Kaempferide ameliorates cisplatin-induced nephrotoxicity via inhibiting oxidative stress and inducing autophagy.

Acute kidney injury (AKI) caused by anti-tumor drugs, such as cisplatin, is a severe complication with no effective treatment currently, leading to the reduction or discontinuation of chemotherapy. Natural products or herbal medicines are gradually considered as promising agents against cisplatin-induced AKI with the advantages of multi-targeting, multi-effects, and less resistance. In this study, we investigated the effects of kaempferide, a natural flavonoid extracted from the rhizome of Kaempferia galanga, in experimental AKI models in vitro and in vivo. We first conducted pharmacokinetic study in mice and found a relative stable state of kaempferide with a small amount of conversion into kaempferol. We showed that both kaempferide (10 µM) and kaempferol (10 µM) significantly inhibited cisplatin-caused injuries in immortalized proximal tubule epithelial cell line HK-2. In AKI mice induced by injection of a single dose of cisplatin (15 mg/kg), oral administration of kaempferide (50 mg/kg) either before or after cisplatin injection markedly improved renal function, and ameliorated renal tissue damage. We demonstrated that kaempferide inhibited oxidative stress and induced autophagy in cisplatin-treated mice and HK-2 cells, thus increasing tubular cell viability and decreasing immune responses to attenuate the disease progression. In addition, treatment with kaempferide significantly ameliorated ischemia-reperfusion-induced renal injury in vitro and in vivo. We conclude that kaempferide is a promising natural product for treating various AKI. This study has great implications for promotion of its use in healthcare products, and help to break through the limited use of cisplatin in the clinic.

Attitudes to Being Vaccinated Against COVID-19: A Survey of People With Epilepsy in China.

Objective: We conducted a survey to assess vaccination coverage, vaccination willingness, and variables associated with vaccination hesitancy to provide evidence on coronavirus disease (COVID-19) vaccination strategies. Methods: This anonymous questionnaire study conducted a multicenter, cross-sectional survey of outpatients and inpatients with epilepsy (PWE) registered in epilepsy clinics, in 2021, in 10 hospitals in seven cities of Shandong Province. Results: A total of 600 questionnaires were distributed, and 557 valid questionnaires were returned. A total of 130 people were vaccinated against COVID-19. Among 427 unvaccinated participants, 69.32% (296/427) were willing to receive the COVID-19 vaccine in the future, and the remaining 30.68% (131/427) were unwilling to receive vaccination. Most (89.9%) of the participants believed that the role of vaccination was crucial in response to the spread of COVID-19. A significant association was found between willingness to receive the COVID-19 vaccine and the following variables: age, marital status, level of education, occupation, residence, seizure type, and seizure control after antiepileptic drug therapy. It is noteworthy that education level, living in urban areas, and seizure freedom were significantly related to willingness to receive COVID-19 vaccination. Conclusions: Vaccination is a key measure for the prevention and control of COVID-19, and most PWE are willing to be vaccinated. Vaccine safety, effectiveness, and accessibility are essential in combatting vaccine hesitation and increasing vaccination rates.

Natural products: potential treatments for cisplatin-induced nephrotoxicity.

Cisplatin is a clinically advanced and highly effective anticancer drug used in the treatment of a wide variety of malignancies, such as head and neck, lung, testis, ovary, breast cancer, etc. However, it has only a limited use in clinical practice due to its severe adverse effects, particularly nephrotoxicity; 20%-35% of patients develop acute kidney injury (AKI) after cisplatin administration. The nephrotoxic effect of cisplatin is cumulative and dose dependent and often necessitates dose reduction or withdrawal. Recurrent episodes of AKI result in impaired renal tubular function and acute renal failure, chronic kidney disease, uremia, and hypertensive nephropathy. The pathophysiology of cisplatin-induced AKI involves proximal tubular injury, apoptosis, oxidative stress, inflammation, and vascular injury in the kidneys. At present, there are no effective drugs or methods for cisplatin-induced kidney injury. Recent in vitro and in vivo studies show that numerous natural products (flavonoids, saponins, alkaloids, polysaccharide, phenylpropanoids, etc.) have specific antioxidant, anti-inflammatory, and anti-apoptotic properties that regulate the pathways associated with cisplatin-induced kidney damage. In this review we describe the molecular mechanisms of cisplatin-induced nephrotoxicity and summarize recent findings in the field of natural products that undermine these mechanisms to protect against cisplatin-induced kidney damage and provide potential strategies for AKI treatment.

BmBlimp-1 gene encoding a C2H2 zinc finger protein is required for wing development in the silkworm Bombyx mori.

Cys2-His2 zinc finger (C2H2-ZF) proteins represent the most common class of transcription factors. These factors have great potential for the management of developmental progression by regulating the specific spatiotemporal expression of genes. In this study, we cloned one C2H2-ZF protein gene of Bombyx mori, BGIBMGA000319, that is orthologous to B-lymphocyte-induced maturation protein-1 (Blimp-1); we thus named it as Bombyx mori Blimp-1 (BmBlimp-1). In the silkworm, the BmBlimp-1 gene is specifically upregulated during day 2 of the pupal to adult stage and is highly expressed in wing discs on day 3 of the pupa. Knockdown of its expression level in the pupal stage results in a crumpled-winged silkworm moth. Using the predicted DNA-binding sequences of BmBlimp-1 to search the silkworm genome to screen target genes of BmBlimp-1, 7049 genes were identified to have at least one binding site of BmBlimp-1 on their 1 kb upstream and downstream genome regions. Comparisons of those genes with a reported pupal wing disc transcriptome data resulted in 4065 overlapping genes being retrieved. GO enrichment analysis of the overlapping genes showed that most of the genes were enriched in the binding term. Combining functional annotation and real-time quantitative PCR, 15 genes were identified as the candidate target genes of BmBlimp-1, including several wing cuticular protein genes, chitin synthase A, and wing disc development genes, such as Wnt1, cubitus interruptus (ci) and engrailed (en). Moreover, the amino acid sequence of the zinc finger motif of Blimp-1 gene was highly conserved among the 15 insect species. We propose that BmBlimp-1 is an important regulatory factor in silkworm wing development.

[Applications of the CRISPR/Cas9 system in insects].

The CRISPR/Cas9 (clustered regularly interspaced short palindromic repeat/CRISPR-associated) system guides Cas9 to specific genomic locations by a short RNA search string. This technology enables the systematic interrogation of mammalian genome editing, repairing damaged genes, silencing harmful genes and improving quality traits. In recent years, with the introduction of the CRISPR/Cas9 system for easy, fast and efficient genetic modification, it has been possible to conduct meaningful functional studies in a broad array of insect species, such as Drosophila, Bombyx mori, Aedes aegypti and butterflies et al. In this review, we summarize the application of CRISPR/Cas9 in different insect species, discuss methods for its promotion, and consider its application for future insect studies.

Lasiokaurin derivatives: synthesis, antimicrobial and antitumor biological evaluation, and apoptosis-inducing effects.

Herein, a series of lasiokaurin derivatives were designed and synthesized. All the derivatives together with lasiokaurin and oridonin were tested for their antimicrobial and antiproliferative activity. Compound 16 showed the most promising antimicrobial activity with MICs of 2.0 and 1.0 µg/mL against Gram-Positive bacteria S. aureus and B. subtilis, respectively. All the synthetic lasiokaurin derivatives showed better antiproliferative activity than parent compound lasiokaurin 1. Compound 10 exhibited the strongest cytotoxicity with IC50 values of 0.47 and 0.20 µM against MGC-803 and CaEs-17 cells, accordingly. Moreover, it was shown to have potent antitumor activity in vivo in a murine model of MGC-803 gastric cancer. Preliminary SARs were also concluded based on obtained data. The apoptosis-inducing effects of 10 were further investigated using CaEs-17 cells. The results showed that lasiokaurin derivative 10 could induce apoptosis via mitochondria related pathway and arrest CaEs-17 cell cycle at S phase. Compound 10 could also affect apoptosis-related proteins that was up-regulation of CDK2 and down-regulation of ATM and cyclin A1.

Neurophysiological mechanisms of bradykinin-evoked mucosal chloride secretion in guinea pig small intestine.

AIM: To investigate the mechanism for bradykinin (BK) to stimulate intestinal secretomotor neurons and intestinal chloride secretion. METHODS: Muscle-stripped guinea pig ileal preparations were mounted in Ussing flux chambers for the recording of short-circuit current (Isc). Basal Isc and Isc stimulated by BK when preincubated with the BK receptors antagonist and other chemicals were recorded using the Ussing chamber system. Prostaglandin E2 (PGE2) production in the intestine was determined by enzyme immunologic assay (EIA). RESULTS: Application of BK or B2 receptor (B2R) agonist significantly increased the baseline Isc compared to the control. B2R antagonist, tetrodotoxin and scopolamine (blockade of muscarinic receptors) significantly suppressed the increase in Isc evoked by BK. The BK-evoked Isc was suppressed by cyclooxygenase (COX)-1 or COX-2 specific inhibitor as well as nonselective COX inhibitors. Preincubation of submucosa/mucosa preparations with BK for 10 min significantly increased PGE2 production and this was abolished by the COX-1 and COX-2 inhibitors. The BK-evoked Isc was suppressed by nonselective EP receptors and EP4 receptor antagonists, but selective EP1 receptor antagonist did not have a significant effect on the BK-evoked Isc. Inhibitors of PLC, PKC, calmodulin or CaMKII failed to suppress BK-induced PGE2 production. CONCLUSION: The results suggest that BK stimulates neurogenic chloride secretion in the guinea pig ileum by activating B2R, through COX increasing PGE2 production. The post-receptor transduction cascade includes activation of PLC, PKC, CaMK, IP3 and MAPK.

A new cell counting method to evaluate anti-tumor compound activity.

Determining cell quantity is a common problem in cytology research and anti-tumor drug development. A simple and low-cost method was developed to determine monolayer and adherent-growth cell quantities. The cell nucleus is located in the cytoplasm, and is independent. Thus, the nucleus cannot make contact even if the cell density is heavy. This phenomenon is the foundation of accurate cell-nucleus recognition. The cell nucleus is easily recognizable in images after fluorescent staining because it is independent. A one-to-one relationship exists between the nucleus and the cell; therefore, this method can be used to determine the quantity of proliferating cells. Results indicated that the activity of the histone deacetylase inhibitor Z1 was effective after this method was used. The nude-mouse xenograft model also revealed the potent anti-tumor activity of Z1. This research presents a new anti-tumor-drug evaluation method.

[Therapeutic effect of anti-anaphylaxis granule on chronic urticaria and its impact on serum levels of RANTES].

OBJECTIVE: To investigate the therapeutic effect of Anti-anaphylaxis Granule (AAG) on chronic urticaria and its impact on cytokine of regulated upon activation of normal T cells expressed and secreted (RANTES), eosinophil chemotactic factor (Eotaxin) and tumor necrosis factor-alpha (TNF-alpha). METHODS: The therapeutic effects of AAG and cetirizine on chronic urticaria patients allocated in two groups were observed respectively, and the serum levels of RANTES, Eotaxin and TNF-alpha in patients were measured by ELISA before and after treatment, and were compared with those in normal subjects. RESULTS: The therapeutic effects of AAG group were better in effective rate (88.5% vs 64.0%) and lower in the recurrent rate (5.6% vs 41.9%) than those cetirizine (all P<0.05). Serum levels of RANTES, Eotaxin and TNF-alpha in patients were higher than those in normal subjects (P<0.01), and they could be significantly reduced after AAG treatment (P<0.01). CONCLUSION: AAG has favorite effect for treatment of chronic urticaria, its regulation on serum levels of RANTES, Eotaxin and TNF-alpha may be the mechanism of action.

Involvement of CGRP and CGRPl receptor in nociception in the basolateral nucleus of amygdala of rats.

The present study was performed to investigate the role of calcitonin gene-related peptide (CGRP) and its receptor in nociception in the basolateral nucleus of amygdala (BLA) of rats. Hindpaw withdrawal latencies (HWLs) to noxious thermal and mechanical stimulations were measured by hot plate and Randall Selitto tests. The HWL to both thermal and mechanical stimulations increased significantly after intra-BLA administration of 1.0 or 2.0 nmol CGRP, but not 0.5 nmol, indicating that CGRP plays an anti-nociceptive role in BLA of rats. The anti-nociceptive effect of 1.0 nmol CGRP was blocked significantly by administration of 1.0 or 2.0 nmol CGRP8-37, a selective antagonist of CGRP1 receptor, which suggests that the anti-nociceptive effect of CGRP is mediated by the CGRP1 receptor. Taken together, the results indicate that both CGRP and CGRP1 receptor play important roles in nociceptive modulation in the BLA of rats.

Expression of calcitonin gene-related peptide type 1 receptor mRNA and their activity-modifying proteins in the rat nucleus accumbens.

The calcitonin receptor-like receptor (CRLR) and the orphan receptor RDC-1 have been proposed to be calcitonin gene-related peptide type 1 (CGRP1) receptors, and receptor activity-modifying proteins (RAMPs) determine the ligand specificity of CRLR. Coexpression of RAMP1 and CRLR resulted in functional CGRP1 receptors; the complex of RAMP2 or RAMP3 and CRLR created functional adrenomedullin receptor. Although high levels of CGRP binding sites in the nucleus accumbens have been reported, little is known about the expression of these novel CGRP receptors. In the present study, we used real-time quantitative RT-PCR to detect and quantitate the relative expression of CGRP, CRLR, RAMP1-3 and RDC-1 in the nucleus accumbens of intact rats and rats with inflammation. Our results demonstrate that CGRP, CRLR, RAMP1 and RAMP2 exist in the nucleus accumbens of intact rats, and that they were significantly upregulated in rats with inflammation. In contrast, no expression was detected for RDC-1 and RAMP3. These findings indicated a functional role for CGRP and its receptors in inflammation and pain modulation.