Arsenic aggravates the progression of diabetic nephropathy through miRNA-mRNA-autophagy axis.

Environmental factors play an important role in the progression of diabetic nephropathy (DN), and previous study has shown that arsenic exposure can promote kidney damage in DN rats, however there is no relevant mechanism study so far. In this study, an arsenic-exposed (10 mg/L and 25 mg/L) DN mouse model was established through drinking water for 14 weeks. The results showed that 25 mg/L arsenic exposure increased the renal fibrosis in DN mice significantly, and urinary mAlb level increased with the increasing of arsenic exposure level. Transcriptome sequencing showed that autophagy-related pathways were significantly activated under the exposure dose of 25 mg/L, and levels of Beclin1 and p-ATG16L1/ATG16L1 were significantly higher in the 25 mg/L arsenic group compared to the control group. Silico analysis predicted the microRNAs those could regulate the hub genes of Mapk1, Rhoa and Cdc42, and dual-luciferase gene reporter assay was used to verify the targeted binding between these mRNAs and microRNAs. Our results suggested that high arsenic exposure could aggravate the progression of DN by altering autophagy, the miRNA-mRNA axles of let-7a-1-3p, let-7b-3p, let-7f-1-3p, miR-98-3p/Cdc42, Mapk1, Rhoa, could be considered promising targets to explore the mechanisms and therapeutic measures of DN after exposure to high levels of arsenic.

Bortezomib-loaded mixed micelles realize a "three-in-one" effect for enhanced breast cancer treatment.

Comprehensively regulating the TME is now regarded as a promising approach for cancer treatment. Herein, a novel "three-in-one" effect is presented for simultaneously killing tumor cells, inhibiting the EMT of CAFs, and improving immune responses. In this study, bortezomib (BTZ) is selected for the treatment of breast cancer; it has multiple pharmacological mechanisms for killing tumor cells through the NF-κB signaling pathway, inhibiting the activity of CAFs by activating caspase-3, and enhancing the function of CD8+ T cells by regulating the expression of immune-stimulating factors. To improve the druggability of BTZ in solid tumors, BTZ-loaded lipid/glycocholic acid mixed micelles (BTZ-LGs) were prepared to verify the "three-in-one" effect in killing tumor cells, inhibiting CAFs, and improving immune responses. In the present work, BTZ-LGs were verified to show enhanced in vitro cytotoxicity in both 4T1 cells and 4T1/NIH3T3 co-cultured cells, as well as a superior in vivo treatment effect in different tumor-bearing mouse models. Additionally, BTZ-LGs could regulate the expression of α-SMA, caspase-3, E-cadherin, and N-cadherin, indicating their good inhibiting ability on both tumor cells and CAFs. More importantly, immunological analysis revealed that BTZ-LGs promoted the expression of the immunostimulatory factor IL-2 in tumor tissues, activated anti-tumor T cells, and overcame tumor-induced CD8+ T cell dysfunction. All these findings suggest that BTZ-LGs can achieve a "three-in-one" effect in terms of killing tumor cells, suppressing CAFs, and improving immune responses. This simple and multi-effective therapeutic strategy offers a promising approach for cancer therapy.

Recent Advances in CXCL12/CXCR4 Antagonists and Nano-Based Drug Delivery Systems for Cancer Therapy.

Chemokines can induce chemotactic cell migration by interacting with G protein-coupled receptors to play a significant regulatory role in the development of cancer. CXC chemokine-12 (CXCL12) can specifically bind to CXC chemokine receptor 4 (CXCR4) and is closely associated with the progression of cancer via multiple signaling pathways. Over recent years, many CXCR4 antagonists have been tested in clinical trials; however, Plerixafor (AMD3100) is the only drug that has been approved for marketing thus far. In this review, we first summarize the mechanisms that mediate the physiological effects of the CXCL12/CXCR4 axis. Then, we describe the use of CXCL12/CXCR4 antagonists. Finally, we discuss the use of nano-based drug delivery systems that exert action on the CXCL12/CXCR4 biological axis.

GA&HA-Modified Liposomes for Co-Delivery of Aprepitant and Curcumin to Inhibit Drug-Resistance and Metastasis of Hepatocellular Carcinoma.

Background: Tumor microenvironment (TME) plays a vital role in the development of hepatocellular carcinoma (HCC). Mounting evidence indicates that peripheral nerves could induce a shift from quiescent hepatic stellate cells (HSCs) to cancer-associated fibroblasts (CAFs) by secreting substance P (SP). The anti-tumor strategy by targeting "SP-HSCs-HCC" axis might be an effective therapy to inhibit tumor growth and metastasis. Objective: In this study, we prepared novel liposomes (CUR-APR/HA&GA-LPs) modified with hyaluronic acid (HA) and glycyrrhetinic acid (GA) for co-delivery aprepitant (APR) and curcumin (CUR), in which APR was chosen to inhibit the activation of HSCs by blocking SP/neurokinin-1 receptor (NK-1R), and CUR was used to induce apoptosis of tumor cells. Results: To mimic the TME, we established "SP+HSCs+HCC" co-cultured cell model in vitro. The results showed that CUR-APR/HA&GA-LPs could be taken up by CAFs and HCC simultaneously, and inhibit tumor cell migration. Meanwhile, the "SP+m-HSCs+HCC" co-implanted mice model was established to evaluate the anti-tumor effect in vivo. The results showed that CUR-APR/HA&GA-LPs could inhibit tumor proliferation and metastasis, and reduce extracellular matrix (ECM) deposition and tumor angiogenesis, indicating a superior anti-HCC effect. Conclusion: Overall, the combination therapy based on HA&GA-LPs could be a potential nano-sized formulation for anti-HCC therapy.

Irinotecan/scFv co-loaded liposomes coaction on tumor cells and CAFs for enhanced colorectal cancer therapy.

BACKGROUND: Cancer-associated fibroblasts (CAFs), as an important component of stroma, not only supply the "soils" to promote tumor invasion and metastasis, but also form a physical barrier to hinder the penetration of therapeutic agents. Based on this, the combinational strategy that action on both tumor cells and CAFs simultaneously would be a promising approach for improving the antitumor effect. RESULTS: In this study, the novel multifunctional liposomes (IRI-RGD/R9-sLip) were designed, which integrated the advantages including IRI and scFv co-loading, different targets, RGD mediated active targeting, R9 promoting cell efficient permeation and lysosomal escape. As expected, IRI-RGD/R9-sLip showed enhanced cytotoxicity in different cell models, effectively increased the accumulation in tumor sites, as well as exhibited deep permeation ability both in vitro and in vivo. Notably, IRI-RGD/R9-sLip not only exhibited superior in vivo anti-tumor effect in both CAFs-free and CAFs-abundant bearing mice models, but also presented excellent anti-metastasis efficiency in lung metastasis model. CONCLUSION: In a word, the novel combinational strategy by coaction on both "seeds" and "soils" of the tumor provides a new approach for cancer therapy, and the prepared liposomes could efficiently improve the antitumor effect with promising clinical application prospects.

Hydrogen sulfide (H2S) signaling in plant development and stress responses.

ABSTRACT: Hydrogen sulfide (H2S) was initially recognized as a toxic gas and its biological functions in mammalian cells have been gradually discovered during the past decades. In the latest decade, numerous studies have revealed that H2S has versatile functions in plants as well. In this review, we summarize H2S-mediated sulfur metabolic pathways, as well as the progress in the recognition of its biological functions in plant growth and development, particularly its physiological functions in biotic and abiotic stress responses. Besides direct chemical reactions, nitric oxide (NO) and hydrogen peroxide (H2O2) have complex relationships with H2S in plant signaling, both of which mediate protein post-translational modification (PTM) to attack the cysteine residues. We also discuss recent progress in the research on the three types of PTMs and their biological functions in plants. Finally, we propose the relevant issues that need to be addressed in the future research. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s42994-021-00035-4.

Identification of four key biomarkers and small molecule drugs in nasopharyngeal carcinoma by weighted gene co-expression network analysis.

Nasopharyngeal carcinoma (NPC) is a heterogeneous carcinoma whose underlying molecular mechanisms involved in tumor initiation, progression, and migration are largely unclear. The aim of the present study was to identify key biomarkers and small-molecule drugs for screening, diagnosing, and treating NPC via gene expression profile analysis. Raw microarray data was used to identify 430 differentially expressed genes (DEGs) in the Gene Expression Omnibus (GEO) database. The key modules associated with histological grade and tumor stage were identified using weighted gene co-expression network analysis. qRT-PCR was used to verify the differential expression of hub genes. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and the connectivity map database were used to identify potential mechanisms and screen small-molecule drugs targeting hub genes. Functional enrichment analysis showed that genes in the green module were enriched in the regulation of cell cycle, p53 signaling pathway, and cell part morphogenesis. Four DEG-related hub genes (CRIP1, KITLG, MARK1, and PGAP1) in the green module, which were considered potential diagnostic biomarkers, were taken as the final hub genes. The expression levels of these four hub genes were verified via qRT-PCR, and the results were consistent with findings from the GEO analysis. Screening was also conducted to identify small-molecule drugs with potential therapeutic effects against NPC. In conclusion, four potential prognostic biomarkers and several candidate small-molecule drugs, which may provide new insights for NPC therapy, were identified.

Acidic tumor microenvironment-sensitive liposomes enhance colorectal cancer therapy by acting on both tumor cells and cancer-associated fibroblasts.

Cancer-associated fibroblasts (CAFs) play a crucial role in facilitating tumor invasion and metastasis, which act as the "soil" in the tumor microenvironment (TME). Accordingly, it would be a promising strategy to enhance the antitumor effect by killing both tumor cells and CAFs simultaneously. Herein, novel TME acid-responsive liposomes for co-delivery of IRI and 398 (IRI&398-s-LPs) were developed, in which the rapid release of both drugs could be triggered under acidic conditions. Notably, a CT-26/3T3 cell co-culture system was used to mimic the real TME both in vitro and in vivo. Cellular immunofluorescence revealed that IRI&398-s-LPs could efficiently decrease the activation of CAFs. In vitro cytotoxicity evaluation demonstrated that IRI&398-s-LPs exhibited higher cytotoxicity than the other liposomal formulations in the CT-26 and CT-26/3T3 cell co-culture system. In vivo NIRF imaging showed that the IRI&398-s-LPs could increase drug accumulation in the tumor sites. Furthermore, IRI&398-s-LPs not only presented superior in vivo anti-tumor activity in CT-26 bearing BALB/c mice, but also enhanced the effect in CT-26/3T3 cell bearing mice with decreased collagen and CAF biomarker expression. Furthermore, IRI&398-s-LPs also presented superior anti-metastatic efficiency in a lung metastasis model. These results indicated that this combinational strategy for eliminating both tumor cells and CAFs provides a new approach for cancer therapy, and the prepared TME-responsive liposomes for co-delivery of drugs hold promising clinical application prospects.

Progress on the Application of Bortezomib and Bortezomib-Based Nanoformulations.

Bortezomib (BTZ) is the first proteasome inhibitor approved by the Food and Drug Administration. It can bind to the amino acid residues of the 26S proteasome, thereby causing the death of tumor cells. BTZ plays an irreplaceable role in the treatment of mantle cell lymphoma and multiple myeloma. Moreover, its use in the treatment of other hematological cancers and solid tumors has been investigated in numerous clinical trials and preclinical studies. Nevertheless, the applications of BTZ are limited due to its insufficient specificity, poor permeability, and low bioavailability. Therefore, in recent years, different BTZ-based drug delivery systems have been evaluated. In this review, we firstly discussed the functions of proteasome inhibitors and their mechanisms of action. Secondly, the properties of BTZ, as well as recent advances in both clinical and preclinical research, were reviewed. Finally, progress in research regarding BTZ-based nanoformulations was summarized.

MEG3 Induces Cervical Carcinoma Cells' Apoptosis Through Endoplasmic Reticulum Stress by miR-7-5p/STC1 Axis.

Background: Many patients with advanced cervical cancer (CC) have a poor prognosis and their mortality rank the first among women with malignant tumors. It's essential to explore the molecular mechanism of CC in clinical practice. Long noncoding RNA maternally expressed gene 3 (MEG3) has been reported to downregulate in CC tissues. However, the underlying mechanism of MEG3 in CC remains poorly elaborated. The current study aimed to explore the potential mechanism of MEG3 inducing endoplasmic reticulum stress (ERs)-mediated apoptosis of CC cells. Methods: The expression of MEG3 and miR-7-5p in CC tissues and cell lines was verified by quantitative reverse transcription/polymerase chain reaction (qRT-PCR). The vector of MEG3, miR-7-5p inhibitor, and sh-SCT1 were transfected into CC cell lines, and their expression was tested by qRT-PCR. Flow cytometry was used to detect apoptosis, and ERs-related protein expression was performed by Western blot. The regulatory relationship between MEG3/SCT1 and miR-7-5p was validated by Dual luciferase reporter assay. Results: CC tissues and cell lines showed downregulated MEG3 and STC1, and upregulated miR-7-5p. Overexpression of MEG3 or miR-7-5p inhibition induced ERs-triggered apoptosis of CC cells. In addition, sh-STC1 can reverse the effects of overexpressing MEG3 on CC cell apoptosis. In addition, dual luciferase reporter assay revealed that miR-7-5p can directly target to MEG3 and STC1. Conclusion: MEG3, act as a competing endogenous RNA of miR-7-5p, accelerates ERs-mediated apoptosis of CC cells through regulating SCT1 expression.

Trichostatin A Induces Autophagy in Cervical Cancer Cells by Regulating the PRMT5-STC1-TRPV6-JNK Pathway.

OBJECTIVE: The aim of this study was to investigate the effects of trichostatin A (TSA) on cervical cancer and the related mechanisms. METHODS: The HeLa and Caski cervical cancer cell lines were treated with different concentrations of TSA. Cell viability was measured by MTT assays. Cell apoptosis was analysed using flow cytometry. Expression of transient receptor potential cation channel, subfamily V, member 6 (TRPV6), protein arginine methyltransferase 5 (PRMT5), and stanniocalcin 1 (STC1) was determined by qRT-PCR and Western blotting. Protein levels of LC3 II/I, beclin1, p62, JNK, and p-JNK were detected by Western blotting. RESULTS: Treatment with TSA significantly decreased HeLa and Caski cell viability and enhanced the apoptosis rate in a dose-dependent manner. TSA markedly elevated beclin1 protein levels and the LC3 II/I ratio and significantly reduced p62 levels in a dose-dependent manner. In addition, TSA (1 µM) significantly suppressed PRMT5 and TRPV6 levels and enhanced STC1 and p-JNK levels. The lysosomal inhibitor bafilomycin-A1 synergistically enhanced the TSA-mediated increase in autophagic flux. Either the overexpression of TRPV6 or the inhibition of JNK signalling markedly enhanced cell viability, inhibited apoptosis, and autophagy and reduced p-JNK levels in TSA-treated cells. The inhibition of STC1 significantly increased TRPV6 protein levels and reduced p-JNK levels. Overexpression of PRMT5 dramatically decreased STC1 and p-JNK protein levels and increased TRPV6 levels. CONCLUSION: TSA suppresses cervical cancer cell proliferation and induces apoptosis and autophagy through regulation of the PRMT5/STC1/TRPV6/JNK axis.

B-lymphoblastic lymphoma with renal lesions as first symptom in a child: a case report and review of literature.

Lymphoblastic lymphoma (LBL) is a type of non Hodgkin's lymphoma. It is highly malignant and aggressive. Most patients have poor prognosis. Extramedullary involvement of B-LBL is very common, and the most vulnerable tissues are skin, bone, and soft tissues. Primary renal B-LBL is rarely reported. In this article, we report an 8-year-old boy who was admitted to hospital due to abdominal pain and vomiting. He was diagnosed with B lymphoblastoma by CT guided renal biopsy and bone marrow puncture. We review the clinical characteristics and diagnosis and treatment process of this case.

STC1 promotes cell apoptosis via NF-κB phospho-P65 Ser536 in cervical cancer cells.

Stanniocalin-1 (STC1) is a secreted glycoprotein hormone and involved in various types of human malignancies. Our previous studies revealed that STC1 inhibited cell proliferation and invasion of cervical cancer cells through NF-κB P65 activation, but the mechanism is poorly understood. In our studies, we found overexpression of STC1 promoted cell apoptosis while silencing of STC1 promoted cell growth of cervical cancer. Phospho-protein profiling and Western blotting results showed the expression of NF-κB related phosphorylation sites including NF-κB P65 (Ser536), IκBα, IKKß, PI3K, and AKT was altered in STC1-overexpressed cervical cancer cells. Moreover, PI3K inhibitor LY294002, AKT-shRNA and IκBα-shRNA could decrease the protein content of phospho-P65 (Ser536), phospho-IκBα, phospho-AKT and phospho-IKKß while increasing the level of P65 compared to STC1 overexpression groups in cervical cancer cells. Also, PI3K inhibitor LY294002, AKT-shRNA and IκBα-shRNA elevated the percentage of apoptosis and suppressed the G1/S transition in those cells. Additionally, STC1 level was decreased in cervical cancer, especial in stage II and III. The results of immunohistochemistry for the cervical cancer microarray showed that a lower level of STC1, phospho-PI3K and P65 protein expression in tumor tissues than that in normal tissues, and a higher level of phospho-P65 protein expression in tumor tissues, which is consistent with the results of the Western blotting. These data demonstrated that STC1 can promote cell apoptosis via NF-κB phospho-P65 (Ser536) by PI3K/AKT, IκBα and IKK signaling in cervical cancer cells. Our results offer the first mechanism that explains the link between STC1 and cell apoptosis in cervical cancer.

[Introduction on the schools of the scalp acupuncture for treatment of the stroke hemiplegia].

Three representative schools of scalp acupuncture for the stroke hemiplegia such as Jiao's scalp acupuncture, Yu's scalp acupuncture and temporal three-needle are introduced and analyzed. Since the schools of scalp acupuncture are numerous and the bases of selection acupoints are complicated, it demands to determine the optimal needling acupoints by means of scientific research. Therefore, the selection acupoints would be adhering to scientific principles. The theoretical basis needs to be explored and studied further.

[Observation on specificity of acupuncture location in treatment of acute apoplexy by scalp penetration needling].

OBJECTIVE: To observe the clinical effects of scalp penetration acupuncture and conventional scalp acupuncture for treatment of acute apoplexy, to seek the effective location and mechanism of scalp acupuncture treatment for acute apoplexy. METHODS: Sixty cases of the apoplexy were randomly divided into an observation group and a control group, 30 cases in each group. Basis on the neurological treatment, the observation group was treated with penetration needling through Baihui (GV 20) to Taiyang (EX-HN 5) on the affected side, with four needles relay; the control group was treated with penetration needling at anterior oblique line of parietotemporal region, with four needles relay. After 14 days of treatment, the neurological deficit scores (NDS) and the therapeutic effects were compared before and after treatment, and the contents of plasma endothelins (ET) and the calcitonin gene-related peptide (CGRP) were tested respectively on the 2nd and 14th day after treatment. RESULTS: The effective rate of 86.7% (26/30) in the observation group was superior to that of 80.0% (24/30) in the control group; the NDS of both groups were obviously decreased after treatment (both P < 0.01), the improvement degree in the observation group was better than that of the control group (P < 0.01); the ET level was obviously decreased and the CGRP level was obviously increased in both groups after treatment (all P < 0.01), and the range of change was more significant in the observation group (P < 0.01). CONCLUSION: Penetration needling through Baihui (GV 20) to Taiyang (EX-HN 5) is an effective treatment for acute apoplexy, which is better than conventional scalp acupuncture.