Development Of Drug Resistance Research Articles

Development of mesoporous magnetic nanoparticles supported idarubicin and investigation of apoptotic and cytotoxic effects on cancer cell lines.

Many methods are used for cancer treatment, especially chemotherapy. In addition to the their therapeutic effects, chemotherapeutic drugs also have serious disadvantages, such as not being cell and tissue-specific, causing toxicity in many tissues, and developing drug resistance. Many methods, especially nanocarriers, have been designed to overcome these disadvantages. In this study, we synthesized mesoporous silica iron oxide nanoparticles with different pore diameters and loaded idarubicin (6MFe3O4-NH2-IDA and 35MFe3O4-NH2-IDA). The synthesized molecules were characterized using FT-IR, XRD, and SEM methods. The cytotoxic effects of unbound idarubicin and idarubicin-loaded nanoparticles on MCF7 and HL-60 cell lines were examined by MTT test. Additionally, the expression of anti-apoptotic (Survivin and BCL-2) and apoptotic (BAX, PUMA, and NOXA) genes of the nanoparticles were measured by PCR method. As a result of the analyses, it was seen that nanoparticles with the desired properties and sizes were synthesized. In MTT analysis, it was observed that both nanoparticles dramatically decreased the IC50 value in cell lines. However, the 35MFe3O4-NH2-IDA molecule was found to have lower IC50 values. IC50 values ​​for pristine IDA, 6MFe3O4-NH2, and 35MFe3O4-NH2 at 24h were found to be 3.56, 1.24 and 0.25 µM in the MCF7 cell line and 4.15, 1.16 and 0.34 µM in the HL-60 cell line, respectively. Additionally, apoptotic gene expression increased, and anti-apoptotic gene expression decreased. Our study demonstrates that the effectiveness of idarubicin can be significantly enhanced by its application with mesoporous nanocarriers. This enhancement is attributed to the controlled release of idarubicin from the nanocarrier, which circumvents drug resistance mechanisms, improves drug solubility, and increases the drug-carrying capacity per unit volume due to the porous structure of the carrier. These findings underscore the potential of the synthesized nanocarrier in cancer treatment and provide a clear direction for future research in this field.

MSphere of Influence: When a sequencer is more than a sequencer.

Blake Billmyre uses functional genomics to help understand the biology of fungal pathogens, with an emphasis on evolution of virulence relevant traits and drug resistance. In this mSphere of Influence article, he reflects on how two papers (Liachko et al., "High-resolution mapping, characterization, and optimization of autonomously replicating sequences in yeast," Genome Research, 2013, and Guo et al., "Integration profiling of gene function with dense maps of transposon integration," Genetics, 2013) impacted his research trajectory and goals. These articles show the power of creative use of sequencing as a tool to drive understanding of fundamental biology.

Non-releasing poly (ionic liquid) based hydrogel accelerates diabetic wound healing

Persistent bacterial colonization, abnormal inflammatory responses, and impaired angiogenesis pose significant challenges to effective wound repair, particularly in diabetic wounds. Employing exogenous bioactive substances in wound dressings is a recognized approach to dynamically respond to the wound microenvironment and accelerate the repair process. However, this strategy can lead to the development of drug resistance and induce further tissue damage. To address these challenges, we are synthesizing a novel hydrogel for diabetic wound treatment using functional poly (ionic liquid) and modified dextran. The hydrogel is characterized by its excellent tissue adhesion, exceptional self-healing capacity, and substantial compressive deformation. It exhibits broad antibacterial activity, reduces the expression of pro-inflammatory cytokines and enhances the healing in diabetic wounds. Its efficacy is superior to that of the positive control group. This innovative non-releasing hydrogel presents as a promising alternative to conventional antibiotics, offering significant potential for the treatment and healing of diabetic chronic wounds.

Class Effect Unveiled: PPARγ Agonists and MEK Inhibitors in Cancer Cell Differentiation.

Epithelial-to-mesenchymal transition (EMT) plays a major role in breast cancer progression and the development of drug resistance. We have previously demonstrated a trans-differentiation therapeutic approach targeting invasive dedifferentiated cancer cells. Using a combination of PPARγ agonists and MEK inhibitors, we forced the differentiation of disseminating breast cancer cells into post-mitotic adipocytes. Utilizing murine breast cancer cells, we demonstrated a broad class effect of PPARγ agonists and MEK inhibitors in inducing cancer cell trans-differentiation into adipocytes. Both Rosiglitazone and Pioglitazone effectively induced adipogenesis in cancer cells, marked by PPARγ and C/EBPα upregulation, cytoskeleton rearrangement, and lipid droplet accumulation. All tested MEK inhibitors promoted adipogenesis in the presence of TGFβ, with Cobimetinib showing the most prominent effects. A metastasis ex vivo culture from a patient diagnosed with triple-negative breast cancer demonstrated a synergistic upregulation of PPARγ with the combination of Pioglitazone and Cobimetinib. Our results highlight the potential for new therapeutic strategies targeting cancer cell plasticity and the dedifferentiation phenotype in aggressive breast cancer subtypes. Combining differentiation treatments with standard therapeutic approaches may offer a strategy to overcome drug resistance.

Novel role of circRNAs in the drug resistance of gastric cancer: regulatory mechanisms and future for cancer therapy.

Cancer, including gastric cancer, has become a serious disease that jeopardizes public life. Currently, the main treatment methods are surgery, radiation therapy, and chemotherapy. One of the primary causes of death for patients with gastric cancer is drug resistance. Several mechanisms of anticancer drugs resistance have been reported, including changes in drugs transport and metabolism, mutations in drug targets, changes in DNA repair systems, inhibition of cell apoptosis and autophagy, gastric cancer stem cells, invasion and migration. It is becoming more widely known that non-coding RNAs, like circRNAs, play a critical role in the resistance of drugs used to treat gastric cancer. CircRNAs have a unique structure and function that is related to gastric cancer resistance, cell proliferation, apoptosis, autophagy, DNA repair systems, migration, and invasion. A clear understanding of the molecular mechanism of circRNAs mediated the resistance of gastric cancer drugs will open a new window for the treatment and management of gastric cancer. Therefore, in this review, we will summarize the current mechanism of drug resistance, and finally discuss the molecular mechanism of circRNAs in regulating the development of drug resistance in gastric cancer.

Characteristics and functional bacteria of an efficient benzocaine-mineralizing bacterial consortium

The extensive use of pharmaceutical and personal care products (PPCPs) has led to widespread residual pollution, which increases the risk of the development of drug resistance in pathogenic microorganisms. Benzocaine is a PPCP that is widely used medical anesthesia and in sunscreen. Microorganisms are essential for the degradation of residual PPCPs. However, no studies have reported the microbial degradation of benzocaine. In this study, through continuous enrichment of the initial consortium HJ1, the highly efficient benzocaine-degrading consortium HJ7 was obtained, HJ7 exhibited a degradation rate that was 1.92 times greater than that of HJ1. Methyl 4-aminobenzoate and 4-aminobenzoic acid were identified as major intermediate products during benzocaine biodegradation by consortium HJ1 or HJ7. Methylobacillus (57.8 % ± 0.9 %) and Pseudomonas (22.1 % ± 0.7 %), which are thought to harbor essential species for benzocaine degradation, were significantly enriched in consortium HJ7. Two benzocaine-degrading strains, Pseudomonas sp. A8 and Microbacterium sp. A741, and one methyl 4-aminobenzoate-degrading strain, Achromobacter sp. A5, were isolated from consortium HJ7, and they synergistically mineralized benzocaine. These findings not only provide new insights into the biotransformation of benzocaine but also provide strain resources for the bioremediation of residual benzocaine in the environment.

Prevalence and dynamics of antimalarial drug resistance mutations among the Plasmodium falciparum isolates in TAK Province, Thailand, during the period of 1998-2001.

Despite the overall decline in malaria cases in Thailand, continuous surveillance in endemic areas remains crucial. This retrospective analysis examined Plasmodium falciparum samples from Tak province, Thailand, collected in 1998, 1999, and 2001, to investigate the prevalence and evolution of antimalarial genotypic drug resistance. The study revealed a high prevalence of drug-resistant P. falciparum, particularly to mefloquine and sulfadoxine/pyrimethamine, with significant mutations in genes associated with resistance. Notably, mutations indicative of artemisinin resistance, such as those in the kelch13 gene, were detected at low frequencies, suggesting an evolving resistance pattern. The underlying cause of these resistance mutations appears to be the historical and widespread use of these antimalarial drugs, which exerted selective pressure on the parasite population. These findings underscore the necessity of ongoing surveillance and adaptive control strategies to manage drug resistance, guide treatment policies, and prevent potential outbreaks, even as malaria cases decrease. Continuous monitoring and research are imperative to sustain malaria elimination efforts and address the dynamic challenges posed by evolving drug-resistant strains.

L3MBTL1, a polycomb protein, promotes Osimertinib acquired resistance through epigenetic regulation of DNA damage response in lung adenocarcinoma

Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (EGFR-TKI) approved for patients with EGFR T790M resistance mutations as first- or second-line treatment of EGFR-positive patients. Resistance to Osimertinib will inevitably develop, and the underlying mechanisms are largely unknown. In this study, we discovered that acquired resistance to Osimertinib is associated with abnormal DNA damage response (DDR) in lung adenocarcinoma cells. We discovered that the polycomb protein Lethal(3) Malignant Brain Tumor-Like Protein 1 (L3MBTL1) regulates chromatin structure, thereby contributing to DDR and Osimertinib resistance. EGFR oncogene inhibition reduced L3MBTL1 ubiquitination while stabilizing its expression in Osimertinib-resistant cells. L3MBTL1 reduction and treatment with Osimertinib significantly inhibited DDR and proliferation of Osimertinib-resistant lung cancer cells in vitro and in vivo. L3MBTL1 binds throughout the genome and plays an important role in EGFR-TKI resistance. It also competes with 53BP1 for H4K20Me2 and inhibits the development of drug resistance in Osimertinib-resistant lung cancer cells in vitro and in vivo. Our findings suggest that L3MBTL1 inhibition is a novel approach to overcoming EGFR-TKI-acquired resistance.

Analyzing and Critically Evaluating the Problems of Antiviral Chemotherapy

Antiviral chemotherapy, an indispensable tool in combating viral infections, faces numerous challenges that often undermine its overall effectiveness and application. This review critically examines the multifaceted issues associated with antiviral chemotherapy, drawing on comprehensive data from NCBI, PubMed, and other reputable academic sources. The primary purpose of this research is to analyze and evaluate key problems such as the development of drug resistance, narrow therapeutic windows, limited spectrum of activity, toxicity, high costs, viral latency, and the complexities inherent in combination therapy. These challenges necessitate a delicate and strategic balance in the development, regulation, and application of antiviral drugs. The research methodology included an exhaustive review of peer-reviewed articles and clinical studies sourced from PubMed and NCBI databases, focusing on ten critical challenges in antiviral chemotherapy. The findings underscore the persistent issue of drug resistance, particularly in RNA viruses like HIV and hepatitis C, which demand ongoing innovation in antiviral drug design and implementation. Additionally, the analysis reveals the significant risks posed by the narrow therapeutic index of many antiviral drugs, which often increases the likelihood of adverse effects, thus limiting their safe and effective use. The study also highlights the formidable challenges posed by viral latency and the limited efficacy of current therapies against emerging and re-emerging viral threats. This research significantly contributes to the understanding of the inherent limitations in existing antiviral therapies and underscores the pressing need for more effective, accessible, and safe treatments. The practical significance lies in offering insights that could guide future research, clinical practice, and policy decisions, ultimately improving global health outcomes in the fight against viral diseases.

Exosomes: Key Factors in Ovarian Cancer Peritoneal Metastasis and Drug Resistance.

Ovarian cancer remains a leading cause of death among gynecological cancers, largely due to its propensity for peritoneal metastasis and the development of drug resistance. This review concentrates on the molecular underpinnings of these two critical challenges. We delve into the role of exosomes, the nano-sized vesicles integral to cellular communication, in orchestrating the complex interactions within the tumor microenvironment that facilitate metastatic spread and thwart therapeutic efforts. Specifically, we explore how exosomes drive peritoneal metastasis by promoting epithelial-mesenchymal transition in peritoneal mesothelial cells, altering the extracellular matrix, and supporting angiogenesis, which collectively enable the dissemination of cancer cells across the peritoneal cavity. Furthermore, we dissect the mechanisms by which exosomes contribute to the emergence of drug resistance, including the sequestration and expulsion of chemotherapeutic agents, the horizontal transfer of drug resistance genes, and the modulation of critical DNA repair and apoptotic pathways. By shedding light on these exosome-mediated processes, we underscore the potential of exosomal pathways as novel therapeutic targets, offering hope for more effective interventions against ovarian cancer's relentless progression.

BH3-mimetics or DNA-damaging agents in combination with RG7388 overcome p53 mutation-induced resistance to MDM2 inhibition.

The development of drug resistance reduces the efficacy of cancer therapy. Tumor cells can acquire resistance to MDM2 inhibitors, which are currently under clinical evaluation. We generated RG7388-resistant neuroblastoma cells, which became more proliferative and metabolically active and were less sensitive to DNA-damaging agents in vitro and in vivo, compared with wild-type cells. The resistance was associated with a mutation of the p53 protein (His193Arg). This mutation abated its transcriptional activity via destabilization of the tetrameric p53-DNA complex and was observed in many cancer types. Finally, we found that Cisplatin and various BH3-mimetics could enhance RG7388-mediated apoptosis in RG7388-resistant neuroblastoma cells, thereby partially overcoming resistance to MDM2 inhibition.

Small HBV surface antigendrives regorafenib resistance in HCC via KIAA1429-dependent m6A modification of CCR9.

A substantial body of literature, including our own, points to a connection between hepatitis B virus (HBV) infection and the development of drug resistance in hepatocellular carcinoma (HCC), particularly against sorafenib. However, the influence of HBV on resistance to regorafenib, another therapeutic agent, has been less studied. In this study, we used the GEO database (GSE87630) and clinical samples to demonstrate that C-C motif chemokine receptor 9 (CCR9) was highly expressed in HBV-related HCC and predicted poor overall survival. Its overexpression correlated with HBsAg-positive HCC patients. Both univariate and multivariable Cox regression analysis elucidated CCR9 was an independent risk factor for poor overall survival in HCC patients. Our in vitro findings further revealed that HBV structural proteins, small HBV surface antigen (SHBs), triggered an upregulation of CCR9. Functional assays showed that SHBs enhanced HCC cell proliferation, migration, and invasion, increased ABCB1 and ABCC1 expression, and promoted regorafenib resistance via CCR9. Intriguingly, overexpression of HBV plasmid and an AAV-HBV mouse model both exhibited a significant elevation in global N6-methyladenosine (m6A) levels. Further investigations revealed that SHBs elevated these m6A levels, upregulated CCR9 and stabilized CCR9 mRNA through KIAA1429-mediated m6A modification, with sites 1373 and 1496 on CCR9 mRNA being critical for modification. In conclusion, SHBs promoted HCC progression and regorafenib resistance via KIAA1429-mediatedm6A modification of CCR9. Our findings suggested that CCR9 could be a potential prognostic biomarker and a valuable molecular therapeutic target of regorafenib resistance in HBV-related HCC.

Dynamics-based protein network features accurately discriminate neutral and rheostat positions

In some proteins, a unique class of non-conserved positions is characterized by their ability to generate diverse functional outcomes through single amino acid substitutions. Due to their ability to tune protein function, accurately identifying such “rheostat” positions is crucial for protein design, for understanding the impact of mutations observed in humans, and for predicting the evolution of pathogen drug resistance. However, identifying rheostat positions has been challenging, due – in part – to the absence of a clear structural relationship with binding sites. In this study, experimental data from our prior study of the E. coli lactose repressor protein (LacI) was used to identify rheostat positions for which mutations tune in vivo EC50 for the allosteric ligand “IPTG”. We next used the rheostat assignments to test the hypothesis that rheostat positions have unique dynamic features that will enable their identification. To that end, we integrated all-atom molecular dynamics simulations with perturbation residue response analysis. Results first revealed distinct dynamic behavior in IPTG-bound LacI as compared to apo LacI that was consistent with IPTG's role as an allosteric inducer. Next, we used a variety of dynamic features to build a classification model that discriminates experimentally-characterized rheostat positions in LacI from postions with other types of substitution outcomes. In parallel, we built a second classifier model based on the 3-D structural “static” network features of LacI. In comparative studies, the dynamic model better identified rheostat positions that were >8 Å from the binding site. In summary, our study provides insights into the dynamic characteristics of rheostat positions and suggests that models built on dynamic features may be useful for predicting the locations of rheostat positions in a wide range of proteins.

Distinct cellular uptake patterns of two anticancer unsymmetrical bisacridines and their metabolic transformation in tumor cells

Unsymmetrical bisacridines (UAs) represent a novel class of anticancer agents. Their high cytotoxicity towards multiple human cancer cell lines and inhibition of human tumor xenograft growth in nude mice signal their potential for cancer treatment. Therefore, the mechanism of their strong biological activity is broadly investigated. Here, we explore the efflux and metabolism of UAs, as both strongly contribute to the development of drug resistance in cancer cells. We tested two highly cytotoxic UAs, C-2028 and C-2045, as well as their glucuronic acid and glutathione conjugates in human cancer cell lines (HepG2 and LS174T). As a point of reference for cell-based systems, we examined the rate of UA metabolic conversion in cell-free systems. A multiple reaction monitoring (MRM)-mass spectrometry (MS) method was developed in the present study for analysis of UAs and their metabolic conversion in complex biological matrices. Individual analytes were identified by several features: their retention time, mass-to-charge ratio and unique fragmentation pattern. The rate of UA uptake and metabolic transformation was monitored for 24 h in cell extracts and cell culture medium. Both UAs were rapidly internalized by cells. However, C-2028 was gradually accumulated, while C-2045 was eventually released from cells during treatment. UAs demonstrated limited metabolic conversion in cells. The glucuronic acid conjugate was excreted, whereas the glutathione conjugate was deposited in cancer cells. Our results obtained from cell-free and cell-based systems, using a uniform MRM-MS method, will provide valuable insight into the mechanism of UA biological activity in diverse biological models.

Elucidating the Role of Pro-renin Receptors in Pancreatic Ductal Adenocarcinoma Progression: A Novel Therapeutic Target in Cancer Therapy.

Pancreatic cancer is a highly aggressive malignancy with a very poor prognosis. The 5- year survival in these patients is very low, and most patients develop drug resistance to current therapies, so additional studies are needed to identify the potential role of new drug targets for the treatment of pancreatic cancer. Recent investigations have been performed regarding the roles of pro-renin receptors (PRR) in the initiation and development of cancers. PRR is a component of the local renin-angiotensin system (RAS). Local tissue RAS has been known in diverse organ systems, including the pancreas. Various investigations have implicated that PRRs are associated with the upregulation of various signaling pathways, like the renin-angiotensin system pathway, PI3K/Akt/mTOR, and the Wnt-signaling pathways, to contribute to pathological conditions, including cancer. In this review, we presented an overview of the role of PRR in the progression of pancreatic adenocarcinoma.

Antifungal mechanism of nanosilver biosynthesized with Trichoderma longibrachiatum and its potential to control muskmelon Fusarium wilt

Fusarium oxysporum (Schl.) f.sp. melonis, which causes muskmelon wilt disease, is a destructive filamentous fungal pathogen, attracting more attention to the search for effective fungicides against this pathogen. In particular, Silver nanoparticles (AgNPs) have strong antimicrobial properties and they are not easy to develop drug resistance, which provides new ideas for the prevention and control of muskmelon Fusarium wilt (MFW). This paper studied the effects of AgNPs on the growth and development of muskmelon, the control efficacy on Fusarium wilt of muskmelon and the antifungal mechanism of AgNPs to F. oxysporum. The results showed that AgNPs could inhibit the growth of F. oxysporum on the PDA and in the PDB medium at 100–200 mg/L and the low concentration of 25 mg/L AgNPs could promote the seed germination and growth of muskmelon seedlings and reduce the incidence of muskmelon Fusarium wilt. Further studies on the antifungal mechanism showed that AgNPs could impair the development, damage cell structure, and interrupt cellular metabolism pathways of this fungus. TEM observation revealed that AgNPs treatment led to damage to the cell wall and membrane and accumulation of vacuoles and vessels, causing the leakage of intracellular contents. AgNPs treatment significantly hampered the growth of mycelia in the PDB medium, even causing a decrease in biomass. Biochemical properties showed that AgNPs treatment stimulated the generation of reactive oxygen species (ROS) in 6 h, subsequently producing malondialdehyde (MDA) and increasing protective enzyme activity. After 6 h, the protective enzyme activity decreased. These results indicated that AgNPs destroy the cell structure and affect the metabolisms, eventually leading to the death of fungus.

CCT3/ACTN4/TFRC axis protects hepatocellular carcinoma cells from ferroptosis by inhibiting iron endocytosis

Sorafenib is widely used in treating advanced hepatocellular carcinoma (HCC). However, its effectiveness in prolonging patient survival is limited by the development of drug resistance. To systematically investigate the resistance mechanisms of Sorafenib, an integrative analysis combining posttranslational modification (PTM) omics and CRISPR/Cas9 knockout library screening was conducted. This analysis identified ubiquitination at lysine 21 (K21) on chaperonin-containing TCP1 subunit 3 (CCT3) as being associated with Sorafenib resistance. Transcriptomic data from HCC patients treated with Sorafenib revealed that CCT3 expression was lower in responders compared to non-responders. Experimentally, inhibiting the expression of CCT3 sensitized HCC cells to Sorafenib and enhanced Sorafenib-induced ferroptosis. Additionally, CCT3 was found to interact with ACTN4, hindering the recycling of transferrin receptor protein 1 (TFRC) to the cell membrane, thus obstructing iron endocytosis. Mechanistically, the inhibition of ferroptosis by CCT3 depends on the deubiquitination of K6-linked non-degradative ubiquitination at its K21, which occurs upon Sorafenib treatment. Moreover, CCT3 knockdown enhanced the anti-tumor effects of Sorafenib in nude mice. In summary, we have identified a novel function of the chaperone protein. Targeting the CCT3/ACTN4/TFRC axis offers a promising strategy to enhance ferroptosis and overcome Sorafenib resistance in HCC.

Bithionol eliminates acute myeloid leukaemia stem-like cells by suppressing NF-κB signalling and inducing oxidative stress, leading to apoptosis and ferroptosis

Acute myeloid leukaemia (AML) is a lethal bone marrow neoplasm caused by genetic alterations in blood cell progenitors. Leukaemic stem cells (LSCs) are responsible for the development of AML, drug resistance and relapse. Bithionol is an old anthelmintic drug with potential antibacterial, antiviral, antifungal, anti-Alzheimer, and antitumour properties. In this work, we focused on the anti-AML LSC properties of bithionol. This compound inhibited the viability of both solid and haematological cancer cells, suppressed AML stem-like cells, and inhibited AML growth in NSG mice at a dosage of 50 mg/kg, with tolerable systemic toxicity. Bithionol significantly reduced the levels of phospho-NF-κB p65 (Ser529) and phospho-NF-κB p65 (Ser536) and nuclear NF-κB p65 translocation in AML cells, indicating that this molecule can suppress NF-κB signalling. DNA fragmentation, nuclear condensation, cell shrinkage, phosphatidylserine externalisation, loss of transmembrane mitochondrial potential, caspase-3 activation and PARP-(Asp 214) cleavage were detected in bithionol-treated AML cells, indicating the induction of apoptosis. Furthermore, this compound increased mitochondrial superoxide levels, and bithionol-induced cell death was partially prevented by cotreatment with the selective ferroptosis inhibitor ferrostatin-1, indicating the induction of ferroptosis. In addition, bithionol synergised with venetoclax in AML cells, indicating the translational potential of bithionol to enhance the effects of venetoclax in patients with AML. Taken together, these data indicate that bithionol is a potential new anti-AML drug.

The small non-coding RNA Vaultrc5 is dispensable to mouse development.

Vault RNAs (vtRNAs) are evolutionarily conserved small non-coding RNAs transcribed by RNA polymerase lll. Vault RNAs were initially described as components of the vault particle, but have since been assigned multiple vault-independent functions including regulation of PKR activity, apoptosis, autophagy, lysosome biogenesis, and viral particle trafficking. The full-length transcript has also been described as noncanonical source of miRNAs which are processed in a DICER-dependent manner. As central molecules in vault-dependent and independent processes, vtRNAs have been attributed numerous biological roles including regulation of cell proliferation and survival, response to viral infections, drug resistance, and animal development. Yet, their impact to mammalian physiology remains largely unexplored. To study vault RNAs in vivo, we generated a mouse line with a conditional Vaultrc5 loss of function allele. Because Vaultrc5 is the sole murine vtRNA, this allele enables the characterization of the physiological requirements of this conserved class of small regulatory RNAs in mammals. Using this strain, we show that mice constitutively null for Vaultrc5 are viable and histologically normal but have a slight reduction in platelet counts pointing to a potential role for vtRNAs in hematopoiesis. This work paves the way for further in vivo characterizations of this abundant but mysterious RNA molecule. Specifically, it enables the study of the biological consequences of constitutive or lineage-specific Vaultrc5 deletion and of the physiological requirements for an intact Vaultrc5 during normal hematopoiesis or in response to cellular stresses such as oncogene expression, viral infection, or drug treatment.

Synthesis, structural modification, and biological activity of a novel bisindole alkaloid iheyamine A

Diseases caused by plant viruses and pathogens pose a serious threat to crop yield and quality. Traditional pesticides have gradually developed drug resistance and brought certain environmental safety issues during long-term overuse. There is an urgent need to discover new candidate compounds to address these issues. In this study, we achieved the efficient synthesis of iheyamine A and its derivatives, and discovered their excellent antiviral activities against tobacco mosaic virus (TMV). Most compounds displayed higher antiviral activities against TMV than commercial ribavirin at 500 μg/mL, with compounds 3a (Inactive effect IC50: 162 µg/mL), 3d (Inactive effect IC50: 249 µg/mL), 6p (Inactive effect IC50: 254 µg/mL), and 7a (Inactive effect IC50: 234 µg/mL) exhibiting better antiviral activities than ningnanmycin at 500 μg/mL (Inactive effect IC50: 269 µg/mL). Meanwhile, the structure–activity relationships of this type of compounds were systematically studied. We chose 3a for further antiviral mechanism research and found that it can directly act on viral coat protein (CP). The interaction of 3a and CP was further verified via molecular docking. These compounds also showed broad-spectrum fungicidal activities against 8 plant pathogenic fungi, especially for P. piricola. This study provides a reference for the role of iheyamine alkaloids in combating plant pathogenic diseases.