characterized by low toxicity, high entrapment efficiency, and biodegradability, and modified them with lactoferrin. Lactoferrin-modified berberine nanoliposomes had uniform particle size and high entrapment efficiency. We used the lactoferrin-modified berberine nanoliposomes to treat a mouse model of Alzheimer's disease established by injection of amyloid-beta 1-42 into the lateral ventricle. Lactoferrin-modified berberine nanoliposomes inhibited acetylcholinesterase activity and apoptosis in the hippocampus, reduced tau over-phosphorylation in the cerebral cortex, and improved mouse behavior. These findings suggest that modification with lactoferrin can enhance the neuroprotective effects of berberine nanoliposomes in Alzheimer's disease.

Gancao Fuzi decoction regulates the Th17/Treg cell imbalance in rheumatoid arthritis by targeting Foxp3 via miR-34a.

ETHNOPHARMACOLOGICAL RELEVANCE: During the Eastern Han Dynasty, Zhang Zhongjing first recorded the Gancao Fuzi decoction (GCFZD) formula in the "Synopsis of the Golden Chamber", which is reportedly an effective and safe treatment for rheumatoid arthritis (RA). However, the mechanism underlying the observed improvement in the T helper 17 (Th17)/regulatory T (Treg) cell imbalance in RA obtained with GCFZD has not been reported. AIM OF THE STUDY: This study aimed to demonstrate whether GCFZD ameliorated RA by modulating the Th17/Treg imbalance in RA mice. MATERIALS AND METHODS: Collagen was used to induce a model of collagen-induced arthritis (CIA) in mice. GCFZD was administered by gavage, and the arthritis index score, imaging and histopathological changes of the ankle joints, and the levels of the immunoglobulin G (IgG) class antibodies and proinflammatory factors in serum were determined. In addition, the frequencies of Th17 and Treg cells, the levels of relevant transcription factors and functional factors and the miR-34a gene in the spleen and the levels of interleukin-17A (IL-17A) and IL-10 in serum were determined. RESULTS: GCFZD significantly reduced the arthritis score, improved joint swelling and bone damage, reduced the pathological score, and decreased the serum levels of IgG class antibody (IgG and IgG2a) and proinflammatory factor [tumour necrosis factor-alpha (TNF-α), IL-1ß and IL-6]. Moreover, the Th17-cell proportion, the expression level of the Th17-specific transcription factor retinoic acid-related orphan receptor γt (RORγt) and functional factor IL-17A in the spleen, and the serum IL-17A level were decreased, whereas the Treg cell proportion, expression levels of the Treg-specific transcription factor forkhead box P3 (Foxp3) and functional factor IL-10 in the spleen, and the serum IL-10 level were increased. Furthermore, GCFZD inhibited miR-34a gene expression while promoting Foxp3 protein expression. CONCLUSIONS: The findings of this study demonstrate the therapeutic effect of GCFZD on mice with CIA, and the mechanism is related to an improvement in the Th17/Treg cell imbalance by targeting Foxp3 via miR-34a.

Protection against H2O2-evoked toxicity in HT22 hippocampal neuronal cells by geissoschizine methyl ether via inhibiting ERK pathway.

Oxidative stress is considered as an important mechanism underlying the pathology of neurodegenerative disorders. In this study, we utilized an in vitro model where oxidative stress process was evoked by exogenous hydrogen peroxide (H2O2) in HT22 murine hippocampal neurons and evaluated the neuroprotective effects of geissoschizine methyl ether (GME), a naturally occurring alkaloid from the hooks of Uncaria rhynchophylla (Miq.) Jacks. After a 24 h H2O2 (350 µM) insult, a significant decrease in cell survival and a sharp increase in intracellular reactive oxygen species were observed in HT22 cells. Encouragingly, GME (10-200 µM) effectively reversed these abnormal cellular changes induced by H2O2. Moreover, mechanistic studies using Western blot revealed that GME inhibited the increase of phospho-ERK protein expression, but not phospho-p38, caused by H2O2. Molecular docking simulation further revealed a possible binding mode that GME inhibited ERK protein, showing that GME favorably bound to ERK via multiple hydrophobic and hydrogen bond interactions. These findings indicate that GME provide effective neuroprotection via inhibiting ERK pathway and also encourage further ex vivo and in vivo pharmacological investigations of GME in treating oxidative stress-mediated neurological disorders.

The potential mechanism of Astragali Radix in the treatment of children with nephrotic syndrome.

BACKGROUND: The molecular mechanism of Astragali Radix in the treatment of children with nephrotic syndrome (NS) is unclear. This study aimed to use network pharmacology to explore this potential mechanism. METHODS: The Traditional Chinese Medicine Systems Pharmacology (TCMSP) database was used to identify the main active ingredients of Astragali Radix. The PharmMapper, Online Mendelian Inheritance in Man (OMIM), and GeneCards databases were then used to identify the active ingredients of Astragali Radix. The String database and Cytoscape software were used to construct the protein-protein network. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed using DAVID Database. RESULTS: In the TCMSP Database, a total of 20 chemical constituents of Astragali Radix were screened. After removing the duplicates and false positive genes, 394 targets of these active ingredients were obtained from PharmMapper. By comparing the NS-related genes in the GeneCards and OMIM Databases, a total of 39 potential NS-related targets were ultimately identified. The protein-protein-interaction network included 39 nodes and 366 edges. The top 5 proteins were albumin (ALB), serine/threonine kinase (AKT1), epidermal growth factor receptor (EGFR), mitogen-activated protein kinase (MAPK), and matrix metallopeptidase 9 (MMP9). The GO analysis showed that the target genes were mainly involved in biological processes (e.g., signal transduction, the positive regulation of cell proliferation, and the positive regulation of migration). The cellular components included a plasma membrane, extracellular exosome, and extracellular space. The molecular functions included protein binding, zinc-ion binding, protein tyrosine kinase activity, and enzyme binding. The KEGG analysis showed that the treatment of NS by Astragali Radix mainly involved pathways in cancer, proteoglycans in cancer, the phosphatidylinositol 3-kinase and protein kinase B (PI3K-Akt) signaling pathway, the rennin-angiotensin-system (Ras) signaling pathways, and Forkhead box protein O1 (FoxO) signaling pathways. CONCLUSIONS: In the present study, the network pharmacology method was used to explore the potential targets and pathways of Astragali Radix in the treatment of NS. We also provided future research directions for the treatment of NS with a complex pathogenesis.

PI3K Plays an Essential Role in Planarian Regeneration and Tissue Maintenance.

Phosphatidylinositol 3-kinase (PI3K) signaling plays a central role in various biological processes, and its abnormality leads to a broad spectrum of human diseases, such as cancer, fibrosis, and immunological disorders. However, the mechanisms by which PI3K signaling regulates the behavior of stem cells during regeneration are poorly understood. Planarian flatworms possess abundant adult stem cells (called neoblasts) allowing them to develop remarkable regenerative capabilities, thus the animals represent an ideal model for studying stem cells and regenerative medicine in vivo. In this study, the spatiotemporal expression pattern of Djpi3k, a PI3K ortholog in the planarian Dugesia japonica, was investigated and suggests its potential role in wound response and tissue regeneration. A loss-of-function study was conducted using small molecules and RNA interference technique, providing evidence that PI3K signaling is required for blastema regrowth and cilia maintenance during planarian regeneration and homeostasis. Interestingly, the mitotic and apoptotic responses to amputation are substantially abated in PI3K inhibitor-treated regenerating animals, while knockdown of Djpi3k alleviates the mitotic response and postpones the peak of apoptotic cell death, which may contribute to the varying degrees of regenerative defects induced by the pharmacological and genetic approaches. These observations reveal novel roles for PI3K signaling in the regulation of the cellular responses to amputation during planarian regeneration and provide insights for investigating the disease-related genes in the regeneration-competent organism in vivo.