This study aimed to investigate the gastroprotective effect of chlorogenic acid (CGA) against Indomethacin (IND)-induced gastric ulcer (GU) in rats and its underlying mechanism, especially through ...autophagic and apoptotic pathways.
Seventy-five rats were divided into five groups; control, IND (50 mg/kg, p.o.), CGA (100 mg/kg, p.o., 14 days), IND pretreated with CGA (50 mg/kg or 100 mg/kg, p.o., 14 days). The stomach tissues were examined to calculate the ulcer index and analyze markers of autophagy (beclin-1, LC3-II/LC3-I and p62), lysosomal function (cathepsin-D) and apoptosis (Bcl-2, Bax and caspase-3), along with expression of Akt/mTOR pathway using western blot or ELISA techniques. In addition, viability of gastric mucosal cells was detected by flowcytometry. Structural changes were assessed histologically, while autophagic and apoptotic changes of gastric mucosa were observed by transmission electron microscopy.
CGA exhibited a dose-dependent gastroprotective effect by reversing IND-induced accumulation of autophagic vacuoles, significant reduction in beclin-1, LC3-II/LC3-I, and p62 levels, and down-regulation of p-Akt/p-mTOR expression. CGA100 also restored normal autolysosomal function by modulation of cathepsin-D levels. Furthermore, pretreatment with CGA100 was significantly associated with an increase in antiapoptotic protein Bcl-2 along with a decrease in proapoptotic Bax and caspase-3 proteins in such a way that impairs IND-induced apoptosis. This was confirmed by CGA-induced significant decrease in annexin V+ cells.
The natural compound CGA offers a novel gastroprotective intervention against IND-induced GU through restoration of normal autophagic flux, impairment of apoptosis in a crosstalk mechanism mediated by Akt/mTOR pathway reactivation, and alleviation of IND-induced lysosomal dysfunction.
•Indomethacin (IND) elicits gastric ulcer (GU) in rats.•IND evokes autophagic flux failure and apoptosis.•Chlorogenic acid (CGA) exerts gastroprotective effect against IND-induced GU.•CGA regulates autophagy and apoptosis crosstalk through Akt/mTOR signaling pathway.•CGA abates IND pathological and ultrastructural aberrations in rat gastric mucosa.
Topoisomerases II are ubiquitous enzymes with significant genotoxic effects in many critical DNA processes. Additionally, epidermal growth factor receptor (EGFR) plays pivotal role in tumour growth ...and angiogenesis. A novel series of naphtho2',3':4,5thiazolo3,2-
a
pyrimidine hybrids have been designed, synthesised and evaluated for their topo IIα/EGFR inhibitory and apoptotic inducer activities. Cytotoxicity of the synthesised hybrids was evaluated against MCF-7, A549 and HCT-116 cell lines. Of the synthesised hybrids, 6i, 6a and 6c experienced superior cytotoxic activity compared to doxorubicin and erlotinib against the tested cancer cells. The molecular mechanism of these hybrids revealed their ability to successfully inhibit topo IIα and EGFR activities in micromolar concentration and may serve as topo II catalytic inhibitor. Moreover, these hybrids significantly arrested cell cycle at G2/M phase together with increased p53, caspae-7, caspase-9 levels and Bax/Bcl-2 ratio. The synthesised hybrids showed efficient binding pattern in molecular docking study and have acceptable drug likeness characters.
Inflammasome targeting and controlling dysbiosis are promising therapeutic approaches to control ulcerative colitis. This report is the first to investigate the mechanisms underlying the ...coloprotective effects of rosuvastatin and
and their combined therapy on dextran sodium sulfate (DSS)-induced colitis in high-fat diet (HFD)-fed rats. Our results demonstrate the aggravation of intestinal inflammation as a consequence of an HFD following DSS administration. An association between dyslipidemia, LDL oxidation, CD36 expression, ROS generation, thioredoxin-interacting protein (TXNIP) upregulation, and NLRP3 inflammasome activation was demonstrated by DSS exposure in HFD-fed rats. We demonstrated that rosuvastatin/
significantly suppressed the DSS/HFD-induced increase in colon weight/length ratio, DAI, MDI, and myeloperoxidase, as well as corrected dysbiosis and improved histological characteristics. Additionally, caspase-1 activity and IL-1β-driven pyroptotic activity was significantly reduced. Rosuvastatin/
showed prominent anti-inflammatory effects as revealed by the IL-10/IL-12 ratio and the levels of TNF-α and IL-6. These latter effects may be attributed to the inhibition of phosphorylation-induced activation of NF-κB and a concomitant reduction in the expression of NLRP3, pro-IL-1β, and pro-IL-18. Furthermore, rosuvastatin/
reduced Ox-LDL-induced TXNIP and attenuated the inflammatory response by inhibiting NLRP3 inflammasome assembly. To conclude, rosuvastatin/Lactobacillus offers a safe and effective strategy for the management of ulcerative colitis.
The herbicide paraquat causes fatal lung toxicity by induction of xanthine oxidase, production of free radicals and inflammation. Febuxostat, a xanthine oxidase inhibitor and anti-gout has recently ...shown anti-inflammatory activity. Accordingly, this study was carried out to investigate whether febuxostat may attenuate paraquat-induced lung toxicity and to explore the possible underlying mechanisms.
Rats were administered either vehicle, a single dose of paraquat (30 mg/kg, i.p.), febuxostat (15 mg/kg, oral), or both for 14 successive days. Serum LDH and sRAGE were estimated. Lung tissue xanthine oxidase activity, SOD, TAC, MDA, and RAGE, HMGB1 gene expression, PI3K/Akt and β-catenin protein expression, MMP-9, IL-8, VEGF and COX-2 gene expression were estimated.
Results showed that paraquat induced lung injury characterized by enhanced oxidative stress and inflammation, upregulated RAGE, HMGB1 gene expression, PI3K/Akt and β-catenin protein expression. Administration of febuxostat inhibited the deleterious effects of paraquat on lung through inhibition of xanthine oxidase activity and related oxidative stress, downregulation of RAGE/PI3K/Akt pathway, and suppression of β-catenin protein expression and its downstream inflammatory mediators.
The present study showed that febuxostat may abrogate paraquat-induced lung toxicity and demonstrated a novel mechanism for its ameliorative effects.
Testicular torsion/detorsion (T/D) is a critical medical condition that necessitates prompt surgical intervention to avoid testicular atrophy and infertility. The use of natural compounds may protect ...against the associated detrimental oxidative stress and inflammatory responses. Interestingly, acetyl-11-keto-β-boswellic acid (AKBA), the main active constituent of Boswellia resin, has shown potent inhibitory effect on 5-lipoxygenase enzyme which converts arachidonic acid into inflammatory mediators. Therefore, this study was conducted to assess the protective mechanisms by which AKBA may protect against testicular T/D injury in rats.
Male rats were randomly distributed into five groups: Sham, AKBA (50 mg/kg, p.o.), unilateral testicular T/D, AKBA at two dose levels (25 or 50 mg/kg for 15 successive days) followed by T/D. Histological examination and Johnsen's score were performed to assess testicular injury and perturbations in spermatogenesis. Biochemical parameters included markers of testicular function (serum testosterone), oxidant/antioxidant status (malondialdehyde, glutathione), inflammation (5-lipoxygenase, leukotriene-B4, myeloperoxidase, interleukin-1β, interleukin-6), apoptosis (Bax, Bcl2, caspase-3), DNA integrity (quantitative DNA fragmentation, DNA laddering, PARP-1), energy production (ATP), in addition to p38 MAPK and JNK protein expression.
In a dose dependent manner, AKBA significantly inhibited testicular T/D-induced upregulation of 5-LOX/LTB4 and p38-MAPK/JNK/Bax pathways and their associated downstream inflammatory and apoptotic cascades. These effects were accompanied with ATP replenishment and DNA preservation, resulting ultimately in salvage of the testis.
Unprecedentedly, the present mechanistic study revealed the pathways by which AKBA may inhibit testicular T/D injury and offered a novel protective approach that may attenuate the severity of this condition.
Phenylpyrazolo3,4-dpyrimidine is considered a milestone scaffold known to possess various biological activities such as antiparasitic, antifungal, antimicrobial, and antiproliferative activities. In ...addition, the urgent need for selective and potent novel anticancer agents represents a major route in the drug discovery process. Herein, new aryl analogs were synthesized and evaluated for their anticancer effects on a panel of cancer cell lines: MCF-7, HCT116, and HePG-2. Some of these compounds showed potent cytotoxicity, with variable degrees of potency and cell line selectivity in antiproliferative assays with low resistance. As the analogs carry the pyrazolopyrimidine scaffold, which looks structurally very similar to tyrosine and receptor kinase inhibitors, the potent compounds were evaluated for their inhibitory effects on three essential cancer targets: EGFRWT, EGFRT790M, VGFR2, and Top-II. The data obtained revealed that most of these compounds were potent, with variable degrees of target selectivity and dual EGFR/VGFR2 inhibitors at the IC50 value range, i.e., 0.3–24 µM. Among these, compound 5i was the most potent non-selective dual EGFR/VGFR2 inhibitor, with inhibitory concentrations of 0.3 and 7.60 µM, respectively. When 5i was tested in an MCF-7 model, it effectively inhibited tumor growth, strongly induced cancer cell apoptosis, inhibited cell migration, and suppressed cell cycle progression leading to DNA fragmentation. Molecular docking studies were performed to explore the binding mode and mechanism of such compounds on protein targets and mapped with reference ligands. The results of our studies indicate that the newly discovered phenylpyrazolo3,4-dpyrimidine-based multitarget inhibitors have significant potential for anticancer treatment.
Background
Compatibility of entomopathogenic nematodes (EPNs) with insecticides is a crucial mainstay of integrated pest management (IPM) programs. This study was designed to evaluate the joint ...action of EPN species and insecticides when employed to deter 3rd and 4th larval instars of cabbage white butterfly,
Pieris rapae
L. (Lepidoptera: Pieridae) under laboratory conditions. EPNs
Steinernema carpocapsae
(All strain),
S. feltiae
(Filipjev),
Heterorhabditis bacteriophora
(HP88), and
H. bacteriophora
(Ar-4), at concentrations of 50, 100, and 125 IJs/larva, were tested with 3 insecticides (lambda-cyhalothrin, emamectin benzoate, and indoxacarb) at LC
25
and LC
50
values. Additionally, expression profiles of 2 detoxification genes (CYP6AE120 and PrGSTs1) when the 4th instar larvae were treated by
H. bacteriophora
(HP88) and lambda-cyhalothrin were examined.
Results
Data indicated that statistically significant mortality of 2 larval instars of
P
.
rapae
was observed in vitro among EPN species and pesticide concentrations. At concentration of 50 IJs/larva, LT
50
values were 2.385 and 3.92 days for
S. carpocapsae
(All strain) and
H. bacteriophora
(Ar-4), respectively, on 3rd instar larvae; also, these values were 3.506 and 3.107 days for
S. feltiae
and
H. bacteriophora
(Ar-4), respectively, on 4th instar larvae Lambda-cyhalothrin was the most toxic insecticide, followed by emamectin benzoate and indoxacarb at LC
25
and LC
50
, respectively. An additive effect was observed between EPN species with LC
25
and LC
50
of the tested insecticides, except for lambda-cyhalothrin at LC
50
with
H. bacteriophora
(Ar-4), and indoxacarb, with all EPNs showing antagonistic effects on mortality of 3rd instar larvae after 3 days post-treatment. The interaction between the tested pesticides at LC
25
and LC
50
and EPN species, showed an additive effect, excluding lambda-cyhalothrin at LC
25
with
S. carpocapsae
(All strain) and LC
25
of indoxacarb with
H. bacteriophora
(Ar-4), which showed potentiation effects. The interaction of
S. feltiae
(Filipjev) with tested insecticides at LC
50
exhibited an antagonistic effect on the mortality of 4th instar
P. rapae
larvae after 3 days post-treatment. The expression of both CYP6AE120 and PrGSTs1 was significantly up-regulated with lambda-cyhalothrin, followed by
H. bacteriophora
(HP88) compared to control.
Conclusions
The findings suggested that combining EPNs and the pesticide concentrations can be a practical strategy for managing
P. rapae
and could pave the way to using new control technologies in protecting organic farm vegetables from lepidopteran pests.
With low COVID-19 vaccination coverage, non-pharmaceutical interventions were critical to mitigating the COVID-19 pandemic in Sudan. We explored changes in social contact patterns, risk perception, ...attitudes, and practices toward protective measures during an evolving COVID-19 outbreak in six illustrative communities in Sudan.
This qualitative study took place in six communities in five Sudanese states using focus group discussions with community members and non-participant structured observations in public spaces between March 2021 and April 2021. A total of 117 participants joined 24 group discussions. We used a two-stage thematic analysis.
The perceived importance of compliance with individual preventative measures among those who believe in COVID-19 was higher than observed compliance with behaviors in most study sites. Adherence was consistently low and mainly driven by enforced movement restrictions. As restrictions were lifted, social contacts outside the household resumed pre-COVID-19 levels, and risk perception and individual and institutional adherence to protective measures diminished. We identified an environment that is socially and economically unsupportive of preventive practices, compounded by widespread rumours, misinformation, and mistrust in the government-led response. However, we identified new social habits that can contribute to reducing COVID-19 transmission.
The unfavourable social and economic environment, coupled with the low visibility of the pandemic and pandemic response, has likely modulated the influence of higher risk perception on adopting precautionary behaviours by individuals. Governments and non-governmental actors should increase the visibility of the pandemic and pandemic response, enforce and incentivise infection control measures in public areas, promote emerging preventive social habits, and actively track and address rumours and misinformation related to COVID-19 and COVID-19 vaccines.
Nitrogen is an essential element for maize growth, but excessive application can lead to various environmental and ecological issues, including water pollution, air pollution, greenhouse gas ...emissions, and biodiversity loss. Hence, developing maize hybrids resilient to low-N conditions is vital for sustainable agriculture, particularly in nitrogen-deficient soils. Combining ability and genetic relationships among parental lines is crucial for breeding superior hybrids under diverse nitrogen levels. This study aimed to assess the genetic diversity of maize inbred lines using simple sequence repeat (SSR) markers and evaluate their combining ability to identify superior hybrids under low-N and recommended conditions. Local and exotic inbred lines were genotyped using SSR markers, revealing substantial genetic variation with high gene diversity (He = 0.60), moderate polymorphism information content (PIC = 0.54), and an average of 3.64 alleles per locus. Twenty-one F1 hybrids were generated through a diallel mating design using these diverse lines. These hybrids and a high yielding commercial check (SC-131) were field-tested under low-N and recommended N conditions. Significant variations (
< 0.01) were observed among nitrogen levels, hybrids, and their interaction for all recorded traits. Additive genetic variances predominated over non-additive genetic variances for grain yield and most traits. Inbred IL3 emerged as an effective combiner for developing early maturing genotypes with lower ear placement. Additionally, inbreds IL1, IL2, and IL3 showed promise as superior combiners for enhancing grain yield and related traits under both low-N and recommended conditions. Notably, hybrids IL1×IL4, IL2×IL5, IL2×IL6, and IL5×IL7 exhibited specific combining abilities for increasing grain yield and associated traits under low-N stress conditions. Furthermore, strong positive associations were identified between grain yield and specific traits like plant height, ear length, number of rows per ear, and number of kernels per row. Due to their straightforward measurability, these relationships underscore the potential of using these traits as proxies for indirect selection in early breeding generations, particularly under low-N stress. This research contributes to breeding nitrogen-efficient maize hybrids and advances our understanding of the genetic foundations for tolerance to nitrogen limitations.
Hepatocellular carcinoma (HCC) is a leading cause of cancer related deaths worldwide. It was suggested that albendazole (ABZ) is a powerful inhibitor of several carcinoma types. However, the ...bioavailability of ABZ is very poor. Additionally, the mechanisms underlying the antitumor effects of ABZ may go beyond its tubulin-inhibiting activity. Therefore, we aimed to examine the effects of ABZ suspension (i.p. and p.o.) and ABZ-loaded cubosomes (LC) on the diethylnitrosamine-induced HCC in mice. ABZ-loaded nanoparticles exhibited a mean particle size of 48.17 ± 0.65 nm and entrapped 93.26 ± 2.48% of ABZ. The in vivo absorption study confirmed a two-fold improvement in the relative bioavailability compared with aqueous ABZ suspension. Furthermore, the oral administration of ABZ cubosomal dispersion demonstrated regression of tumor production rates that was comparable with ABZ (i.p.). ABZ relieved oxidative stress, improved liver function, and decreased necroinflammation score. The antiangiogenic activity was evident as ABZ effectively downregulated tissue expression of CD34, mRNA expression of CD309 and VEGF at the protein expression level. Besides, lower levels of MMP-9 and CXCR4 indicated antimetastatic activity. ABZ showed a considerable level of apoptotic activity as indicated by increased mRNA expression level of p53 and the increased Bax/BCL-2 ratio and active caspase-3. Additionally, Ki-67 expression levels were downregulated showing an antiproliferative potential. These protective effects contributed to increasing survival rate of diethylnitrosamine-treated mice. These effects found to be mediated via interrupting ERK1/2-HIF-1α-p300/CREB interactions. Therefore, our findings revealed that disrupting ERK1/2-HIF-1α-p300/CREB interplay might create a novel therapeutic target for the management of HCC.
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•The antitumor effects of albendazole go beyond its tubulin-inhibiting activity.•Albendazole interfered with the ERK1/2-HIF-1α-p300/CREB crosstalk.•Disruption of the ERK1/2-HIF-1α-p300/CREB interaction creates a novel HCC target.•Albendazole-loaded cubosomes exhibited superior antitumor effects against HCC.•Albendazole-loaded cubosomes prolonged survival of diethylnitrosamine-treated mice.
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