International Journal of Molecular Sciences

Peptides are potential therapeutic alternatives against global diseases, such as antimicrobial-resistant infections and cancer. Venoms are a rich source of bioactive peptides that have evolved over time to act on specific targets of the prey. Peptides are one of the main components responsible for the biological activity and toxicity of venoms. South American organisms such as scorpions, snakes, and spiders are important producers of a myriad of peptides with different biological activities. In this review, we report the main venom-derived peptide families produced from South American organisms and their corresponding activities and biological targets. Full article

The renal condition is one of the crucial predictors of longevity; therefore, early diagnosis of any dysfunction plays an important role. Kidneys are highly susceptible to the aging process. Unfavorable conditions may lead to a significant disturbance of the body’s homeostasis. Apart from physiological changes, there are some conditions such as hypertension, diabetes or obesity which contribute to the acceleration of the aging process. A determination of macroscopic and microscopic changes is essential for assessing the progression of aging. With age, we observe a decrease in the volume of renal parenchyma and an increase in adipose tissue in the renal sinuses. Senescence may also be manifested by the roughness of the kidney surface or simple renal cysts. The main microscopic changes are a thickening of the glomerular basement membrane, nephrosclerosis, an accumulation of extracellular matrix, and mesangial widening. The principal aspect of stopping unfavorable changes is to maintain health. Studies have shown many useful ways to mitigate renal aging. This review is focused especially on medications such as renin-angiotensin-aldosterone system blockers or resveratrol, but even eating habits and lifestyle. Full article

Mucositis is a common and most debilitating complication associated with the cytotoxicity of chemotherapy. The condition affects the entire alimentary canal from the mouth to the anus and has a significant clinical and economic impact. Although oral and intestinal mucositis can occur concurrently in the same individual, these conditions are often studied independently using organ-specific models that do not mimic human disease. Hence, the purpose of this scoping review was to provide a comprehensive yet systematic overview of the animal models that are utilised in the study of chemotherapy-induced mucositis. A search of PubMed/MEDLINE and Scopus databases was conducted to identify all relevant studies. Multiple phases of filtering were conducted, including deduplication, title/abstract screening, full-text screening, and data extraction. Studies were reported according to the updated Preferred Reporting Items for Systematic reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines. An inter-rater reliability test was conducted using Cohen’s Kappa score. After title, abstract, and full-text screening, 251 articles met the inclusion criteria. Seven articles investigated both chemotherapy-induced intestinal and oral mucositis, 198 articles investigated chemotherapy-induced intestinal mucositis, and 46 studies investigated chemotherapy-induced oral mucositis. Among a total of 205 articles on chemotherapy-induced intestinal mucositis, 103 utilised 5-fluorouracil, 34 irinotecan, 16 platinum-based drugs, 33 methotrexate, and 32 other chemotherapeutic agents. Thirteen articles reported the use of a combination of 5-fluorouracil, irinotecan, platinum-based drugs, or methotrexate to induce intestinal mucositis. Among a total of 53 articles on chemotherapy-induced oral mucositis, 50 utilised 5-fluorouracil, 2 irinotecan, 2 methotrexate, 1 topotecan and 1 with other chemotherapeutic drugs. Three articles used a combination of these drugs to induce oral mucositis. Various animal models such as mice, rats, hamsters, piglets, rabbits, and zebrafish were used. The chemotherapeutic agents were introduced at various dosages via three routes of administration. Animals were mainly mice and rats. Unlike intestinal mucositis, most oral mucositis models combined mechanical or chemical irritation with chemotherapy. In conclusion, this extensive assessment of the literature revealed that there was a large variation among studies that reproduce oral and intestinal mucositis in animals. To assist with the design of a suitable preclinical model of chemotherapy-induced alimentary tract mucositis, animal types, routes of administration, dosages, and types of drugs were reported in this study. Further research is required to define an optimal protocol that improves the translatability of findings to humans. Full article

Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers worldwide. We aimed to identify potential genetic markers that could predict the prognosis of HNSCC. A total of 44 samples of GSE83519 from Gene Expression Omnibus (GEO) datasets and 546 samples of HNSCC from The Cancer Genome Atlas (TCGA) were adopted. The differently expressed genes (DEGs) of the samples were screened by GEO2R. We integrated the expression information of DEGs with clinical data from GES42743 using the weighted gene co-expression network analysis (WGCNA). A total of 17 hub genes were selected by the module membership (|MM| > 0.8), and the gene significance (|GS| > 0.3) was selected from the turquoise module. GOLM1 and FAM49B genes were chosen based on single-gene analysis results. Survival analysis showed that the higher expression of GOLM1 and FAM49B genes was correlated with a worse prognosis of HNSCC patients. Immunohistochemistry and multiplex immunofluorescence techniques verified that GOLM1 and FAM49B genes were highly expressed in HNSCC cells, and high expressions of GOLM1 were associated with the pathological grades of HNSCC. In conclusion, our study illustrated a new insight that GOLM1 and FAM49B genes might be used as potential biomarkers to determine the development of HNSCC, while GOLM1 and FAM49B have the possibility to be prognostic indicators for HNSCC. Full article

Banana Fusarium wilt, which is caused by Fusarium oxysporum f.sp. cubense Tropical Race 4 (FOC TR4), is one of the most serious fungal diseases in the banana-producing regions in east Asia. Pseudomonas aeruginosa Gxun-2 could significantly inhibit the growth of FOC TR4. Strain Gxun-2 strongly inhibited the mycelial growth of FOC TR4 on dual culture plates and caused hyphal wrinkles, ruptures, and deformities on in vitro cultures. Banana seedlings under pot experiment treatment with Gxun-2 in a greenhouse resulted in an 84.21% reduction in the disease. Comparative transcriptome analysis was applied to reveal the response and resistance of FOC TR4 to Gxun-2 stress. The RNA-seq analysis of FOC TR4 during dual-culture with P. aeruginosa Gxun-2 revealed 3075 differentially expressed genes (DEGs) compared with the control. Among the genes, 1158 genes were up-regulated, and 1917 genes were down-regulated. Further analysis of gene function and the pathway of DEGs revealed that genes related to the cell membrane, cell wall formation, peroxidase, ABC transporter, and autophagy were up-regulated, while down-regulated DEGs were enriched in the sphingolipid metabolism and chitinase. These results indicated that FOC TR4 upregulates a large number of genes in order to maintain cell functions. The results of qRT-PCR conducted on a subset of 13 genes were consistent with the results of RNA-seq data. Thus, this study serves as a valuable resource regarding the mechanisms of fungal pathogen resistance to biocontrol agents. Full article

Crop traits are controlled by multiple genes; however, the complex spatio-temporal transcriptional behavior of genes cannot be fully understood without comprehending the role of transcription factors (TFs) and the underlying mechanisms of the binding interactions of their cis-regulatory elements. NAC belongs to one of the largest families of plant-specific TFs and has been associated with the regulation of many traits. This review provides insight into the cis-regulation of genes by wheat NACs (TaNACs) for the improvement in yield-related traits, including phytohormonal homeostasis, leaf senescence, seed traits improvement, root modulation, and biotic and abiotic stresses in wheat and other cereals. We also discussed the current potential, knowledge gaps, and prospects of TaNACs. Full article

Oncolytic adenoviruses are promising new anticancer agents. To realize their full anticancer potential, they are being engineered to express therapeutic payloads. Tumor suppressor p53 function contributes to oncolytic adenovirus activity. Many cancer cells carry an intact TP53 gene but express p53 inhibitors that compromise p53 function. Therefore, we hypothesized that oncolytic adenoviruses could be made more effective by suppressing p53 inhibitors in selected cancer cells. To investigate this concept, we attenuated the expression of the established p53 inhibitor synoviolin (SYVN1) in A549 lung cancer cells by RNA interference. Silencing SYVN1 inhibited p53 degradation, thereby increasing p53 activity, and promoted adenovirus-induced A549 cell death. Based on these observations, we constructed a new oncolytic adenovirus that expresses a short hairpin RNA against SYVN1. This virus killed A549 cells more effectively in vitro and inhibited A549 xenograft tumor growth in vivo. Surprisingly, increased susceptibility to adenovirus-mediated cell killing by SYVN1 silencing was also observed in A549 TP53 knockout cells. Hence, while the mechanism of SYVN1-mediated inhibition of adenovirus replication is not fully understood, our results clearly show that RNA interference technology can be exploited to design more potent oncolytic adenoviruses. Full article

This study aimed at analyzing the DNA methylation pattern and TP53 mutation status of intrinsic breast cancer (BC) subtypes for improved characterization and survival prediction. DNA methylation of 17 genes was tested by methylation-specific PCR in 116 non-familial BRCA mutation-negative BC and 29 control noncancerous cases. At least one gene methylation was detected in all BC specimens and a 10-gene panel statistically significantly separated tumors from noncancerous breast tissues. Methylation of FILIP1L and MT1E was predominant in triple-negative (TN) BC, while other BC subtypes were characterized by RASSF1, PRKCB, MT1G, APC, and RUNX3 hypermethylation. TP53 mutation (TP53-mut) was found in 38% of sequenced samples and mainly affected TN BC cases (87%). Cox analysis revealed that TN status, age at diagnosis, and RUNX3 methylation are independent prognostic factors for overall survival (OS) in BC. The combinations of methylated biomarkers, RUNX3 with MT1E or FILIP1L, were also predictive for shorter OS, whereas methylated FILIP1L was predictive of a poor outcome in the TP53-mut subgroup. Therefore, DNA methylation patterns of specific genes significantly separate BC from noncancerous breast tissues and distinguishes TN cases from non-TN BC, whereas the combination of two-to-three epigenetic biomarkers can be an informative tool for BC outcome predictions. Full article

The hydrangea (Hydrangea macrophylla (Thunb). Ser.), an ornamental plant, has good marketing potential and is known for its capacity to change the colour of its inflorescence depending on the pH of the cultivation media. The molecular mechanisms causing these changes are still uncertain. In the present study, transcriptome and targeted metabolic profiling were used to identify molecular changes in the RNAome of hydrangea plants cultured at two different pH levels. De novo assembly yielded 186,477 unigenes. Transcriptomic datasets provided a comprehensive and systemic overview of the dynamic networks of the gene expression underlying flower colour formation in hydrangeas. Weighted analyses of gene co-expression network identified candidate genes and hub genes from the modules linked closely to the hyper accumulation of Al³⁺ during different stages of flower development. F3′5′H, ANS, FLS, CHS, UA3GT, CHI, DFR, and F3H were enhanced significantly in the modules. In addition, MYB, bHLH, PAL6, PAL9, and WD40 were identified as hub genes. Thus, a hypothesis elucidating the colour change in the flowers of Al³⁺-treated plants was established. This study identified many potential key regulators of flower pigmentation, providing novel insights into the molecular networks in hydrangea flowers. Full article

Delayed cerebral ischemia (DCI) and vasospasm are two complications of subarachnoid hemorrhages (SAHs) which entail high risks of morbidity and mortality. However, it is unknown why only some patients who suffer SAHs will experience DCI and vasospasm. The purpose of this review is to describe the main genetic single nucleotide polymorphisms (SNPs) that have demonstrated a relationship with these complications. The SNP of the nitric oxide endothelial synthase (eNOS) has been related to the size and rupture of an aneurysm, as well as to DCI, vasospasm, and poor neurological outcome. The SNPs responsible for the asymmetric dimetilarginine and the high-mobility group box 1 have also been associated with DCI. An association between vasospasm and the SNPs of the eNOS, the haptoglobin, and the endothelin–1 receptor has been found. The SNPs of the angiotensin-converting enzyme have been related to DCI and poor neurological outcome. Studies on the SNPs of the Ryanodine Receptor yielded varying results regarding their association with vasospasm. Full article

The ovarian reserve is finite and begins declining from its peak at mid-gestation until only residual follicles remain as women approach menopause. Reduced ovarian reserve, or its extreme form, premature ovarian insufficiency, stems from multiple factors, including developmental, genetic, environmental exposures, autoimmune disease, or medical/surgical treatment. In many cases, the cause remains unknown and resulting infertility is not ultimately addressed by assisted reproductive technologies. Deciphering the mechanisms that underlie disorders of ovarian reserve could improve the outcomes for patients struggling with infertility, but these disorders are diverse and can be categorized in multiple ways. In this review, we will explore the topic from a perspective that emphasizes the prevention or mitigation of ovarian damage. The most desirable mode of fertoprotection is primary prevention (intervening before ablative influence occurs), as identifying toxic influences and deciphering the mechanisms by which they exert their effect can reduce or eliminate exposure and damage. Secondary prevention in the form of screening is not recommended broadly. Nevertheless, in some instances where a known genetic background exists in discrete families, screening is advised. As part of prenatal care, screening panels include some genetic diseases that can lead to infertility or subfertility. In these patients, early diagnosis could enable fertility preservation or changes in family-building plans. Finally, Tertiary Prevention (managing disease post-diagnosis) is critical. Reduced ovarian reserve has a major influence on physiology beyond fertility, including delayed/absent puberty or premature menopause. In these instances, proper diagnosis and medical therapy can reduce adverse effects. Here, we elaborate on these modes of prevention as well as proposed mechanisms that underlie ovarian reserve disorders. Full article

Occupational exposure to quartz dust is associated with fatal diseases. Quartz dusts generated by mechanical fracturing are characterized by a broad range of micrometric to nanometric particles. The contribution of this nanometric fraction to the overall toxicity of quartz is still largely unexplored, primarily because of the strong electrostatic adhesion forces that prevent isolation of the nanofraction. Furthermore, fractured silica dust exhibits special surface features, namely nearly free silanols (NFS), which impart a membranolytic activity to quartz. Nanoquartz can be synthetized via bottom-up methods, but the surface chemistry of such crystals strongly differs from that of nanoparticles resulting from fracturing. Here, we report a top-down milling procedure to obtain a nanometric quartz that shares the key surface properties relevant to toxicity with fractured quartz. The ball milling was optimized by coupling the dry and wet milling steps, using water as a dispersing agent, and varying the milling times and rotational speeds. Nanoquartz with a strong tendency to form submicrometric agglomerates was obtained. The deagglomeration with surfactants or simulated body fluids was negligible. Partial lattice amorphization and a bimodal crystallite domain size were observed. A moderate membranolytic activity, which correlated with the number of NFS, signaled coherence with the previous toxicological data. A membranolytic nanoquartz for toxicological investigations was obtained. Full article

The role of exogenous microRNAs (miRNAs) in renal fibrosis is poorly understood. Here, the effect of exogenous miRNAs on renal fibrosis was investigated using a renal fibrosis mouse model generated by unilateral ureteral obstruction (UUO). miRNA microarray analysis and quantitative reverse-transcription polymerase chain reaction showed that miR−122−5p was the most downregulated (0.28-fold) miRNA in the kidneys of UUO mice. The injection of an miR−122−5p mimic promoted renal fibrosis and upregulated COL1A2 and FN1, whereas an miR−122−5p inhibitor suppressed renal fibrosis and downregulated COL1A2 and FN1. The expression levels of fibrosis-related mRNAs, which were predicted targets of miR−122−5p, were evaluated. The expression level of TGFBR2, a pro-fibrotic mRNA, was upregulated by the miR−122−5p mimic, and the expression level of FOXO3, an anti−fibrotic mRNA, was upregulated by the miR−122−5p inhibitor. The protein expressions of TGFBR2 and FOXO3 were confirmed by immunohistochemistry. Additionally, the expression levels of LC3, downstream anti-fibrotic mRNAs of FOXO3, were upregulated by the miR−122−5p inhibitor. These results suggest that miR−122−5p has critical roles in renal fibrosis. Full article

The existence of a tight relationship between inflammation and epigenetics that in primary breast tumor cells can lead to tumor progression and the formation of bone metastases was investigated. It was highlighted how the induction of tumor progression and bone metastasis by Interleukin-1 beta, in a non-metastatic breast cancer cell line, MCF-7, was dependent on the de-methylating actions of ten-eleven translocation proteins (TETs). In fact, the inhibition of their activity by the Bobcat339 molecule, an inhibitor of TET enzymes, determined on the one hand, the modulation of the epithelial-mesenchymal transition process, and on the other hand, the reduction in the expression of markers of bone metastasis, indicating that the epigenetic action of TETs is a prerequisite for IL-1β-dependent tumor progression and bone metastasis formation. Full article

Obesity affects 42.4% of adults and 19.3% of children in the United States. Childhood obesity drives many comorbidities including hypertension, fatty liver disease, and type 2 diabetes mellitus. Prior research suggests that aberrant compositional development of the gut microbiome, with low-grade inflammation, precedes being overweight. Therefore, childhood may provide opportunities for interventions that shape the microbiome to mitigate obesity-related diseases. Children with obesity have gut microbiota compositional and functional differences, including increased proinflammatory bacterial taxa, compared to lean controls. Restoration of the gut microbiota to a healthy state may ameliorate conditions associated with obesity and help maintain a healthy weight. Pediatric bariatric (weight-loss) surgery is an effective treatment for childhood obesity; however, there is limited research into the role of the gut microbiome after weight-loss surgery in children. This review will discuss the magnitude of childhood obesity, the importance of the developing microbiome in establishing metabolic pathways, interventions such as bariatric surgery that may modulate the gut microbiome, and future directions for the potential development of microbiome-based therapeutics to treat obesity. Full article

Pure titanium is used in dental implants owing to its excellent biocompatibility and physical properties. However, the aging of the material during storage is detrimental to the long-term stability of the implant after implantation. Therefore, in this study, we attempted to improve the surface properties and circumvent the negative effects of material aging on titanium implants by using a portable handheld nonthermal plasma device capable of piezoelectric direct discharge to treat pure titanium discs with nitrogen gas. We evaluated the osteogenic properties of the treated samples by surface morphology and elemental analyses, as well as in vitro and in vivo experiments. The results showed that nonthermal atmospheric-pressure nitrogen plasma can improve the hydrophilicity of pure titanium without damaging its surface morphology while introducing nitrogen-containing functional groups, thereby promoting cell attachment, proliferation, and osseointegration to some extent. Therefore, nitrogen plasma treatment may be a promising method for the rapid surface treatment of titanium implants. Full article

In hospitalized COVID-19 patients, disease progression leading to acute kidney injury (AKI) may be driven by immune dysregulation. We explored the role of urinary cytokines and their relationship with kidney stress biomarkers in COVID-19 patients before and after the development of AKI. Of 51 patients, 54.9% developed AKI. The principal component analysis indicated that in subclinical AKI, epidermal growth factor (EGF) and interferon (IFN)-α were associated with a lower risk of AKI, while interleukin-12 (IL-12) and macrophage inflammatory protein (MIP)-1β were associated with a higher risk of AKI. After the manifestation of AKI, EGF and IFN-α remained associated with a lower risk of AKI, while IL-1 receptor (IL-1R), granulocyte-colony stimulating factor (G-CSF), interferon-gamma-inducible protein 10 (IP-10) and IL-5 were associated with a higher risk of AKI. EGF had an inverse correlation with kidney stress biomarkers. Subclinical AKI was characterized by a significant up-regulation of kidney stress biomarkers and proinflammatory cytokines. The lack of EGF regenerative effects and IFN-α antiviral activity seemed crucial for renal disease progression. AKI involved a proinflammatory urinary cytokine storm. Full article

Variants in genes encoding for microRNAs have been associated with their deregulation in breast cancer (BC). Sequencing of microRNAs deregulated in BC was performed using DNA from Chilean patients with a strong family history and negative for mutations in BRCA1/BRCA2. Seventeen variants were identified, three of which were selected for a case-control association study: rs376491654 (miR-335), rs755634302 (miR-497), and rs190708267 (miR-155). For rs190708267 C>T, the heterozygous T allele was detected in four BC cases and absent in controls, while homozygous TT cases were not detected. Variants were modelled in silico, cloned in a plasmid, expressed in BC cell lines, and functional in vitro assays were performed. Overexpression of the miR-155-T allele increased mature miR-155-5p levels in both BC cell lines, suggesting that its presence alters pre-miR-155 processing. Moreover, BC cells overexpressing the miR-155-T allele showed increased proliferation, migration, and resistance to cisplatin-induced death compared to miR-155-C overexpressing cells. Of note, the 3′UTR of APC, GSK3β, and PPP1CA genes, all into the canonical Wnt signaling pathway, were identified as direct targets. APC and GSK3β mRNA levels decreased while PP1 levels increased. These results suggest a pathogenic role of the variant rs190708267 (miR-155) in BRCA 1/2 negative BC, conferring susceptibility and promoting traits of aggressiveness. Full article

Currently, X-ray diffraction analysis (XRD) with high spatial and time resolution (TR-XRD) is based on the known theory of X-ray scattering, where the main parameter of USP—its duration—is not taken into account. In the present work, it is shown that, for scattering of attosecond USPs on DNA and RNA trinucleotides, the pulse length is the most important scattering parameter. The diffraction pattern changes considerably in comparison with the previously known scattering theory. The obtained results are extremely important in TR-XRD when using attosecond pulses to study trinucleotides of DNA and RNA, because with the previously known scattering theory, which does not take into account the duration of USP, one cannot correctly interpret, and therefore “decode”, DNA and RNA structures. Full article