Icariin alleviates diabetic renal interstitial fibrosis aggravation by inhibiting miR-320a-3p targeting BMP6.

Diabetic nephropathy is a common complication of diabetes, accumulating evidence underscores the pivotal role of tubulointerstitial fibrosis in the progression of diabetic nephropathy. However, the underlying mechanisms remain incompletely understood. Although the mechanisms in diabetic nephropathy fibrosis have been the focus of many studies, only limited information is currently available concerning microRNA regulation in tubulointerstitial fibrosis. In this study, we aimed to investigate the roles of miR-320a-3p and bone morphogenetic protein-6 (BMP6) in tubulointerstitial fibrosis. After inducing fibrosis with high glucose in HK-2 cells, we found that miR-320a-3p is significantly up-regulated, whereas BMP6 is markedly down-regulated. These changes suggest close link between miR-320a-3p and BMP6 in tubulointerstitial fibrosis. To elucidate this phenomenon, miR-320a-3p mimic, inhibitor and siBMP6 were employed. We observed in miR-320a-3p mimic group the fibrosis marker include alpha smooth muscle actin and type I collagen was significantly up-regulated, whereas BMP6 exhibited the opposite trend. Additionally, we found icariin could alleviate tubulointerstitial fibrosis by downregulation the miR-320a-3p expression. In conclusion, miR-320a-3p promotes tubulointerstitial fibrosis during the development of DN by suppressing BMP signal pathway activity via inhibiting BMP6 expression. Suggesting that miR-320a-3p represents a potential therapeutic target for tubulointerstitial fibrosis induced by diabetic nephropathy.

Shenqi Fuzheng injection restores the sensitivity to gefitinib in non-small cell lung cancer by inhibiting the IL-22/STAT3/AKT pathway.

CONTEXT: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Gefitinib is a first-line treatment for NSCLC. However, its effectiveness is hindered by the development of drug resistance. At present, Shenqi Fuzheng injection (SFI) is widely accepted as an adjuvant therapy in NSCLC. OBJECTIVE: This study investigates the molecular mechanism of SFI when combined with gefitinib in regulating cell progression among EGFR-TKI-resistant NSCLC. MATERIALS AND METHODS: We established gefitinib-resistant PC9-GR cells by exposing gefitinib escalation from 10 nM with the indicated concentrations of SFI in PC9 cells (1, 4, and 8 mg/mL). Quantitative real-time polymerase chain reaction was performed to assess gene expression. PC9/GR and H1975 cells were treated with 50 ng/mL of interleukin (IL)-22 alone or in combination with 10 mg/mL of SFI. STAT3, p-STAT3, AKT, and p-AKT expression were evaluated using Western blot. The effects on cell proliferation, clonogenicity, and apoptosis in NSCLC cells were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation and flow cytometry assays. RESULTS: SFI treatment alleviated the development of gefitinib resistance in NSCLC. PC9/GR and H1975 cells treated with SFI significantly exhibited a reduction in IL-22 protein and mRNA overexpression levels. SFI effectively counteracted the activation of the STAT3/AKT signaling pathway induced by adding exogenous IL-22 to PC9/GR and H1975 cells. Moreover, IL-22 combined with gefitinib markedly increased cell viability while reducing apoptosis. In contrast, combining SFI with gefitinib and the concurrent treatment of SFI with gefitinib and IL-22 demonstrated the opposite effect. DISCUSSION AND CONCLUSION: SFI can be a valuable therapeutic option to address gefitinib resistance in NSCLC by suppressing the IL-22/STAT3/AKT pathway.

Effects of Mud Content on the Setting Time and Mechanical Properties of Alkali-Activated Slag Mortar.

High mud content in the sand has a negative impact on cement mortar but there is little research on Alkali-activated slag (AAS) mortar. In order to explore the impacts of mud content in the sand on the performance of AAS mortar, this paper used sand that contains silt, clay, and a mixture of silt and clay; tested the setting time of AAS with different mud contents of 0%, 2%, 4%, 6%, 8%, and 10%; and measured the unconfined compressive strength and beam flexural strength of 3 d, 7 d, and 28 d AAS mortar specimens. The microstructure of AAS mortar with different kinds of mud was observed by scanning electron microscope (SEM), the elemental composition of the hydration product was tested by energy dispersive spectroscopy (EDS), and the AAS interaction mechanism with different kinds of mud was analyzed. The main conclusions are: the higher the mud content in the sand, the shorter the initial setting time and the longer the final setting time of AAS, mainly because the mud in the sand affects the hydration process; mud content above 4% causes a rapid decrease in the compressive and flexural strengths of AAS mortar, mainly because the mud affects the hydration process and hinders the bonding of the hydration product with the sand. When there is no mud in the sand, the main hydration product of AAS is dense calcium-alumina-silicate-hydrate (C-A-S-H) gel. When the sand contains silt, the hydration product of AAS is loose C-A-S-H gel. When the sand contains clay, the hydration products of AAS contain C-A-S-H gel and a small amount of sodium-aluminum-silicate-hydrate (N-A-S-H), and needle-like crystals. Loose gel and crystals have a negative effect on the AAS mortar strength.

Effects of Borax, Sucrose, and Citric Acid on the Setting Time and Mechanical Properties of Alkali-Activated Slag.

The setting time of alkali-activated slag (AAS) binders is extremely short, while traditional retarders of Portland cement may be invalid for AAS. To find an effective retarder with a less negative impact on strength, borax (B), sucrose (S), and citric acid (CA) were selected as potential retarders. The setting time of AAS with different admixtures dosages of 0%, 2%, 4%, 6%, and 8%, and the unconfined compressive strength and beam flexural strength of 3 d, 7 d, and 28 d AAS mortar specimens were tested. The microstructure of AAS with different additives was observed by scanning using an electron microscope (SEM), and the hydration products were analyzed by energy dispersive spectroscopy (EDS), X-ray diffraction analysis (XRD), and thermogravimetric analysis (DT-TGA) to explain the retarding mechanism of AAS with different additives. The results showed that the incorporation of borax and citric acid could effectively prolong the setting time of AAS more than that of sucrose, and the retarding effect is more and more obvious with the increase in borax and citric acid dosages. However, sucrose and citric acid negatively influence AAS's unconfined compressive strength and flexural stress. The negative effect becomes more evident with the increase in sucrose and citric acid dosages. Borax is the most suitable retarder for AAS among the three selected additives. SEM-EDS analysis showed that the incorporation of borax does three things: produces gels, covers the surface of the slag, and slows down the hydration reaction rate.

CIDP/autoimmune nodopathies with nephropathy: a case series study.

OBJECTIVE: The co-morbidity of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)/autoimmune nodopathies with nephropathy has been gradually known in recent years. This study was intended to explore the clinical, serological and neuropathological features of seven patients with CIDP/autoimmune nodopathies and nephropathy. METHODS: Among 83 CIDP patients, seven were identified with nephropathy. Their clinical, electrophysiological and laboratory examination data were collected. The nodal/paranodal antibodies were tested. The sural biopsies were performed in all the patients, and renal biopsies were operated in 6 patients. RESULTS: Six patients had chronic onsets and one had an acute onset. Four patients exhibited peripheral neuropathy preceding nephropathy while two showed concurrent onset of neuropathy and nephropathy, and one started with nephropathy. All the patients showed demyelination in electrophysiological examination. Nerve biopsies showed mild to moderate mixed neuropathies including demyelinating and axonal changes in all patients. Renal biopsies showed membranous nephropathy in all 6 patients. Immunotherapy was effective in all patients, with two patients showing good response to corticosteroid treatment alone. Four of the patients were positive to anti-CNTN1 antibody. Compared with anti-CNTN1 antibody-negative patients, antibody-positive patients had a higher proportion of ataxia (3/4 vs. 1/3), autonomic dysfunction (3/4 vs. 1/3), less frequent antecedent infections (1/4 vs. 2/3), higher cerebrospinal fluid proteins (3.2 g/L vs. 1.69 g/L), more frequent conduction block on electrophysiological examination (3/4 vs. 1/3), higher myelinated nerve fiber density, and positive CNTN1 expression in the glomeruli of kidney tissues. CONCLUSION: Anti-CNTN1 antibody was the most frequent antibody in this group of patients with CIDP/autoimmune nodopathies and nephropathy. Our study suggested that there might be some clinical and pathological differences between the antibody positive and negative patients.

Efficacy and safety of EGFR­TKIs plus Shenqi Fuzheng injection for non-small cell lung cancer patients with EGFR-sensitive mutations.

PURPOSE: The aim of this retrospective study is to evaluate the impact on efficacy and safety between epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) alone and in combination with Shenqi Fuzheng injection (SFI) in patients with advanced NSCLC harboring epidermal growth factor receptor (EGFR) activating mutations. METHODS: Retrospectively, information of 88 patients receiving EGFR-TKIs as first-line targeted treatment or in combination with SFI in the Affiliated Drum Tower Hospital of Nanjing University Medical College and the Affiliated Cancer Hospital of Anhui University of Science and Technology was collected. The primary endpoint was to assess progression-free survival (PFS) and safety of EGFR-TKIs alone or in combination with SFI. RESULTS: Between January 2016 and December 2019, a total of 88 patients were enrolled in this research, including 50 cases in the EGFR-TKIs single agent therapy group and 38 cases in the SFI combined with EGFR-TKIs targeted-therapy group. The median PFS (mPFS) of monotherapy group was 10.50 months (95%CI 9.81-11.19), and 14.30 months (95%CI 10.22-18.38) in the combination therapy group. Compared to the single EGFR-TKIs administration, combinational regimen with SFI exhibited a lower incidence of rash and diarrhea in patients and was even better tolerated. CONCLUSIONS: SFI combined with the first-generation EGFR-TKIs are more efficient, can prominently prolong the PFS and attenuate the adverse reactions in patients with advanced NSCLC with EGFR-sensitive mutations.

Subsarcolemmal and cytoplasmic p62 positivity and rimmed vacuoles are distinctive for PLIN4-myopathy.

PLIN4-myopathy is a recently identified autosomal dominant muscular disorder caused by the coding 99 bp repeat expansion in PLIN4, presenting with distal or proximal weakness. Here, we report one family and one sporadic case of adult-onset PLIN4-associated limb-girdle weakness, whose diagnoses were achieved by a comprehensive genetic analysis workup. We provided additional evidence that the combination of subsarcolemmal/cytoplasmic ubiquitin/p62 positive deposits and rimmed vacuoles could serve as a strong indicator of PLIN4-myopathy. Moreover, we found novel myopathological features that were ultrastructural subsarcolemmal filamentous materials and membrane-bound granulofilamentous inclusions formed by the co-deposition of disrupted lipid droplets and p62 protein aggregates.

Effect of Clay Minerals on Tensile Failure Characteristics of Shale.

The effects of mass fraction, elastic modulus, and the spatial distribution of clay minerals on the failure behaviors of shale under the Brazilian disc split are investigated in this study based on a developed PFC2D model. The feasibility of this established numerical model is validated by the load-displacement curves and fracture morphology of shale in the laboratory test. The influences of the mass fraction, elastic modulus, and spatial distribution of clay minerals on the tensile strength and failure behaviors of shale are comprehensively analyzed using the developed numerical model. The results show that the clay content has the strongest influence on the tensile strength of shale. The number of matrix cracks is sensitive to the clay distribution, and the complexity of the matrix fracture network in shale shows a positive correlation with the clay content. In addition, the variation of the clay modulus has a linear correlation with the macro elastic modulus of shale.

Prediction of Concrete Compressive Strength in Saline Soil Environments.

Saline soil in Western China contains high concentrations of chloride ions, sulfate ions, and other corrosive ions, and the performance of concrete will substantially deteriorate from exposure to this environment. Therefore, it is of great significance to study and predict the concrete compressive strength in saline soil environments. In this paper, the effects of corrosion on concrete were analyzed from the aspects of surface damage, damage depth, and X-ray diffraction (XRD) of the corrosion products. The effects of corrosion were quantified by damage depth and corrosion depth. Then, considering the corrosion effects combined with Fick's diffusion law, a time-dependent model of concrete compressive strength and a time-dependent model of damage depth were established. The results show that the deterioration of concrete gradually developed from the surface to the interior, and that the interface of the concrete specimen was equivalent to three parts: a failure zone, a filling zone, and an undisturbed zone. The results also showed that the time-varying model of concrete compressive strength proposed by the author was fully applicable, with an error of less than five percent. The service life of concrete predicted by the damage depth was found to be about 253 months (21.1 years), and the service life predicted by the time-varying compressive strength model was about 187 months (15.6 years). Both prediction results were far less than the normal concrete service life of 50 years. In addition, the long-term compressive strength of the corroded concrete was about 90% of that of the noncorroded concrete, which did not deteriorate with the corrosion time.

NCAPD3 enhances Warburg effect through c-myc and E2F1 and promotes the occurrence and progression of colorectal cancer.

BACKGROUND: NCAPD3 is one of the three non-SMC subunits of condensin II complex, which plays an important role in the chromosome condensation and segregation during mitosis. Notably, elevated levels of NCAPD3 are found in many somatic cancers. However, the clinical role, biological functions of NCAPD3 in cancers especially in colorectal cancer (CRC) and the underlying molecular mechanisms remain poorly elucidated. METHODS: Clinical CRC and adjacent normal tissues were used to confirm the expression of NCAPD3. The association of NCAPD3 expression with clinicopathological characteristics and patient outcomes were analyzed by using online database. In vivo subcutaneous tumor xenograft model, NCAPD3 gene knockout following azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced tumor mouse model, Co-IP, western blot, qRT-PCR, IHC, ChIP assays and cell functional assays were used to investigate the biological functions of NCAPD3 in CRC and the underlying molecular mechanisms. RESULTS: NCAPD3 was overexpressed in CRC tissues and positively correlated with poor prognosis of CRC patients. NCAPD3 knockout suppressed CRC development in AOM/DSS induced and xenograft mice models. Moreover, we found that NCAPD3 promoted aerobic glycolysis in CRC. Mechanistically, NCAPD3 up-regulated the level of c-Myc and interacted with c-Myc to recruit more c-Myc to the gene promoter of its downstream glycolytic regulators GLUT1, HK2, ENO1, PKM2 and LDHA, and finally enhanced cellular aerobic glycolysis. Also, NCAPD3 increased the level of E2F1 and interacted with E2F1 to recruit more E2F1 to the promoter regions of PDK1 and PDK3 genes, which resulted in the inhibition of PDH activity and TCA cycle. CONCLUSIONS: Our data demonstrated that NCAPD3 promoted glucose metabolism reprogramming and enhanced Warburg effect in colorectal tumorigenesis and CRC progression. These findings reveal a novel mechanism underlying NCAPD3 mediated CRC cell growth and provide new targets for CRC treatment.

A novel compound heterozygous mutation in the COA7 gene responsible for a Chinese patient with spinocerebellar ataxia with axonal neuropathy type 3.

OBJECTIVE: Spinocerebellar ataxia with axonal neuropathy type 3 (SCAN3) is a very rare autosomal recessive hereditary disease. Mutations in the COA7 gene, which encodes cytochrome c oxidase assembly factor 7, have been recently reported as the causative gene of SCAN3. So far, only five SCAN3 patients with COA7 mutations have been documented. Herein, we report the clinical, electrophysiological, histological, and genetic findings of a Chinese patient with SCAN3. MATERIALS AND METHODS: The patient was a 31-year-old woman who presented with early-onset peripheral neuropathy and progressive ataxia. She was asked about her medical history and underwent electrophysiological examination, nerve and muscle biopsy, and gene detection. RESULTS: Whole exome next-generation sequencing identified a novel compound heterozygous mutation of COA7 (c.17A>G p.D6G; c.554G>A, p.W185*) in this patient. Magnetic resonance imaging showed cerebellum and spinal cord atrophy. Nerve conduction studies and sural nerve biopsies revealed sensorimotor axonal neuropathy. Muscle biopsies showed mitochondrial abnormalities. Respiratory chain enzyme assay of skin fibroblasts showed normal respiratory chain complex activities. Additionally, the clinical data on previously reported SCAN patients with identified genetic causes in PubMed was summarized. Compared with SCAN1 and SCAN2 patients, SCAN3 patients had earlier onset age, less cognitive impairment, and no ocular signs. CONCLUSION: We reported the first patient diagnosed with SCAN3 in China. A novel mutation in the gene COA7 (c.554G>A, p.W185*) expanded the genetic spectrum of the disease.

Cholesterol promotes EGFR-TKIs resistance in NSCLC by inducing EGFR/Src/Erk/SP1 signaling-mediated ERRα re-expression.

BACKGROUND: The use of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) brings remarkable benefits for the survival of patients with advanced NSCLC harboring EGFR mutations. Unfortunately, acquired resistance seems to be inevitable and limits the application of EGFR-TKIs in clinical practice. This study reported a common molecular mechanism sustaining resistance and potential treatment options to overcome EGFR-TKIs resistance. METHODS: EGFR-TKIs resistant NSCLC cells were established and confirmed by MTT assay. Cholesterol content was detected and the promotional function of cholesterol on NSCLC growth was determined in vivo. Then, we identified ERRα expression as the downstream factor of cholesterol-mediated drug resistance. To dissect the regulatory mechanism, we conducted experiments, including immunofluorescence, co-immunoprecipitation, luciferase reporter assay and chromatin immunoprecipitation assay. RESULTS: Long-term exposure to EGFR-TKIs generate drug resistance with the characteristic of cholesterol accumulation in lipid rafts, which promotes EGFR and Src to interact and lead EGFR/Src/Erk signaling reactivation-mediated SP1 nuclear translocation and ERRα re-expression. Further investigation identifies ERRα as a target gene of SP1. Functionally, re-expression of ERRα sustains cell proliferation by regulating ROS detoxification process. Lovastatin, a drug used to decrease cholesterol level, and XCT790, an inverse agonist of ERRα, overcome gefitinib and osimertinib resistance both in vitro and in vivo. CONCLUSIONS: Our study indicates that cholesterol/EGFR/Src/Erk/SP1 axis-induced ERRα re-expression promotes survival of gefitinib and osimertinib-resistant cancer cells. Besides, we demonstrate the potential of lowing cholesterol and downregulation of ERRα as effective adjuvant treatment of NSCLC.

Claudin1 decrease induced by 1,25-dihydroxy-vitamin D3 potentiates gefitinib resistance therapy through inhibiting AKT activation-mediated cancer stem-like properties in NSCLC cells.

Claudins, the integral tight junction proteins that regulate paracellular permeability and cell polarity, are frequently dysregulated in cancer; however, their roles in regulating EGFR tyrosine kinase inhibitors (EGFR-TKIs) resistance in non-small cell lung cancer (NSCLC) are unknown. To this end, we performed GEO dataset analysis and identified that claudin1 was a critical regulator of EGFR-TKI resistance in NSCLC cells. We also found that claudin1, which was highly induced by continuous gefitinib treatment, was significantly upregulated in EGFR-TKI-resistant NSCLC cells. By knocking down claudin1 in cell lines and xenograft models, we established that gefitinib resistance was decreased. Moreover, claudin1 knockdown suppressed the expression levels of pluripotency markers (Oct4, Nanog, Sox2, CD133, and ALDH1A1). Claudin1 loss inhibited phosphorylated AKT (p-AKT) expression and reduced cancer cell stemness by suppressing AKT activation. Furthermore, SKL2001, a ß-catenin agonist, upregulated the expression levels of claudin1, p-AKT, and pluripotency markers, and 1,25-dihydroxy-vitamin D3 (1,25(OH)2D3) reduced claudin1 expression, AKT activation, and cancer cell stemness by inhibiting ß-catenin, and suppressed claudin1/AKT pathway mediated cancer stem-like properties and gefitinib resistance. Collectively, inhibition of claudin1-mediated cancer stem-like properties by 1,25(OH)2D3 may decrease gefitinib resistance through the AKT pathway, which may be a promising therapeutic strategy for inhibiting gefitinib resistance in EGFR-mutant lung adenocarcinoma.

PPARα agonist fenofibrate relieves acquired resistance to gefitinib in non-small cell lung cancer by promoting apoptosis via PPARα/AMPK/AKT/FoxO1 pathway.

Recent studies show that intracellular accumulation of cholesterol leads to acquired resistance to gefitinib in non-small cell lung cancer (NSCLC) cells. In this study we investigated how to regulate the cholesterol levels in gefitinib-resistant NSCLC cells. We showed that intracellular cholesterol levels in gefitinib-resistant cell lines (PC-9/GR, H1975, H1650, and A549) were significantly higher than that in gefitinib-sensitive cell line (PC-9). Treatment with gefitinib (5 µM) significantly increased intracellular cholesterol levels in PC-9/GR, H1975, and H1650 cells. Gefitinib treatment downregulated the expression of PPARα, LXRα, and ABCA1, leading to dysregulation of cholesterol efflux pathway. We found that a lipid-lowering drug fenofibrate (20, 40 µM) dose-dependently increased the expression of PPARα, LXRα, and ABCA1, decreased the intracellular cholesterol levels, and enhanced the antiproliferative effects of gefitinib in PC-9/GR, H1975, and H1650 cells. We revealed that fenofibrate increased the gefitinib-induced apoptosis via regulating the key proteins involved in the intrinsic apoptosis pathway. In PC-9/GR, H1975 and H1650 cells, fenofibrate dose-dependently increased the expression of AMPK, FoxO1, and decreased the expression of AKT, which were remarkably weakened by knockdown of PPARα. In PC-9/GR cell xenograft mice, combined administration of gefitinib (25 mg · kg-1 · d-1) and fenofibrate (100 mg · kg-1 · d-1) caused remarkable inhibition on tumor growth as compared to treatment with either drug alone. All the results suggest that fenofibrate relieves acquired resistance to gefitinib in NSCLC by promoting apoptosis via regulating PPARα/AMPK/AKT/FoxO1 pathway. We propose that combination of gefitinib and fenofibrate is a potential strategy for overcoming the gefitinib resistance in NSCLC.

Icariin Ameliorates Diabetic Renal Tubulointerstitial Fibrosis by Restoring Autophagy via Regulation of the miR-192-5p/GLP-1R Pathway.

Tubulointerstitial fibrosis is one of the most common pathological features of diabetic nephropathy. Autophagy, an intracellular mechanism to remove damaged or dysfunctional cell parts and maintain metabolic homeostasis, is inhibited in diabetic neuropathy. Icariin is a traditional Chinese medicine extract known for nourishing the kidney and reinforcing Yang. In this study, we investigated the effects and mechanism of Icariin on renal function, autophagy, and fibrosis in type 2 diabetic nephropathic rats and in high-glucose-incubated human renal tubular epithelial cells and rat renal fibroblasts (in vitro). Icariin improved diabetes, renal function, restored autophagy, and alleviated fibrosis in type 2 diabetic neuropathic rats and in vitro. After we applied autophagy-related gene 5-small interfering RNA, we found that fibrosis improvement by Icariin was related to autophagy restoration. By detecting serum sex hormone levels, and using dihydrotestosterone, siRNA for androgen receptor, and the androgen receptor antagonist Apalutamide (ARN-509), we found that Icariin had an androgen-like effect and restored autophagy and reduced fibrosis by regulating the androgen receptor. In addition, miR-192-5p levels were increased under high glucose but reduced after dihydrotestosterone and Icariin treatment. Furthermore, dihydrotestosterone and Icariin inhibited miR-192-5p overexpression-induced fibrosis production and autophagy limitation. Glucagon-like peptide-1 receptor (GLP-1R) was downregulated by high glucose and overexpression of miR-192-5p and could be restored by dihydrotestosterone and Icariin. By using ARN-509, we found that Icariin increased GLP-1R expression by regulating the androgen receptor. GLP-1R-siRNA transfection weakened the effects of Icariin on autophagy and fibrosis. These findings indicate that Icariin alleviates tubulointerstitial fibrosis by restoring autophagy through the miR-192-5p/GLP-1R pathway and is a novel therapeutic option for diabetic fibrosis.

NCAPD2 inhibits autophagy by regulating Ca2+/CAMKK2/AMPK/mTORC1 pathway and PARP-1/SIRT1 axis to promote colorectal cancer.

Non-SMC condensin I complex subunit D2 (NCAPD2) is one of the three non-SMC subunits in condensin I. Previous studies have shown that NCAPD2 plays an important role in the chromosome condensation and segregation. However, its role in the development of colorectal cancer (CRC) and specific molecular mechanisms still need to be further studied. Here we show that NCAPD2 inhibits autophagy and blocks autophagic flux via Ca2+/CAMKK/AMPK/mTORC1 pathway and PARP-1/SIRT1 axis. NCAPD2 acts as a tumor promoter both in vitro and in vivo. NCAPD2 knockout suppresses colorectal cancer development in AOM/DSS induced mice model. Therefore, our findings support a role for NCAPD2 in autophagy to promote CRC development and highlight NCAPD2 as a potential target for CRC therapy.

GGC Repeat Expansion in the NOTCH2NLC Gene Is Associated With a Phenotype of Predominant Motor-Sensory and Autonomic Neuropathy.

There is still a considerable proportion of patients with inherited peripheral neuropathy (IPN) whose pathogenic genes are unknown. This study was intended to investigate whether the GGC repeat expansion in the NOTCH2NLC is presented in some patients with IPN. A total of 142 unrelated mainland Chinese patients with highly suspected diagnosis of IPN without any known causative gene were recruited. Repeat-primed polymerase chain reaction (RP-PCR) was performed to screen GGC repeat expansion in NOTCH2NLC, followed by fluorescence amplicon length analysis-PCR (AL-PCR) to determine the GGC repeat size. Detailed clinical data as well as nerve, muscle, and skin biopsy were reviewed and analyzed in the NOTCH2NLC-related IPN patients. In total, five of the 142 patients (3.52%) were found to have pathogenic GGC expansion in NOTCH2NLC, with repeat size ranging from 126 to 206 repeats. All the NOTCH2NLC-related IPN patients presented with adult-onset motor-sensory and autonomic neuropathy that predominantly affected the motor component of peripheral nerves. While tremor and irritating dry cough were noted in four-fifths of the patients, no other signs of the central nervous system were presented. Electrophysiological studies revealed both demyelinating and axonal changes of polyneuropathy that were more severe in lower limbs and asymmetrically in upper limbs. Sural nerve pathology was characterized by multiple fibers with thin myelination, indicating a predominant demyelinating process. Muscle pathology was consistent with neuropathic changes. P62-positive intranuclear inclusions were observed in nerve, skin, and muscle tissues. Our study has demonstrated that GGC expansion in NOTCH2NLC is associated with IPN presenting as predominant motor-sensory and autonomic neuropathy, which expands the phenotype of the NOTCH2NLC-related repeat expansion spectrum. Screening of GGC repeat expansions in the NOTCH2NLC should be considered in patients presenting with peripheral neuropathy with tremor and irritating dry cough.

GGC repeat expansions in NOTCH2NLC causing a phenotype of distal motor neuropathy and myopathy.

BACKGROUND: The expansion of GGC repeat in the 5' untranslated region of the NOTCH2NLC has been associated with various neurogenerative disorders of the central nervous system and, more recently, oculopharyngodistal myopathy. This study aimed to report patients with distal weakness with both neuropathic and myopathic features on electrophysiology and pathology who present GGC repeat expansions in the NOTCH2NLC. METHODS: Whole-exome sequencing (WES) and long-read sequencing were implemented to identify the candidate genes. In addition, the available clinical data and the pathological changes associated with peripheral nerve and muscle biopsies were reviewed and studied. RESULTS: We identified and validated GGC repeat expansions of NOTCH2NLC in three unrelated patients who presented with progressive weakness predominantly affecting distal lower limb muscles, following negative results in an initial WES. We found intranuclear inclusions with multiple proteins deposits in the nuclei of both myofibers and Schwann cells. The clinical features of these patients are compatible with the diagnosis of distal motor neuropathy and rimmed vacuolar myopathy. INTERPRETATION: These phenotypes enrich the class of features associated with NOTCH2NLC-related repeat expansion disorders (NRED), and provide further evidence that the neurological symptoms of NRED include not only brain, spinal cord, and peripheral nerves damage, but also myopathy, and that overlapping symptoms might exist.

The Differential Metabolic Profiles Between Deltamethrin-Resistant and -Susceptible Strains of Aedes albopictus (Diptera: Culicidae) by 1H-NMR.

Metabolomics can indicate the physiological and biochemical responses of mosquitoes to different stimulants, including insecticides, which allow them to adapt to different inhospitable environments. Though metabolic differences between insecticide-resistant and -susceptible strains have been established for other mosquito species, such as Anopheles and Culex, it is yet to be done for Aedes albopictus (Skuse). In this study, nuclear magnetic resonance (NMR) spectroscopy-based metabolomic analysis performed on Ae. albopictus deltamethrin-resistant and -susceptible strains showed significant differences in amino acid, organic acid, and sugar metabolism. Concentrations of neutral amino acids and sugars tended to be lower in the deltamethrin-resistant strain than in the deltamethrin-suceptible strain, but the concentration of basic and acidic amino acids and organic acids increased. All these changes might accommodate biochemical and physiological needs in deltamethrin-resistant mosquitoes, such as enzyme synthesis and detoxification. This was further confirmed by the predictable draft metabolic map. This is the first report using NMR spectroscopy to investigate the metabolic differences between deltamethrin-resistant and -susceptible strains of Ae. albopictus. To a certain degree, this demonstrates how Ae. albopictus develop insecticide resistance by metabolic reprograming to survive under the insecticide pressure.

EGFR activation-induced decreases in claudin1 promote MUC5AC expression and exacerbate asthma in mice.

Claudin1 plays a critical role in maintaining the epithelial barrier, and mucus hypersecretion induced by epidermal growth factor receptor (EGFR) activation is a pivotal pathological feature of asthma. The relationship between claudin1 expression and mucus hypersecretion and EGFR activation is still poorly understood. In this report, we showed that claudin1 expression correlated with asthma stage, in both patients with asthma and in the house dust mite (HDM)-induced mouse asthma model. Claudin1 knockdown induced MUC5AC overexpression both in 16HBE cells and in mouse airways. In addition, claudin1 expression negatively correlated with asthma severity as demonstrated by significantly higher MUC5AC expression, more severe airway inflammation, and increased airway hyperreactivity in mouse lungs with claudin1 knockdown following HDM challenge. EGFR activation reduced claudin1 expression and increased MUC5AC expression, both in vitro and in vivo. Erlotinib alleviated murine allergic airway inflammation, restored claudin1 expression and decreased MUC5AC expression. These results suggest that EGFR activation-induced decreases in claudin1 promote goblet-cell metaplasia, and restoring claudin1 to maintain barrier integrity by EGFR antagonism may provide a novel therapeutic strategy for asthma.