Intravenous N-acetylcysteine in respiratory disease with abnormal mucus secretion.

OBJECTIVE: Evidence for the mucolytic and expectorant efficacy of intravenous (IV) N-acetylcysteine (NAC) is limited. This study aimed to evaluate in a large, multicenter, randomized, controlled, subject, and rater-blinded study whether IV NAC is superior to placebo and non-inferior to ambroxol in improving sputum viscosity and expectoration difficulty. PATIENTS AND METHODS: A total of 333 hospitalized subjects from 28 centers in China with respiratory disease (such as acute bronchitis, chronic bronchitis and exacerbations, emphysema, mucoviscidosis, and bronchiectasis) and abnormal mucus secretion were randomly allocated in a 1:1:1 ratio to receive NAC 600 mg, ambroxol hydrochloride 30 mg, or placebo as an IV infusion twice daily for 7 days. Mucolytic and expectorant efficacy was assessed by ordinal categorical 4-point scales and analyzed by stratified and modified Mann-Whitney U statistics. RESULTS: NAC showed consistent and statistically significant superiority to placebo and non-inferiority to ambroxol in change from baseline to day 7 in both sputum viscosity scores [mean (SD) difference 0.24 (0.763), p<0.001 vs. placebo] and expectoration difficulty score [mean (SD) difference 0.29 (0.783), p=0.002 vs. placebo]. Safety findings confirm the good tolerability profile of IV NAC reported from previous small studies, and no new safety concerns were identified. CONCLUSIONS: This is the first large, robust study of the efficacy of IV NAC in respiratory diseases with abnormal mucus secretion. It provides new evidence for IV NAC administration in this indication in clinical situations where the IV route is preferred.

Comparison of intravenous and perineural dexmedetomidine in prolongation of analgesia for peripheral nerve block: a meta-analysis and systematic review.

OBJECTIVE: We conducted a meta-analysis and systematic review to compare the efficacy of perineural vs. intravenous dexmedetomidine as local anesthetic adjuvant. MATERIALS AND METHODS: Two researchers searched MEDLINE, OVID, PubMed, Embase, Cochrane Central, Web of Science and Wanfang data for randomized controlled trials comparing the effect of intravenous vs. perineural injection of dexmedetomidine as a local anesthetic adjuvant in prolongation of analgesia for peripheral nerve block, without any language restrictions. RESULTS: We identified 14 randomized controlled trials. The results revealed that the duration of analgesia [Standard mean difference (SMD): -0.55, 95% CI, (-1.05, -0.05) p=0.032, I2=85.4%] and the duration of sensory block [SMD: -2.68, 95% CI, (-4.53, -0.83) p=0.004, I2=97.3%], were significantly longer, the onset time of motor block [SMD: 0.65, 95% CI, (0.02, 1.27) p=0.043, I2=85.0%] was shorter in the perineural dexmedetomidine group, when compared with the systematic dexmedetomidine group. There was no significant difference in the duration of motor block [SMD: -0.32, 95% CI, (-1.11, -0.46) p=0.416, I2=89.8%] and the onset time of sensory block [SMD: 0.09, 95% CI, (-0.33, 0.52) p=0.668, I2=59.9%] between the two groups. Meanwhile, perineural dexmedetomidine reduced analgesic consumption in 24 hours [SMD: 0.43, 95% CI, (0.06, 0.80) p=0.022, I2=58.7%] compared with the intravenous dexmedetomidine group. CONCLUSIONS: Our meta-analysis currently generates the evidence that perineural dexmedetomidine administration offers advantages not only in prolonging the duration of analgesia and sensory block, but also in shortening the onset time of motor block, when compared with the intravenous administration.

Propofol decreased the etomidate-induced myoclonus in adult patients: a meta-analysis and systematic review.

OBJECTIVE: Myoclonus is one of the main complications of etomidate anesthesia, which would develop into serious consequences during surgery. The present analysis was performed to evaluate systematically the effect of propofol on preventing etomidate-induced myoclonus in adult patients. MATERIALS AND METHODS: Systematic electronic literature search was performed in the databases PubMed, Cochrane Library, OVID, Wanfang and China National Knowledge Infrastructure (CNKI) from inception to May 20, 2021, without any language restrictions. All randomized controlled trials evaluating the efficacy of propofol on preventing etomidate-induced myoclonus were enrolled. The primary outcome included the incidence and degree of etomidate-induced myoclonus. RESULTS: 1,420 patients (with 602 received etomidate anesthesia and 818 received propofol plus etomidate anesthesia) from 13 studies were eventually included. Whatever the intravenous propofol dose for anesthesia induction 0.8-2 mg/kg (RR:4.04, 95% CI [2.42,6.74] p<0.0001, I2=56.5%), or the dose of propofol for anesthesia induction 0.5-0.8 mg/kg (RR:3.26, 95% CI [2.03,5.22] p<0.0001, I2=0%), or the dose of propofol for anesthesia induction 0.25-0.5mg/kg (RR:1.68, 95% CI [1.1,2.56] p=0.0160, I2=0%), combination of propofol and etomidate could significantly decrease the occurrence of etomidate-related myoclonus (RR=2.99, 95% CI [2.40, 3.71] p<0.0001, I2=43.4%), compared with etomidate alone. In addition, propofol plus etomidate attenuated the incidence of mild (RR:3.40, 95% CI [1.7,6.82] p=0.0010, I2=54.3%), moderate (RR:5.4, 95% CI [3.01, 9.67] p<0.0001, I2=12.6%), severe (RR:4.15, 95% CI [2.11, 8.13] p<0.0001, I2=0%) of etomidate-induced myoclonus without adverse effects except for the increased incidence of pain on injection (RR:0.47, 95% CI [0.26, 0.83] p=0.0100, I2=41.5%) compared with etomidate alone. CONCLUSIONS: The meta-analysis currently generates the evidence of combination of propofol with the dosage of 0.25-2 mg/kg and etomidate can alleviate the occurrence and severity of etomidate-induced myoclonus, with decreased incidence of postoperative nausea and vomiting (PONV) and comparative side effects of hemodynamic and respiratory depression of patients in comparison with etomidate alone.

Systematic review: exosomal microRNAs associated with pancreatic cancer for early detection and prognosis.

OBJECTIVE: Pancreatic cancer (PC) is one of the most common malignant tumors of the digestive system with a high degree of malignancy. Currently, there have been many studies on exosomal microRNAs (miRNAs) discovery in pancreatic cancer. This systematic review aimed to give an overview about known exosomal miRNAs and discuss their diagnostic performance, as well as prognostic value in PC. MATERIALS AND METHODS: PubMed and Web of Science were used for systematic literature research for this review. This literature research was mainly to identify studies that performed plasmatic and serological testing for exosomal miRNAs in pancreatic cancer patients and controls. Two independent reviewers separately extracted data on study characteristics and results. RESULTS: In total, nine prior studies were included in this review. Of which, eleven different single exosomal miRNAs and three exosomal miRNA panels were reported. CONCLUSIONS: When single exosomal miRNA was used as a diagnostic tool, the specificity is generally high, but the sensitivity is commonly low. When multiple of exosomal miRNAs were used simultaneously, higher sensitivities can be obtained at relatively reasonable specificity levels with certain miRNA combinations. Developing a combination of miRNA markers may be a promising approach for early detection of pancreatic cancer.

MicroRNA-155 plays critical effects on Th2 factors expression and allergic inflammatory response in type-2 innate lymphoid cells in allergic rhinitis.

OBJECTIVE: Allergic rhinitis (AR) is a chronic inflammatory disease. This study aimed to investigate the role of microRNA-155 (miR-155) in type-2 innate lymphoid cells (ILC2s) on AR. PATIENTS AND METHODS: Nasal mucosa tissues and peripheral blood samples were collected. mRNA expression of miR-155, interleukin-25 (IL-25), and interleukin-33 (IL-33) in nasal mucosa tissues was determined using quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). The AR model was established by injecting with murine IL-33. The frequency of ILC2s was quantified using flow cytometry. MiR-155 agomir or antagomir was intranasally administrated to mice. MiR-155 and helper T cell 2 (Th2) cytokines were measured with quantitative Real-time PCR (qRT-PCR), enzyme-linked immunosorbent assay (ELISA) or Western blotting, respectively. Hematoxylin and eosin (HE) staining was used for the histopathological examination. RESULTS: Compared with controls, mRNA levels miR-155 (p<0.001), IL-25 (p<0.05), and IL-33 (p<0.001) were increased in nasal mucosa tissues of AR patients and AR mice, and ILC2s ratios were enhanced in human peripheral blood (p<0.0001), which were much higher after intranasal administration with miR-155 agomir (p<0.0001). MiR-155 expression of AR mice was significantly reduced after intranasal administration with miR-155 antagomir (p<0.05). Frequencies of ILC2s in human peripheral blood significantly correlated with miR-155 (r=0.4803, p=0.0130). MiR-155 up-regulation markedly increased frequencies of nasal rubbing/sneezing and levels of IL-4, IL-5, IL-9, and IL-13. Pathological changes were worsened after miR-155 agomir and ameliorated after miR-155 antagomir administration. MiR-155 agomir mice (p<0.001) showed higher ILC2s, whereas lower in miR-155 antagomir mice compared to AR mice (p<0.05). CONCLUSIONS: MiR-155 played critical effects on Th2 factor expression and allergic inflammatory response in ILC2 cells in AR.

MiR-122-5p suppresses cell proliferation, migration and invasion by targeting SATB1 in nasopharyngeal carcinoma.

OBJECTIVE: Mounting evidence has suggested that microRNAs (miRNAs) play crucial roles in the progression of nasopharyngeal carcinoma (NPC). However, the molecular mechanism remains not fully understood. We aimed to examine the expression and biological function of miR-122-5p in NPC. MATERIALS AND METHODS: Quantitative Real Time-Polymerase Chain Reaction was conducted to examine the expression of miR-122-5p. Cell Counting Kit-8 assay, colony formation assay, wound healing assay and transwell assay were performed to measure cell proliferation, colony formation, migration and invasion. Luciferase reporter assay and Western blot assay were used to confirm the target gene of miR-122-5p. RESULTS: The results showed that miR-122-5p was significantly downregulated in NPC cell lines. Additionally, it was demonstrated that special AT-rich sequence-binding protein 1 (SATB1) was targeted by miR-122-5p. Furthermore, our results revealed that miR-122-5p inhibits cell proliferation, colony formation, cell migration and cell invasion by targeting SATB1. CONCLUSIONS: Our data suggested that miR-122-5p functions as a tumor suppressor and may be a therapeutic target for NPC.

Haploinsufficiency caused by a nonsense mutation in NCSTN underlying hidradenitis suppurativa in a Chinese family.

Hidradenitis suppurativa (HS) is a chronic disease of follicular occlusion. It involves the axilla, groin, perianal and perineal regions, and is characterized by recurrent draining sinuses, skin abscesses and disfiguring scars. Loss-of-function mutations in the genes encoding γ-secretase have been identified as a cause of HS. We collected skin samples from three patients with HS from a Chinese family carrying a NCSTN mutation (c.1258C>T (p.Q420X)) and three unrelated healthy controls (HCs). Expression level of nicastrin in skin tissue and cultured keratinocytes and fibroblasts of patients and HCs was determined by real-time quantitative PCR and western blotting. We found that the mRNA and protein levels of nicastrin were significantly reduced in the whole skin, epidermis, dermis, and cultured keratinocytes and fibroblasts compared with HCs. Therefore, we conclude that haploinsufficiency of the NCSTN gene caused by the nonsense mutation c.1258C>T (p.Q420X) contributes to the occurrence of HS in this family.

Mechanism of curcumin analog MHMD-induced cell death in A549 lung cancer cells.

OBJECTIVE: To investigate the anticancer properties of a chemosynthetic curcumin analog, (1E,6E)-4-((furan-2-yl)methylene)-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione (C26H22O7, abbreviated MHMD) in A549 cells. MATERIALS AND METHODS: Inverted microscope was used to observe the alteration on cytomorphology. MTT assay was used to detect cell viability. Acridine-orange staining was used to measure autophagy, and AnnexinV/PI staining and Hoechst/PI staining to measure apoptosis and necrosis. RESULTS: MTT assays showed that at 12 h, 24 h, 48 h, MHMD reduced cell viability with an IC50 of 27.46 µM, 18.86 µM, and 11.23 µM, respectively. Typical characteristics were observed in concert with cell death, including treated-cells getting brighter, rounder, and becoming non-adherent gradually. Additionally, acridine-orange staining suggested that autophagy didn't involve in MHMD-induced cell death. However, apoptosis and necrosis played important roles in MHMD-induced cell death by Hoechst33342/PI staining. It showed apoptosis was the main cause at low concentrations (≤ 4 µM), while with the concentrations rising, necrosis was the leading role. AnnexinV/PI staining again indicated the occurrence of apoptosis at 4 µM. Furthermore, the caspases inhibitor z-VAD-fmk could prevent MHMD-induced cell death, which showed much higher cell viability than those only treated with MHMD (4 µM). Moreover, MTT assay also demonstrated that MHMD did possess a greater anti-proliferative ability than curcumin. CONCLUSIONS: The curcumin analog MHMD is able to induce A549 cell death in a time and dose-dependent manner via apoptosis and necrosis. And MHMD could be a more effective drug than curcumin.

Effect of autologous adipose-derived stem cells in renal cold ischemia and reperfusion injury.

OBJECTIVE: The aim of this study was to investigate the effect of autologous adipose-derived stem cells (ADSCs) on renal cold ischemia and reperfusion (I/R) injury via intravenous infusion on rats. METHODS: A renal cold I/R injury rat model was established. Rats were equally randomized into Sham group, Cold I/R group (cold I/R plus culture medium only), and ADSC-treated group (cold I/R plus immediate intrarenal administration of 2 × 10(6) autologous ADSCs, followed by intravenous autologous ADSCs 6 hours after reperfusion). All rats were killed 24 hours after the I/R procedure. RESULTS: Serum creatinine levels were significantly reduced in the ADSC-treated group compared with the Cold I/R group (P < .01). The renal tissue in the ADSC-treated group had well conserved renal architecture compared with the Cold I/R group. The mRNA expression of tumor necrosis factor α was significantly lower and Bcl-2 was higher in the ADSC-treated group than in the Cold I/R group (P < .05). CONCLUSIONS: Autologous ADSC infusions ameliorated renal damage undergoing cold I/R injury and improved the renal function, partly through inhibiting inflammatory reactions and reducing apoptosis.

Extracellular matrix metalloproteinase inducer: a novel poor prognostic marker for human seminomas

OBJECTIVE: Extracellular matrix metalloproteinase inducer (EMMPRIN) is a glycosylated member of the immunoglobulin superfamily whose function in human seminomas is unknown. We have recently determined that EMMPRIN possesses the ability to stimulate fibroblast and endothelial cell matrix metalloproteinase production, and that its expression was frequently up-regulated in several tumours of the urinary system. Thus, EMMPRIN expression might be associated with the progression of human seminomas. The aim of this study was to investigate whether the presence of EMMPRIN in seminoma tissues might help to predict the patients' prognosis. METHODS: Paraffin-embedded tissues from 65 patients with seminomas and 20 normal testes were processed for immunohistochemical staining using a mouse monoclonal antibody generated against human EMMPRIN, as primary antibody, and a biotinylated goat-anti-mouse IgG, as secondary antibody. In addition, the correlation of EMMPRIN expression with clinicopathologic characteristics and patients' prognosis was also analysed. RESULTS: EMMPRIN was detected in cancerous tissues of 53 patients with seminoma, but not normal testes. Thirty- five patients showed weakly to moderately positive and 18 patients intensely positive expression. Moreover, positive EMMPRIN staining correlated significantly with various clinicopathological factors (increased TNM stage and higher histological differentiation type) as well as decreased tumour-specific survival (log-rank, p=0.02). In particular, EMMPRIN expression was an independent prognosticator as shown by Cox regression analysis (p<0.001). CONCLUSION: EMMPRIN expression in a primary tumour predicts an unfavourable prognosis in human seminoma, suggesting its crucial role in the progression of this tumour (AU)

FOXP3 T regulatory cells in lesions of oral lichen planus correlated with disease activity.

OBJECTIVE: The aim of this study was to determine the correlation between the number of FOXP3(+) T cell in lesions and the disease activity of patients with oral lichen planus (OLP). MATERIALS AND METHODS: The expression of FOXP3 was investigated using immunohistochemical staining and real-time RT-PCR in 23 OLP lesions and 12 controls. Changes of FOXP3(+) Treg in peripheral blood from three patients' pre and post-treatment were assessed using flow cytometry. RESULTS: Few FOXP3(+) cells were detected in controls, but an increased number of FOXP3(+) cells were observed in lesions (n = 20, 40.99 +/- 24.68 cells per high-power field - hpf). Furthermore, the frequency of FOXP3(+) Treg in reticular OLP (n = 7, 63.6 +/- 23.2 cells per hpf) was significantly higher than that in erythematous/erosive OLP (n = 13, 28.8 +/- 16.8 cells per hpf, P = 0.001). In addition, negative correlation was found between the number of FOXP3(+) Treg and disease activity (correlation oefficient = -0.557, P = 0.013). The proportion of FOXP3(+) Treg showed remarkable increase in peripheral blood from patients after treatment (1.39 +/- 0.71%vs 4.91 +/- 1.59%). CONCLUSIONS: These data indicated that FOXP3(+) Treg were involved in the pathogenesis of OLP and correlated with disease's subtype and activity.

Activation of the human FP prostanoid receptor disrupts mitosis progression and generates aneuploidy and polyploidy.

Studies have shown prostaglandin F(2alpha) (PGF(2alpha)) to be an endogenous tumor promoter in mouse models of skin carcinogenesis; however, the mechanisms by which PGF(2alpha) affects cell cycle events remain unknown. Here we performed cell cycle analyses on HEK cells stably expressing the human FP receptor and found that treatment with PGF(2alpha) delays mitosis and is associated with an increased expression of cyclin B1 and Cdc2 kinase activity. In addition, multipolar spindles and misaligned chromosomes were observed in a significant proportion of cells treated with PGF(2alpha). Defective cytokinesis was also observed which resulted in gross aneuploidy and polyploidy. Expression of dominant negative Rho attenuated the cell cycle delay and prevented the generation of micronuclei following treatment with PGF(2alpha). This suggests that FP receptor activation of Rho signaling by PGF(2alpha) can interfere with nuclear division. Aneuploidy is associated with genomic instability and may underlie the tumor-promoting properties of PGF(2alpha).