Alzheimer’s disease (AD) is a chronic neurodegenerative disease that mainly causes dementia. It is a serious threat to the health of the global elderly population. Considerable money and effort has been invested in the development of drug therapy for AD worldwide. Many drug therapies are currently under development or in clinical trials, based on two known mechanisms of AD, namely, Aβ toxicity and the abnormal Tau hyperphosphorylation. Numerous drugs are also being developed for other AD associated mechanisms such as neuroinflammation, neurotransmitter imbalance, oxidative damage and mitochondrial dysfunction, neuron loss and degeneration. Even so, the number of drugs that can successfully improve symptoms or delay the progression of the disease remains very limited. However, multi-drug combinations may provide a new avenue for drug therapy for AD. In addition, early diagnosis of AD and timely initiation of treatment may allow drugs that act on the early pathological processes of AD to help improve the symptoms and prevent the progression of the condition.

Alzheimer’s disease (AD) is an age-related neurodegenerative disease with two major hallmarks: extracellular amyloid plaques made of amyloid-β (Aβ) and intracellular neurofibrillary tangles (NFTs) of abnormally hyperphosphorylated tau. The number of NFTs correlates positively with the severity of dementia in AD patients. However, there is still no efficient therapy available for AD treatment and prevention so far. A deeper understanding of AD pathogenesis has identified novel strategies for the generation of specific therapies over the past few decades. Several studies have suggested that the prion-like seeding and spreading of tau pathology in the brain may be a key driver of AD. Tau protein is considered as a promising candidate target for the development of therapeutic interventions due to its considerable pathological role in a variety of neurodegenerative disorders. Abnormal tau hyperphosphorylation plays a detrimental pathological role, eventually leading to neurodegeneration. In the present review, we describe the recent research progresses in the pathological mechanisms of tau protein in AD and briefly discuss tau-based therapeutic strategies.

Senile plaques (SPs) are one of the pathological features of Alzheimer’s disease (AD) and they are formed by the overproduction and aggregation of amyloid-beta (Aβ) peptides derived from the abnormal cleavage of amyloid precursor protein (APP). Thus, understanding the regulatory mechanisms during Aβ metabolism is of great importance to elucidate AD pathogenesis. Recent studies have shown that epigenetic modulation—including DNA methylation, non-coding RNA alterations, and histone modifications—is of great significance in regulating Aβ metabolism. In this article, we review the aberrant epigenetic regulation of Aβ metabolism.

rTg4510 mice are transgenic mice expressing P301L mutant tau and have been developed as an animal model of tauopathies including Alzheimer’s disease (AD). Besides cognitive impairments, rTg4510 mice also show abnormal hyperactivity behavior. Cornel iridoid glycoside (CIG) is an active ingredient extracted from Cornus officinalis, a traditional Chinese herb. The purpose of the present study was to investigate the effects of CIG on the emotional disorders such as hyperactivity, and related mechanisms. The emotional hyperactivity was detected by locomotor activity test and Y maze test. Immunofluorescent and immunohistochemical analyses were conducted to measure neuron loss and phosphorylated tau. Western blotting was used to detect the expression of related proteins. The results showed that intragastric administration of CIG for 3 months decreased the hyperactivity phenotype, prevented neuronal loss, reduced tau hyperphosphorylation and aggregation in the amygdala of rTg4510 mice. Meanwhile, CIG alleviated the synaptic dysfunction by increasing the expression of N-methyl-D-aspartate receptors (NMDARs) subunits GluN1 and GluN2A and αamino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) subunits GluA1 and GluA2, and increased the level of phosphorylated Ca²⁺/calmodulin dependent protein kinase II α (p-CaMK IIα) in the brain of rTg4510 mice. In conclusion, CIG may have potential to treat the emotional disorders in tauopathies such as AD through reducing tau pathology and improving synaptic dysfunction.

Alzheimer’s disease (AD), also defined as a tauopathology, is a common neurodegenerative disease. Hyper-phosphorylation, cleavage or truncation, and aggregation of tau contribute to AD. Thus, targeting the post-translational modifications on tau may be a therapeutic strategy to treat AD. This study understood how cornel iridoid glycoside (CIG) affects tau post-translational modifications and synaptic abnormalities. The 10-month old P301S tau transgenic mice were given CIG at 100 and 200 mg/kg every day orally for 1 month. Hyperphosphorylated and truncated tau, synapse-associated proteins and glutamatergic receptors were all detected using Western blotting. The interactions between Morroniside (MOR) or Loganin (LOG) and tau were detected using Autodock and Surface Plasmon Resonance (SPR). The effects of CIG on the aggregation of tau were investigated using a cell-free system. CIG attenuated tau hyperphosphorylation at Thr205, Ser212, Ser262, Thr231 and Ser235 (AT180), but had no effect on tau truncation in the brains of 10-month old P301S mice. Binding free energies and interactions revealed that MOR and LOG bound with tau. We also found that CIG upregulated synapse-associated proteins such as PSD-95, syntaxin1A and synaptotagmin. In addition, CIG restored N-methyl-D-aspartic acid receptor and glutamate receptor levels. CIG improves post-translational modification of tau as well as synaptic abnormalities. The data presented here reveal that CIG may be used in the treatment of AD.

This study aimed to elucidate the molecular mechanisms by which berberine protects against cerebral ischemia/reperfusion (I/R) injury. The oxygen-glucose deprivation/reperfusion (OGD/R) PC12 model was established. Cell counting kit-8 (CCK-8) was used to detect the toxicity of berberine and the viability of PC12 cells. Hoechst 33258 staining and flow cytometry were used to observe the nuclear morphology, and changes of apoptosis and reactive oxygen species (ROS), respectively. Western blotting and immunofluorescence assay were employed to detect autophagy-related proteins [microtubule-associated protein 1A/1B-light chain 3 (LC3), P62/SQSTM-1, Beclin-1] and endoplasmic reticulum (ER) stress-related markers [glucose-regulated protein 78 (GRP78), C/EBP homologous protein (CHOP), Bcl-2-associated X (Bax) and cleaved caspase-3]. The GFP-RFP-LC3 adenovirus was used to assay the change of autophagic flux. Our results showed that berberine could increase the viability of PC12 cells, decrease the concentrations of ROS after OGD/R treatment, and suppress OGD/R-induced ER stress and autophagy. Moreover, the results revealed the involvement of the mammalian target of rapamycin (mTOR) pathway in the induction of autophagy, and berberine could activate the phosphorylation of mTOR and thus mitigate autophagy. In conclusion, our study suggested that berberine may protect against OGD/R-induced apoptosis by regulating ER stress and autophagy, and it holds promises in the treatment of cerebral I/R injury.

Examining the spontaneous BOLD activity to understand the neural mechanism of Parkinson’s disease (PD) with mild cognitive impairment (MCI) is a focus in resting-state functional MRI (rs-fMRI) studies. This study aimed to investigate the alteration of brain functional connectivity in PD with MCI in a systematical way at two levels: functional connectivity analysis within resting state networks (RSNs) and functional network connectivity (FNC) analysis. Using group independent component analysis (ICA) on rs-fMRI data acquired from 30 participants (14 healthy controls and 16 PD patients with MCI), 16 RSNs were identified, and functional connectivity analysis within the RSNs and FNC analysis were carried out between groups. Compared to controls, patients with PD showed decreased functional connectivity within putamen network, thalamus network, cerebellar network, attention network, and self-referential network, and increased functional connectivity within execution network. Globally disturbed, mostly increased functional connectivity of FNC was observed in PD group, and insular network and execution network were the dominant network with extensively increased functional connectivity with other RSNs. Cerebellar network showed decreased functional connectivity with caudate network, insular network, and self-referential network. In general, decreased functional connectivity within RSNs and globally disturbed, mostly increased functional connectivity of FNC may be characteristics of PD. Increased functional connectivity within execution network may be an early marker of PD. The multi-perspective study based on RSNs may be a valuable means to assess functional changes corresponding to specific RSN, contributing to the understanding of the neural mechanism of PD.

Glioblastoma multiforme, an intrusive brain cancer, has the lowest survival rate of all brain cancers. The chemotherapy utilized to prevent their proliferation and propagation is limited due to modulation of complex cancer signalling pathways. These complex pathways provide infiltrative and drug evading properties leading to the development of chemotherapy resistance. Therefore, the development and discovery of such interventions or therapies that can bypass all these resistive barriers to ameliorate glioma prognosis and survival is of profound importance. Medicinal plants are comprised of an exorbitant range of phytochemicals that have the broad-spectrum capability to target intrusive brain cancers, modulate anti-cancer pathways and immunological responses to facilitate their eradication, and induce apoptosis. These phytocompounds also interfere with several oncogenic proteins that promote cancer invasiveness and metastasis, chemotherapy resistance and angiogenesis. These plants are extremely vital for promising anti-glioma therapy to avert glioma proliferation and recurrence. In this review, we acquired recent literature on medicinal plants whose extracts/bioactive ingredients are newly exploited in glioma therapeutics, and also highlighted their mode of action and pharmacological profile.

Inflammation plays an important role in the development of several cancers. Inflammatory cytokines, including tumor necrosis factor-α (TNF-α), are associated with the induction of inflammation. Chronic inflammation contributes to the progression of cancer through several mechanisms, including increased cytokine production and activation of transcription factors, such as nuclear factor-κB (NF-κB). Zerumbone (ZER), a component of subtropical ginger (Zingiber zerumbet Smith), seems to have anti-inflammatory, anti-cancer, and antioxidant activities. In this study, we aimed to explore the protective function and mechanisms of ZER against TNF-α-induced cancer-promoting cytokines. We found that the viability of stimulated human fibroblast cell lines was reduced after treatment with ZER (IC₅₀=18 µmol/L), compared to un-stimulated fibroblasts (IC₅₀=40 µmol/L). Besides, ZER inhibited mRNA expression and protein secretion of transforming growth factor-β (TGF-β), interleukin-33 (IL-33), monocyte chemoattractant protein-1 (MCP-1), and stromal cell-derived factor 1 (SDF-1), which were produced by TNF-α-induced fibroblasts, as measured by quantitative real time-PCR (qRT-PCR) and ELISA assays. The mRNA expression levels of TGF-β, IL-33, SDF-1, and MCP-1 showed 8, 5, 2.5, and 4-fold reductions, respectively. Moreover, secretion of TGF-β, IL-33, SDF-1, and MCP-1 was reduced to 3.65±0.34 ng/mL, 6.3±0.26, 1703.6±295.2, and 5.02±0.18 pg/mL, respectively, compared to the untreated group. In addition, the conditioned media (CM) of TNF-α-stimulated fibroblasts increased the NF-κB expression in colorectal cancer cell lines (HCT-116 and Sw48), while in the vicinity of ZER, the expression of NF-κB was reversed. Considering the significant effects of ZER, this component can be used as an appropriate alternative herbal treatment for cancer-related chronic inflammation.

Cigarette smoking contributes to the development of pulmonary artery hypertension (PAH). As the basic pathological change of PAH, pulmonary vascular remodeling is considered to be related to the abnormal proliferation of pulmonary artery smooth muscle cells (PASMCs). However, the molecular mechanism underlying this process remains not exactly clear. The aim of this research was to study the molecular mechanism of PASMCs proliferation induced by smoking. Human PASMCs (HPASMCs) were divided into 6 groups: 0% (control group), cigarette smoking extract (CSE)-treated groups at concentrations of 0.5%, 1%, 2%, 5%, 10% CSE respectively. HPASMCs proliferation was observed after 24 h. HPASMCs were divided into two groups: 0 (control group), 0.5% CSE group. The mRNA and protein expression levels of transient receptor potential channel 1 (TRPC1) and cyclin D1 in HPASMCs after CSE treatment were respectively detected by RT-PCR and Western blotting. The intracellular calcium ion concentration was measured by the calcium probe in each group. In the negative control group and TRPC1-siRNA transfection group, the proliferation of HPASMCs and the expression of cyclin D1 mRNA and protein were detected. Data were compared with one-way ANOVA (for multiple-group comparison) and independent t-test (for two-group comparison) followed by the least significant difference (LSD) test with the computer software SPSS 17.0. It was found that 0.5% and 1% CSE could promote the proliferation of HPASMCs (P<0.05), and the former was more effective than the latter (P<0.05), while 3% and above CSE had inhibitory effect on HPASMCs (P<0.05). The mRNA and protein expression levels of TRPC1 and cyclin D1 in 0.5% and 1% CSE groups were significantly higher than those in the control group (P<0.05), while those in 3% CSE group were significantly decreased (P<0.05). Moreover, the proliferation of HPASMCs and the expression of cyclin D1 mRNA and protein in TRPC1-siRNA transfection group were significantly reduced as compared with those in the negative control group (P<0.05). It was concluded that low concentration of CSE can promote the proliferation of HPASMCs, while high concentrations of CSE inhibit HPASMCs proliferation. These findings suggested that CSE induced proliferation of HPASMCs at least in part via TRPC1-mediated cyclin D1 expression.

Acute respiratory distress syndrome (ARDS) is one of the most fatal diseases worldwide. Pulmonary fibrosis occurs early in ARDS, and its severity plays a crucial role in ARDS mortality rate. Some studies suggested that fibroproliferation is an essential mechanism in ARDS. Mitofusion2 (Mfn2) overexpression plays a role in inhibiting cell proliferation. However, the role and potential mechanism of Mfn2 on the proliferation of fibroblasts is still unknown. In this study, we aimed at exploring the effect of Mfn2 on the human embryonic lung fibroblasts (HELF) and discussed its related mechanism. The HELF were treated with the Mfn2 overexpressing lentivirus (adv-Mfn2). The cell cycle was detected by flow cytometry. MTT, PCR and Western blotting were used to investigate the effect of Mfn2 on the proliferation of the HELF, collagen expression, the RAS-RAF-1-ERK1/2 pathway and the expression of cycle-related proteins (p21, p27, Rb, Raf-1, p-Raf-1, Erk1/2 and p-Erk1/2). The co-immunoprecipitation assay was used to explore the interaction between Mfn2 and Ras. The results showed that the overexpression of Mfn2 inhibited the proliferation of the HELF and induced the cell cycle arrest at the G₀/G₁ phase. Meanwhile, Mfn2 also inhibited the expression of collagen I, p-Erk and p-Raf-1. In addition, an interaction between Mfn2 and Ras existed in the HELF. This study suggests that the overexpression of Mfn2 can decrease the proliferation of HELF in ARDS, which was associated with the inhibition of the RAS-RAF-1-ERK1/2 pathway. The results may offer a potential therapeutic intervention for patients with ARDS.

The effects of low ratio of n-6/n-3 polyunsaturated fatty acids (PUFA) have been clarified against atherosclerosis. Increasing evidence indicated that plant sterols (PS) have a significant cholesterol-lowering effect. This study explored the effects of PS combined with n-6/n-3 (2:1) PUFA on atherosclerosis and investigated the possible mechanism. In ApoE^−/− mice, the milk fat in high fat diets was replaced with n-6/n-3 (2:1) PUFA alone or supplemented with 6% PS for 16 weeks. Results demonstrated that PS combined with PUFA exerted commentary and synergistic effects on ameliorating atherosclerosis, improving lipid metabolism and lipid deposition in liver, and alleviating inflammatory response. These changes were accompanied with decreased serum TC, TG, LDL-C and increased fecal cholesterol efflux, as well as the lower inflammatory cytokine CRP, IL-6, TNF-α. It is suggested that the underlying mechanism of PS combined with n-6/n-3 (2:1) PUFA promoting the fecal cholesterol efflux may be mediated by liver X receptor α/ATP-binding cassette transporter A1 pathway.

An emerging body of evidence indicates that transient receptor potential TRP channels act as important mediators for a wide variety of physiological functions and are potential targets for drug discovery. Our previous study has identified transient receptor potential channel 3 (TRPC3) and TRPC6 as cation channels through which most of the damaging calcium enters, aggravates pathological changes in vivo and increases ischemia/reperfusion (I/R) injury in mice. This study aimed to verify the effects of TRPC3 inhibitor Pyr3 on myocardial I/R injury in mice. C57BL/6J wild-type male mice (8 to 12 weeks old) were anesthetized with 3.3% chloral hydrate. A murine I (30 min)/R (24 h) injury model was established by temporary occlusion of the left anterior descending (LAD) coronary artery. Pyr3 was administered at concentrations of 0, 2.5, 5, or 10 mg/kg via the right jugular vein 5 min before reperfusion. We observed that the selective TRPC3 inhibitor, 10 mg/kg Pyr3, significantly decreased the infarct size of left ventricle, and reduced the myocardial cell apoptosis rate and inflammatory response in mice. In a conclusion, TRPC3 can function as a candidate target for I/R injury prevention, and Pyr3 may directly bind to TRPC3 channel protein, inhibit TRPC3 channel activity, and improve TRPC3-related myocardial I/R injury. Pyr3 may be used for clarification of TRPC3 functions and for treatments of TRPC3-mediated diseases.

Angiopoietin-like protein 2 (ANGPTL2) stimulates inflammation and is important in the pathogenesis of diabetic kidney disease (DKD). Irbesartan is helpful in reducing diabetes-induced renal damage. In this study, the effects of irbesartan on DKD and its renal protective role involving ANGPTL2 in DKD rats were examined. Wistar rats were divided into normal, DKD, and DKD + irbesartan groups. The DKD + irbesartan group was treated once daily for 8 weeks with 50 mg/kg irbesartan via intragastric gavage. The 24-h urinary albumin was determined each week, renal pathological changes were observed, and expression of ANGPTL2 and nuclear factor-kappa B (NF-κB) in rat renal tissue was assessed by immunohistochemistry. Mouse podocytes cultured in a high concentration of glucose were classified into four groups based on the irbesartan concentrations (0, 25, 50, and 75 ºg/mL). Expression of ANGPTL2 and phosphorylated IκB-α was assessed by Western blotting. The mRNA levels of ANGPTL2 and monocyte chemotactic protein 1 (MCP-1) were assessed by real-time polymerase chain reaction. The DKD rats displayed proteinuria, podocyte injury, and increased ANGPTL2 and NF-κB expression. All were relieved by irbesartan treatment. In podocytes cultured in elevated glucose, ANGPTL2 and phosphorylated IκB-α were overexpressed at the protein level, and ANGPTL2 and MCP-1 were highly expressed at the mRNA level. Irbesartan down-regulated ANGPTL2 and phosphorylated IκB-αexpression at the protein level and inhibited ANGPTL2 and MCP-1 expression at the mRNA level. The ameliorative effects of irbesartan against DKD involves podocyte protection and suppression of ANGPTL2.

Immunopathological mechanisms of schistosomiasis, a debilitating parasitic disease, are still unclear. In this study, we investigated the involvement of CX3C chemokine ligand 1 (CX3CL1) and its sole receptor CX3CR1 in the development of liver fibrosis in schistosomiasis. The animal model of schistosomiasis was established by infection of C57BL/6 mice with Schistosoma japonicum cercariae; mice injected with carbon tetrachloride (CCl₄) were used as positive control of liver injury. After 4 and 8 weeks, the degree of liver lesions was assessed by hematoxylin and eosin staining, serum levels of hyaluronic acid (HA) were analyzed by a chemiluminescence immunoassay, liver fibrosis was evaluated by immunohistochemistry analysis of α-smooth muscle actin (α-SMA) expression, and CX3CL1 and CX3CR1 expression in the liver was measured by immunohistochemistry and real-time PCR. The results showed that at 8 weeks after Schistosoma infection, serum HA levels were increased and α-SMA-expressing cells appeared in the liver, indicating fibrogenesis. CX3CL1- and CX3CR1-positive cells were observed in the outer layer of granulomas formed around Schistosoma eggs in liver tissues, which was consistent with the significant upregulation of hepatic CX3CL1 and CX3CR1 mRNA expression at 4 and 8 weeks post-infection. Furthermore, correlation analysis revealed positive association between CX3CL1 and CX3CR1 expression and serum HA levels at 8 weeks post-infection, indicating a link between fibrogenesis and the CX3CL1/CX3CR1 axis in schistosomiasis. In conclusion, our data suggest the involvement of CX3CL1 and CX3CR1 in the progression of liver fibrosis caused by Schistosoma infection.

Acute focal cerebral ischemic stroke (IS) is a leading cause of morbidity and mortality worldwide. Acupuncture is an emerging alternative therapy that has been beneficial to acute brain ischemia. However, the underlying protective mechanism of its neuroprotective effect remains unclear. Human original circadian rhythm will be lost after IS, which seriously affects the quality of life and functional recovery of stroke patients. We hypothesize that acupuncture treats IS by regulating the balance of Clock and Bmal1. This study aims to explore the effect of acupuncture at acupoints GV20 and BL23 on neuroprotection and anti-apoptosis in middle cerebral artery occlusion (MCAO) rats and expression of apoptosis and circadian rhythm related proteins. Male Sprague-Dawley (SD) rats were randomly divided into five groups: normal group (Normal), sham model group (Sham MCAO), MCAO model group (MCAO), sham electroacupuncture group (Sham EA) and electroacupuncture group (EA). The MCAO model was prepared by electrocoagulation. The first acupuncture treatment was performed within 2 h after surgery, and then acupuncture therapy was performed on 1st day, 2nd day and 3rd day respectively. After their neurological examination at 72 h of ischemia, the rats from each group were sacrificed. Triphenyltetrazolium chloride (TTC) staining was used to evaluate the brain infarct size. Ultrastructural observation on cerebral ischemic cortex and serum inflammatory cytokines were evaluated. TUNEL staining was used to detect cell apoptosis of brain tissue. The expression levels of proteins Bax, bcl-2, caspase-3, Clock and Bmal1 in the cerebral ischemic region were detected by immunofluorescence staining. Here, we presented evidence that EA at GV20 and BL23 could significantly improve the neurological deficit score and infarct size, and alleviate the cell apoptosis of brain tissue. Moreover, acupuncture treatment upregulated the anti-apoptotic Bcl-2/Bax ratio and reversed the upregulation of caspase-3 following 72-h cerebral ischemia. In addition, the expression levels of circadian proteins Clock and Bmal1 were upregulated in EA group while compared with MCAO group. Our study demonstrated that acupuncture exerted neuroprotective effect against neuronal apoptosis after stroke and the mechanism might be related with regulation of circadian rhythm proteins Clock and Bmal1.

Anaplastic thyroid carcinoma (ATC) is a rare but extremely lethal malignancy. However, little is known about the pathogenesis of ATC. Given its high mortality, it is critical to improve our understanding of ATC pathogenesis and to find new diagnostic biomarkers. In the present study, two gene microarray profiles (GSE53072 and GSE65144), which included 17 ATC and 17 adjacent non-tumorous tissues, were obtained. Bioinformatic analyses were then performed. Immunohistochemistry (IHC) and receiver operating characteristic (ROC) curves were then used to detect transmembrane protein 158 (TMEM158) expression and to assess diagnostic sensitivity. A total of 372 differentially expressed genes (DEGs) were identified. Through protein-protein interaction (PPI) analysis, we identified a significant module with 37 upregulated genes. Most of the genes in this module were related to cell-cycle processes. After co-expression analysis, 132 hub genes were selected for further study. Nine genes were identified as both DEGs and genes of interest in the weighted gene co-expression network analysis (WGCNA). IHC and ROC curves confirmed that TMEM158 was overexpressed in ATC tissue as compared with other types of thyroid cancer and normal tissue samples. We identified 8 KEGG pathways that were associated with high expression of TMEM158, including aminoacyl-tRNA biosynthesis and DNA replication. Our results suggest that TMEM158 may be a potential oncogene and serve as a diagnostic indicator for ATC.

Tetraspanin CD151 was found to be upregulated in malignant cell types and has been identified as a tumor metastasis promoter. In this study, we aimed to examine the role of the CD151-integrin complex in lung cancer metastasis and the underlying mechanisms. CD151 QRD^194–196 →AAA^194–196 mutant was generated and used to transfect A549 human lung adenocarcinoma cells. We found that there was no significant difference in CD151 protein expression between CD151 and CD151-AAA mutant groups. In vitro, CD151-AAA mutant delivery abrogated the migration and invasion of A549 cells, which was promoted by CD151 gene transfer. Furthermore, CD151-AAA delivery failed to activate FAK and p130Cas signaling pathways. Western blot and immunohistochemical staining showed strong CD151 expression in lung cancerous tissues but not in adjacent normal tissues. Increased level of CD151 protein was observed in 20 of the patients and the positive rate of CD151 protein in specimens was 62.5% (20/32). In addition, CD151 was co-localized with α3 integrin at the cell-cell contact site in carcinoma tissues. These results suggested that the disruption of the CD151-α3 integrin complex may impair the metastasis-promoting effects and signaling events induced by CD151 in lung cancer. Our findings identified a key role for CD151-α3 integrin complex as a promoter in the lung cancer.

The mutation status of KRAS is a significant biomarker in the prognosis of rectal cancer. This study investigated the feasibility of MRI-based radiomics in predicting the mutation status of KRAS with a composite index which could be an important criterion for KRAS mutation in clinical practice. In this retrospective study, a total of 127 patients with rectal cancer were enrolled. The 3D Slicer was used to extract the radiomics features from the MRI images, and sparse support vector machine (SVM) with linear kernel was applied for feature reduction. The radiomics classifier for predicting the KRAS status was then constructed by Linear Discriminant Analysis (LDA) and its performance was evaluated. The composite index was determined with LDA model. Out of 127 rectal cancer subjects, there were 44 KRAS mutation cases and 83 wild cases. A total of 104 radiomics features were extracted, 54 features were filtered by linear SVM with L1-norm regularization and 6 features that had no significant correlations within them were finally selected. The radiomics classifier constructed using the 6 features featured an AUC value of 0.669 (specificity: 0.506; sensitivity: 0.773) with LDA. Furthermore, the composite index (Radscore) had statistically significant difference between the KRAS mutation and wild groups. It is suggested that the MRI-based radiomics has the potential in predicting the KRAS status in patients with rectal cancer, which may enhance the diagnostic value of MRI in rectal cancer.

Estrogen deficiency, which mainly occurs in postmenopausal women, is a primary reason for osteoporosis in clinical diagnosis. However, the molecular regulation of osteoporosis in menopausal females is still not adequately explained in the literature, with the diagnosis and treatment for osteoporosis being limited. Herein, exosomal microRNAs (miRNAs) were used to evaluate their diagnosis and prediction effects in menopausal females with osteoporosis. In this study, 6 menopausal females without osteoporosis and 12 menopausal females with osteoporosis were enrolled. The serum exosomes were isolated, and the miRNA expression was detected by miRNA high-throughput sequencing. Exosomal miRNA effects were analyzed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. The miRNA-targeted genes were evaluated by Targetscan 7.2 and the protein-protein interactions (PPI) by STRING. Hub genes were analyzed by the CytoHubba app of Cytoscape. The results showed that 191 aberrant miRNAs were found in the group of menopausal females with osteoporosis, including 72 upregulated miRNAs and 121 downregulated miRNAs. Aberrant miRNAs were involved in many signaling pathways, such as the Wnt, MAPK, and Hippo pathways. Based on PPI network analysis, FBXL3, FBXL13, COPS2, UBE2D3, DCUN1D1, DCUN1D4, CUL3, FBXO22, ASB6, and COMMD2 were the 10 most notable genes in the PPI network. In conclusion, aberrant serum exosomal miRNAs were associated with an altered risk of osteoporosis in menopausal females and may act as potential biomarkers for the prediction of risk of osteoporosis in menopausal females.

Endoscopic cervical foraminotomy is increasingly used for cervical spondylotic radiculopathy (CSR), but there is great concern about radiation exposure because of the heavy dependence of this surgical method on fluoroscopy. The objective of this study was to introduce in detail an advanced surgical technique of keyhole foraminotomy via a percutaneous posterior full-endoscopic approach as a treatment for CSR and investigate its clinical outcomes. We retrospectively reviewed 33 consecutive patients with CSR who underwent keyhole foraminotomy via a percutaneous posterior full-endoscopic approach from October 2015 to April 2017. The patients’ general characteristics, including operative time, blood loss, hospital stay, complications, and recurrence, were obtained. Clinical outcomes were evaluated using the visual analogue scale (VAS) for radicular pain, the neck disability index (NDI) for functional assessment, and the modified MacNab criteria for patient satisfaction. All operations were successfully performed (mean operation time, 62 min), with no measurable blood loss or severe related complications. The mean follow-up was 25 months. The VAS and NDI scores were significantly improved as compared with those in the preoperative period (preoperative vs. final follow-up: 7.6±1.6 vs. 3.83±7.34 for VAS, P<0.01; 69.5%±10.5% vs. 17.54%±13.40% for NDI, P<0.01). Of the 33 patients, 32 (97.0%) had good-to-excellent global outcomes and all patients obtained symptomatic improvement. In conclusion, keyhole foraminotomy via a percutaneous posterior full-endoscopic approach is an efficient, safe, and feasible procedure for the treatment of CSR. Its simplified single-step blunt incision for localization appears to decrease radiation exposure risks.

Female infertility after occupational exposure to inhaled anesthetic agents has attracted critical attention, but systematic studies focusing on the impact of inhaled anesthetics on the female reproductive system have not been well-established. We used a murine model to study the effect of isoflurane exposure on infertility in female adult mice and investigated the potential underlying mechanism. One hundred adult female C57 mice were randomly allocated into 5 groups exposed in air containing 0, 2500, 5000, 10 000 or 20 000 ppm isoflurane for 15 consecutive days. Estrous cycle length was measured based on vaginal smear examination, ovarian histopathologic enumeration of follicles, and serum estradiol (E₂), anti-Mullerian hormone (AMH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) levels to assess the effect of isoflurane on ovarian reserve. Compared to the control group, significant prolongation of the estrous cycle of the adult female mice was observed in the 20 000 ppm isoflurane exposure group. Serum AMH was significantly decreased, and FSH and LH levels profoundly increased in the 5000, 10 000, and 20 000 ppm isoflurane exposure groups compared to the control group. The histopathologic examination revealed a reduced number of developing follicles and an increased number of atretic follicles after isoflurane exposure, but the difference was not statistically significant. Thus, exposure to a higher concentration of isoflurane might have an adverse effect on ovarian reserve in sexually-mature female mice.

A nerve stimulation-guided lumbar plexus block is a well-established technique. It is not clear whether ultrasound guidance has additional value for this deep block technique. This study aimed to examine whether ultrasound guidance using a paramedian transverse scan through the intertransverse space (PMTS-ITS) approach in combination with nerve stimulation reduces the onset time of a complete sensory block. Forty-four patients who were scheduled to undergo arthroscopic knee surgery with an ultrasound visibility score (UVS) of ≥10 for the lumbar plexus were enrolled and randomly allocated to the ultrasound guidance with nerve stimulation group (group U-N) or nerve stimulation group (group N) in this prospective, randomized, parallel-group, active-controlled study. The primary outcome was the onset time of a complete sensory block. The results showed that the onset time of a complete sensory block to pinprick and cold was 10 (10–40) min and 10 (10–40) min in group U-N, respectively, and 30 (10–40) min and 20 (10–40) min in group N (P=0.005, P=0.004), respectively. The performance time was 658±87 s in group U-N and 528±97 s in group N (P<0.001). There was no (0%) patient who required 5 or more needle passes in group U-N and 6 (27.3%) in group N (P=0.028). The block failure rate was 9.1% in group U-N and 31.8% in group N (P>0.05). In conclusion, ultrasound guidance using the PMTS-ITS approach in combination with nerve stimulation led to a faster onset of a complete sensory block than nerve stimulation alone for a lumbar plexus block in patients with a UVS ≥10. Ultrasound guidance with nerve stimulation significantly decreased the number of patients who required 5 or more needle passes.

Lorenz-RR scatter plot has an obvious shortcoming in that it does not indicate the time when the scatter point happens. On the Lorenz RR scatter plot, one cannot know the time during which the cardiac rhythms take place. Since occurrence of cardiac rhythms is time-related, time should be introduced to such plots. In this study, time was used as abscissa and RR interval (the time interval between the previous RR wave and the R wave) as the ordinate and time was compressed into a visually observable length, and thereby a timed RR-interval scatter plot, or t-RR scatter plot, for short, was developed. On t-RR scatter plot, the patterns were band-shaped or were of linear type. On the t-RR plot, the sinus rhythm presented bands of various widths, with the spiculate or burred upper and lower boundaries, having diurnal variation. Premature beats showed separate layers (“stratification”), the layer number corresponding the number of RR-intervals. With simple premature beats, the layers were clearly separated. With parasystole rhythm, the upper and lower bands or layers might become thicker. With arial premature beats, the space or distance between layers varied. Ventricular premature beats presented equal space or distance between layers. With tachycardia, the lower layer became a “solid” layer. With atrial fibration, the “stratification” disappeared, presenting thicker or widened layers or bands, with neat lower boundary. With atrial flutter, the layers went parallel, with the layers being evenly separated or some distances being exact multiples of others. The second degree atrioventricular block displayed two layers, the lower and upper bands being equally away from the X-axis, presenting a straight line (pacing at a fixed rate) or a thicker or wider bands, with a neat upper boundary (the lowest pacing rate). When the scatter plot presented uncharacteristic patterns or had some scattered points, which rendered diagnosis difficult, a reverse technology could be used. Briefly, upon selection of scattered points, they were subjected to computerization, by regression, to reveal the piece of electrocardiogram (ECG) containing an R wave (QRS complex). Then ECG was analyzed to diagnose the cardiac rhythms. In conclusion, t-RR is a novel methodology which helps us understand heart rhythms from a new perspective.

The authors examined the original data of their work and noticed a misuse of the image of the bands of AKT and actin in fig. 2A (as shown below on the upper panel).

Prof. Mei YE works in the Department of Gastroenterology, Zhongnan Hospital, Wuhan University, and Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, as shown above. Her affiliation was incorrectly indicated in the article.

he article “Application of Virtual Reality Technology in Disaster Medicine”, written by Yu-yu DUAN, Jia-yao ZHANG, Mao XIE, Xiao-bo FENG, Song XU, Zhe-wei YE, was originally published electronically on the publisher’s internet portal on October 2019 without open access.

The article “Voltage-gated Sodium Channels and Blockers: An Overview and Where Will They Go?”, written by Zhi-mei LI, Li-xia CHEN, Hua LI, was originally published electronically on the publisher’s internet portal on December 2019 without open access.