Search Results (131)

Invasive alien plants (IAPs) disrupt biodiversity, ecosystem functions, rural livelihoods, and human health/well-being. Hence, the negative impact of Cenchrus setaceus (syn. Pennisetum setaceum) as an invasive weed poses many concerns in terms of environmental and socio-economic impact. The abundance in previous research on invasion ecology, weed biology, and the management of C. setaceus establishes the chance to carry out an in-depth evaluation of this invasive alien species for a cohesive understanding, closely linked to policy development. This systematic review aims to provide a comprehensive evaluation of previous research, identify knowledge gaps, and incorporate recent practical research findings on C. setaceus to elucidate management options. Standard methods were used to collect the literary evidence on multiple thematic aspects linked with its traits and management. Results revealed the substantial negative impacts of C. setaceus on ecosystems, ascribed to multiple physiological, biochemical, and ecological features. Further, a multitude of plant traits such as rapid seed distribution and efficient reproductive strategies imposed serious challenges in the control of C. setaceus. Deployment of integrated control methods for at least three years in depleting seed bank conjunction by planting native grass may help in its confinement. In conclusion, policy measures like strict biosecurity/legal regulations, explicit elucidation of weed biology, early detection and response, ecological modeling, and long-term monitoring with community participation can expand the horizon of C. setaceus control and help achieve its sustainable management. Full article

Background: Chronic inflammation and the development of cancer are closely linked, with components that comprise the tumour microenvironment—including proinflammatory cytokines—exerting essential tumourigenic effects. These proinflammatory cytokines include IL-1β, which has been reported to be overexpressed in several cancers and shown to activate several signalling pathways. These pathways may involve kinases such as AKT (serine/threonine kinase) and Src (Proto-oncogene tyrosine-protein kinase), and have a broad capacity to activate nuclear factors, including NF-κB (Nuclear Factor kappa-light-chain-enhancer of activated B cells), which can regulate the transcription of genes encoding proteins such as cIAP1 (Cellular Inhibitor of Apoptosis Protein 1), Bcl-2 (B-cell lymphoma 2), and cyclin D1, thereby regulating processes like apoptosis and cell cycle inhibition. Objectives: The aim of this study was to investigate the role of IL-1β (Interleukin-1 beta) in regulating cell death and proliferation in RS4:11 leukaemic lymphoblasts via the PI3K (Phosphoinositide 3-kinase)/AKT/Src/NF-κB pathway using an in vitro experimental approach. Methods: We employed flow cytometry to determine the expression levels and phosphorylation status of various proteins; proliferation was assessed using the CCK-8 kit, and apoptosis was evaluated with the Annexin V kit. Results: Our findings indicate that the IL-1β-activated signalling pathway modulates these cellular processes in leukaemic lymphoblasts. Conclusions: We therefore conclude that IL-1β exerts significant effects on cell death and proliferation in leukaemic lymphoblasts through the PI3K/AKT/NF-κB pathway, with the study’s findings indicating that an inflammatory environment may promote such lymphoblasts to acquire neoplastic characteristics. As such, the proteins involved in the effects evaluated in this work could be considered as potential therapeutic targets for the treatment of Acute Lymphoblastic Leukaemia (ALL). Full article

Repetitive non-concussive head impacts (NCHIs) may contribute to long-term neurodegenerative conditions. However, objective, multimodal methods for monitoring acute changes in brain health biomarkers following NCHIs remain underdeveloped. In this exploratory study, we examined the effects of ten kicking and ten heading trials related to association football on linear and nonlinear measures of postural control and corticospinal inhibition. Postural control was assessed via force platform analysis in dual-stance and single-leg protocols, and corticospinal inhibition was measured using transcranial magnetic stimulation with electromyography. Large effects of condition were found for anteroposterior postural complexity (CI-AP), anteroposterior sway amplitude, mediolateral centre of pressure shift and cortical silent period (η² > 0.14). Pairwise comparisons revealed large post-heading effects, particularly in CI-AP, which decreased significantly relative to baseline (d_z = 0.71, p = 0.018) and showed a moderate negative effect relative to post-kicking testing (d_z = 0.53, p = 0.069). These findings suggest a possible reduction in postural control adaptability following exposure to ten NCHIs, consistent with patterns observed in mild traumatic brain injury. Whilst confirmatory research with larger samples is warranted, nonlinear measures of postural control complexity demonstrate promise as a sensitive biomarker for detecting acute NCHI-related changes. Full article

Background/Objectives: Obesity and dysglycemia are increasingly associated with intestinal barrier dysfunction and alterations in gut microbiota. Intestinal hyperpermeability is emerging as a therapeutic target in metabolic disorders, but human data integrating barrier biomarkers, epithelial morphology, and microbial composition remain scarce. Methods: Forty-six adults (82.6% female; 38.3 ± 7.8 years) were stratified into lean normoglycemic controls (CON), individuals with obesity and normoglycemia (NOB), and those with obesity and dysglycemia (DOB). Biochemical/inflammatory biomarkers, such as lipopolysaccharide (LPS) and LPS-binding protein (LBP), were measured. Duodenal biopsies were obtained by upper digestive videoendoscopy. Histomorphometry, expression of junctional and cytoskeletal proteins, and enzymatic activity of the duodenal epithelium were used as markers of intestinal permeability. Fecal microbiota composition (FMC) was analyzed by amplifying the V4 region of the 16S rRNA gene, which was sequenced using next-generation sequencing technology. Results: Duodenal histomorphometry did not differ across groups. Intestinal alkaline phosphatase (IAP) was significantly lower in DOB compared to CON. LPS correlated positively with fat mass, and LBP with the waist-to-hip ratio. The villus-to-crypt ratio correlated negatively with BMI, while IAP correlated inversely with fasting glucose and HbA1c. β-actin expression was inversely associated with BMI, glucose, insulin, and HOMA-IR. Microbiota diversity indices were similar between groups, although specific taxa, particularly within the Clostridiales order, were reduced in dysglycemia. Conclusions: Reduced IAP activity and consistent correlations between barrier biomarkers and metabolic parameters highlight intestinal barrier dysfunction as a relevant feature of obesity and dysglycemia. Subtle microbiota alterations further support a link between gut ecology and metabolic control. These findings underscore the intestinal barrier as a promising therapeutic target in metabolic disorders. Full article

Advanced renal cell carcinoma (RCC) has a poor prognosis; this drives the exploration of alternative systemic therapies to identify more effective treatment options. Recent research has revealed that crebanine, an alkaloid derivative of the Stephania genus, induces apoptotic effects in various cancers; however, a thorough investigation of the role of crebanine in RCC has not been conducted thus far. For this study, we evaluated tumor cell viability, clonogenicity, cell-cycle distributions, morphological changes, and cell mortality with the aim of exploring the antitumor effects of crebanine in RCC. Furthermore, we compared gene and protein expressions using RNA sequencing analysis and Western blotting. The findings indicated that crebanine significantly inhibited RCC colonies and caused G1-phase cell-cycle arrest with sub-G1-phase accumulation, thus leading to suppressed cell proliferation and cell death. In addition, Hoechst 33342 staining was used to observe apoptotic cells, which revealed chromatin condensation and a reduction in the nuclear volume associated with apoptosis. Further, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that differentially expressed genes are involved in the initiation of DNA replication, centrosome duplication, chromosome congression, and mitotic processes in the cell cycle along with signaling pathways, such as I-kappaB kinase/NF-kappaB signaling, Hippo signaling, and intrinsic apoptotic pathways. Consistent with GO and KEGG analyses, increased levels of cleaved caspase-3, cleaved caspase-7, and cleaved PARP, and decreased levels of cIAP1, BCL2, survivin, and claspin were observed. Finally, the expressions of G1/S phase transition cyclin D1, cyclin E/CDK2, and cyclin A2/CDK2 complexes were downregulated. Overall, these findings supported the potential of crebanine as an adjuvant therapy in RCC. Full article

Background/Objectives: Retinoic acid has been shown to inhibit melanoma progression; however, its underlying mechanisms remain unclear. In this study, we investigated the role of the retinoic acid-inducible gene TIG3 in regulating melanoma cell growth, as well as elucidating its involvement in apoptosis. Methods: The expression of TIG3 in melanoma tissues was analyzed using a cDNA microarray. Cell viability and cell death were measured using the WST-1 and LDH assay kits, respectively. The gene expression changes that were induced by TIG3 were identified through RNA sequencing, while apoptosis-related pathways were examined using a human apoptosis protein array. The protein expression levels were further validated using Western blot analysis. Results: TIG3 expression was significantly downregulated in melanoma tissues. The overexpression of TIG3 in melanoma cells led to reduced cell viability and increased cell death. TIG3 suppressed the expression of several apoptosis-regulating proteins, including PON2, Fas, cIAP-1, Claspin, Clusterin, HTRA2, and Livin, while promoting the expression of cleaved Caspase-3. Supplementation with cIAP-1, HTRA2, or Livin partially reversed TIG3-induced Caspase-3 expression and cell death. Conclusions: Our findings suggest that TIG3 may contribute to the anti-melanoma effects of retinoic acid, with IAP family proteins playing a key role in the TIG3-mediated regulation of melanoma cell survival. Full article

Transcription factors (TFs) play central roles in gene regulation and disease progression but have long been considered undruggable due to the absence of well-defined binding pockets and their reliance on protein–protein or protein–DNA interactions. Proteolysis-targeting chimeras (PROTACs) offer a novel strategy to overcome these limitations by inducing selective degradation of TFs via the ubiquitin–proteasome system. This review highlights recent advances in TF-targeting PROTACs, focusing on key oncogenic TFs such as androgen receptor (AR), estrogen receptor alpha (ERα), BRD4, c-Myc, and STAT family members. Strategies for ligand design—including small molecules, peptides, and nucleic acid-based elements—are discussed alongside the use of various E3 ligases such as VHL, CRBN, and IAP. Several clinically advanced PROTACs, including ARV-110 and ARV-471, demonstrate the therapeutic potential of this technology. Despite challenges in pharmacokinetics and E3 ligase selection, emerging data suggest that PROTACs can successfully target TFs, paving the way for new treatment strategies across oncology and other disease areas. Full article

Objectives: The aim of this study was to evaluate the effects of spinal cord stimulation (SCS) on pain, neuropathic symptoms, and other health-related metrics in patients with chronic painful peripheral neuropathy (PN) from multiple etiologies. Methods: A prospective single center observational longitudinal cohort study assessed SCS efficacy from April 2023 to May 2024, with follow-ups at 2, 4, 6, and 12 months in 19 patients suffering from the painful polyneuropathy of diverse etiologies: diabetic (DPN), idiopathic (CIAP), chemotherapy-induced (CIPN), and others. Patients were implanted with a neurostimulator (WaveWriter Alpha^TM, Boston Scientific Corporation, Valencia, CA, USA) and percutaneous leads targeting the lower limbs (T10–T11) and, if necessary, the upper limbs (C4–C7). Stimulation programming was individualized based on patient preference and best response. Assessments were performed before and after implantation and included pain intensity (VAS and DN4), neuropathic pain symptoms (NPSI and SF-MPQ-2), autonomic symptoms (SFN-SIQ and SAS), sensory and small fiber nerve injury (UENS), functionality (GAF), sleep (CPSI), global impression of change (CGI and PGI), and quality of life (EQ-VAS and EQ-5D). Intra-epidermal nerve fiber density (IENFD) via skin biopsy was also performed at baseline (diagnostic) and after 12 months to assess potential small fiber re-growth. Statistical analyses were conducted to determine the evolution of treatment success. Results: To date, 19 patients have undergone implantation and completed follow-up. SCS produced a significant consistent and sustained improvement in pain intensity by 49% in DN4 and 76% in VAS, in neuropathic pain symptoms by 73%, in autonomic symptoms by 26–30%, in the sensorimotor physical exam by 8%, in functionality by 44%, in sleep by 74%, and in quality of life (69% for EQ-VAS and 134% EQ-5D). Both clinicians and patients had a meaningful global impression of change, at 1.1 and 1.3, respectively. Distal intra-epidermal nerve fiber density improved by 22% at 12 months while proximal intra-epidermal nerve fiber density decreased by 18%. Conclusions: SCS is an effective therapy for managing various types of PN. Full article

Receptors for advanced glycation end products (RAGE) are multiligand cell surface receptors found most abundantly in lung tissue. This study sought to evaluate the role of RAGE in lung development by using a transgenic (TG) mouse model that spatially and temporally controlled RAGE overexpression. Histological imaging revealed that RAGE upregulation from embryonic day (E) 15.5 to E18.5 led to a thickened alveolar parenchyma and reduced alveolar surface area, while RAGE overexpression from E0 to E18.5 caused a significant loss of tissue and decreased architecture. Mitochondrial dysfunction was a hallmark of RAGE-mediated disruption, with decreased levels of anti-apoptotic BCL-W and elevated pro-apoptotic BID, SMAC, and HTRA2, indicating compromised mitochondrial integrity and increased intrinsic apoptotic activity. Extrinsic apoptotic signaling was similarly dysregulated, as evidenced by the increased expression of TNFRSF21, Fas/FasL, and Trail R2 in E0-18.5 RAGE TG mice. Additionally, reductions in IGFBP-3 and IGFBP-4, coupled with elevated p53 and decreased p27 expression, highlighted disruptions in the cell survival and cycle regulatory pathways. Despite the compensatory upregulation of inhibitors of apoptosis proteins (cIAP-2, XIAP, and Survivin), tissue loss and structural damage persisted. These findings underscore RAGE’s role as a pivotal modulator of lung development. Specifically, the timing of RAGE upregulation significantly impacts lung development by influencing pathways that cause distinct histological phenotypes. This research may foreshadow how RAGE signaling plausibly contributes to developmental lung diseases. Full article

Jacaranone derived from Senecio scandens, a traditional Chinese medicine used for centuries, has been documented to exhibit anti-inflammatory and antiproliferative properties in various tumor cell lines. However, the mechanism of action and relationship between inflammation and apoptosis induced by jacaranone remain inadequately elucidated. In this study, the targets of jacaranone and cancer were identified from various databases, while potential targets and pathways were predicted through the analysis of the protein–protein interactions (PPI) network and pathway enrichment. Through a comprehensive network pharmacology analysis and corroborating experimental findings, we revealed that jacaranone induces tumor cell death by fine-tuning the tumor necrosis factor receptor 1 (TNFR1) downstream signaling pathway. TNFR1 serves as a key node that assembles into complexes I and II, regulating pathways including the nuclear factor (NF)-κB signaling pathway and the cell apoptosis pathway, which play crucial roles in cellular life activities. Jacaranone successfully guides survival signaling pathways to apoptotic mechanisms by inhibiting the assembly of complex I and promoting the formation of complex II. In particular, the main action mechanism of jacaranone lies in inducing the degradation of the inhibitor of apoptosis protein (cIAP)-2. cIAP-2 serves as an E3 ubiquitin ligase that ubiquitinates receptor-interacting serine/threonine-protein kinase 1 (RIPK1), thereby hindering the formation of complex I and effectively reducing the phosphorylation of Inhibitor of κB kinase (IKK) β. When the deubiquitylation process of RIPK1 is triggered, it may promote the formation of complex II, which ultimately leads to cell apoptosis. This fully demonstrates the key role of jacaranone in regulating TNFR1 complexes, especially through the degradation of cIAP-2. Taken together, jacaranone hinders the assembly of TNFR1 complex I and promotes the formation of complex II to induce apoptosis of cancer cells. Our findings unveil a novel mechanism underlying jacaranone, while also presenting a fresh approach for the development of new pharmaceuticals. Full article

Background: Breast cancer influences more than 2 million women worldwide annually. Since apoptotic dysregulation is a cancer hallmark, targeting apoptotic regulators encompasses strategic drug development for cancer therapy. One such class of apoptotic regulators is inhibitors of apoptosis proteins (IAP) which are a class of E3 ubiquitin ligases that actively function to support cancer growth and survival. Methods: The current study reports design, synthesis, docking analysis (based on binding to IAP-BIR3 domains), anti-proliferative and anti-tumor potential of the azomethine derivative, 1-(4-chlorophenyl)-N-(4-ethoxyphenyl)methanimine (BCS3) on breast cancer (in vitro and in vivo) and its possible mechanisms of action. Results: Strong selective cytotoxic activity was observed in MDA-MB-231, MCF-7, and MDA-MB-468 breast cancer cell lines that exhibited IC50 values, 1.554 µM, 5.979 µM, and 6.462 µM, respectively, without affecting normal breast cells, MCF-10A. For the evaluation of the cytotoxic potential of BCS3, immunofluorescence, immunoblotting, and FACS (apoptosis and cell cycle) analyses were conducted. BCS3 antagonized IAPs, thereby causing MDM2-p53 and Bcl-2-Caspase-mediated intrinsic and extrinsic apoptosis. It also modulated p53 expression causing p21-CDK1/cyclin B1-mediated cell cycle arrest at S and G2/M phases. The in vitro findings were consistent with in vivo findings as observed by reduced tumor volume and apoptosis initiation (TUNEL assay) by IAP downregulation. BCS3 also produced potent synergistic effects with doxorubicin on tumor inhibition. Conclusions: Having witnessed the profound anti-proliferative potential of BCS3, the possible adverse effects related to anti-cancer therapy were examined following OECD 407 guidelines which confirmed its systemic safety profile and well tolerability. The results indicate the promising effect of BCS3 as an IAP antagonist for breast cancer therapy with fewer adverse effects. Full article

The natural 5-azaindoles, marine sponge guitarrin C and D, were observed to exert inhibitory activity against a highly active alkaline phosphatase (ALP) CmAP of the PhoA family from the marine bacterium Cobetia amphilecti, with IC₅₀ values of 8.5 and 110 µM, respectively. The superimposition of CmAP complexes with p-nitrophenyl phosphate (pNPP), a commonly used chromogenic aryl substrate for ALP, and the inhibitory guitarrins C, D, and the non-inhibitory guitarrins A, B, and E revealed that the presence of a carboxyl group at C6 together with a hydroxyl group at C8 is a prerequisite for the inhibitory effect of 5-azaindoles on ALP activity. The 10-fold more active guitarrin C could compete with pNPP for binding sites in the ALP active site due to similarities in size, three-dimensional structure, and the orientation of the COOH group along the phosphate group. However, the inhibition of CmAP and calf intestinal ALP (CIAP) by guitarrin C was observed to occur via a non-competitive mode of action, as evidenced by a twofold decrease in V_max and an unchanged K_m. In contrast, the kinetic model with guitarrin D, with an additional OH group at C7, reflected a mixed type of inhibition, with a decrease in both values. The sensitivity of CIAP to guitarrins C and D was shown to be slightly lower than that of CmAP, with IC₅₀ values of 195 and 230 µM, respectively. Nevertheless, these findings prompted the prediction of complexes of human ALP isoenzymes with guitarrins C and D. Full article

Many plant viruses are transmitted by insect vectors, and the transmission process is regulated by key genes within the vector. However, few of these genes have been reported. Previous studies in our laboratory have shown that the expression of the signal transducer and activator of transcription 5B (STAT5B) in viruliferous vector aphids carrying barley yellow dwarf virus (BYDV) was upregulated, and the complement component 1 Q subcomponent binding protein (C1QBP) within the aphid interacted with the coat protein (CP) and aphid transmission protein (ATP) of BYDV. In this study, we examined the expression levels of STAT5B and C1QBP in the vector aphid Sitobion avenae (Fabricius) (Hemiptera: Aphididae) using the qPCR method. We conducted this analysis during the acquisition accession periods (AAPs) and inoculation accession periods (IAPs) of the BYDV species GAV (BYDV-GAV). Furthermore, the effects of STAT5B and C1QBP on the acquisition, retention, and transmission of BYDV-GAV in S. avenae were verified using the RNA interference (RNAi) method. The results show the following: (1) the expression levels of STAT5B and C1QBP were significantly upregulated during the AAPs and IAPs of BYDV-GAV; (2) the silencing of STAT5B led to a significant increase in BYDV-GAV retention during IAPs; and (3) the silencing of C1QBP resulted in a notable decrease in BYDV-GAV acquisition during the AAPs, as well as a significant increase in BYDV-GAV retention during the IAPs. These results suggest that STAT5B and C1QBP in S. avenae play a role in BYDV-GAV transmission. These findings highlight the functions of the STAT5B and C1QBP genes and identify C1QBP as a potential target gene for further RNAi-based studies to control the transmission of BYDV-GAV. Full article

The use of CpGV strains as the basis for bioinsecticides is an effective and safe way to control Cydia pomonella. The research is aimed at the identification and study of new CpGV strains. Objects of identification and bioinformatic analysis: 18 CpGV strains. Sequencing was carried out on a NextSeq550. Genome assembly and annotation were carried out using Spades, Samtools 1.9, MinYS, Pilon, Gfinisher, Quast, and Prokka. Comparative genomic analysis was carried out in relation to the reference genome present in the «Madex Tween» strain-producer (biological standard) according to the average nucleotide identity (ANI) criterion. The presence/absence of IAP, cathepsin, MMP, and chitinase in the genetic sequences of the strains was determined using simply phylogeny. Entomopathogenic activity was assessed against C. pomonella according to the criterion of biological efficacy. Thus, molecular genetic identification revealed that 18 CpGV strains belong to a genus of Betabaculovirus. For all the strains under study ANI values of 99% or more were obtained, and the presence of the cathepsin, chitinase, IAP, and MMP genes was noted. The strains BZR GV 1, BZR GV 3, BZR GV 7, BZR GV 10, and BZR GV L-8 showed the maximum biological efficacy: 100% on the 15th day of observation. Strains BZR GV 4, BZR GV 8, and BZR GV 13 showed efficacy at the level of the «Madex Tween» preparation: 89.5% on the 15th day of observation. The strains with the highest mortality rate of the host insect were identified: BZR GV 9, BZR GV 10, BZR GV L-6, and BZR GV L-8. Full article

Survivin, a member of the IAP family, functions as a homodimer and inhibits caspases, the key enzymes involved in apoptosis. Several Survivin inhibitors, including YM-155, Debio1143, EM1421, LQZ-7I, and TL32711, have emerged as potential anticancer drugs awaiting validation in clinical trials. Due to the high cost and adverse side effects of synthetic drugs, natural compounds with similar activity have also been in demand. In this study, we conducted molecular docking assays to evaluate the ability of Wi-A and Wi-N to block Survivin dimerization. We found that Wi-A, but not Wi-N, can bind to and prevent the homodimerization of Survivin, similar to YM-155. Therefore, we prepared a Wi-A-rich extract from Ashwagandha leaves (Wi-AREAL). Experimental analyses of human cervical carcinoma cells (HeLa and ME-180) treated with Wi-AREAL (0.05–0.1%) included assessments of viability, apoptosis, cell cycle, migration, invasion, and the expression levels (mRNA and protein) of molecular markers associated with these phenotypes. We found that Wi-AREAL led to growth arrest mediated by the upregulation of p21^WAF1 and the downregulation of several proteins (CDK1, Cyclin B, pRb) involved in cell cycle progression. Furthermore, Wi-AREAL treatment activated apoptosis signaling, as evidenced by reduced PARP-1 and Bcl-2 levels, increased procaspase-3, and elevated Cytochrome C. Additionally, treating cells with a nontoxic low concentration (0.01%) of Wi-AREAL inhibited migration and invasion, as well as EMT (epithelial–mesenchymal transition) signaling. By combining computational and experimental approaches, we demonstrate the potential of Wi-A and Wi-AREAL as natural inhibitors of Survivin, which may be helpful in cancer treatment. Full article