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Adrenocortical carcinoma (ACC) is a rare but aggressive disease that lacks definitive treatment. We aim to evaluate role of ASXL1 in ACC and exploit its therapeutic merits therein. We performed in silico reproduction of datasets of the Cancer Genome Atlas (TCGA), GDSC (Genomics of Drug Sensitivity in Cancer) and Human Protein Atlas using platforms of cBioPortal, UALCAN, NET-GE, GSEA and GEPIA. Validation in ACC was performed in tissue, in vitro and in vivo using the NCI-H295R and SW-13 cells. ASXL1 was gained in over 50% of ACC cases with its mRNA overexpressed in DNA gained cases. ASXL1 overexpression was associated with recurrence and worsened prognosis in ACC. ASXL1 gain was associated with resistance to etoposide, doxorubicin and cisplatin (EDP). ASXL1 expression was positively correlated with FSCN1 expression. Targeting ASXL1 significantly impaired fitness of ACC cells, which could be in part rescued by FSCN1 overexpression. Targeting FSCN1 however could not rescue resistance to EDP induced by ASXL1 overexpression. Targeting ASXL1 sensitized ACC cells to EDP regimen but constitutive ASXL3 overexpression in SW-13 cells could induce resistance upon prolonged treatment. Functional gain of ASXL1 was common in ACC and exerted pro-tumorigenic and chemoresistance role. Targeting ASXL1 hold promise to ACC treatment.

Cuproptosis is a newly discovered cell death induced by excessive copper in mitochondria distinct from any known forms of apoptosis. Role of cuproptosis has not been well-reported in cancer, especially in clear-cell renal cell carcinoma (ccRCC). We comprehensively interrogated cuproptotic gene signature in ccRCC by reproducing multi-omics datasets and found cuproptosis was decreased in ccRCC compared with normal kidney. Cuproptosis identified a subgroup with significantly better prognosis. Functional annotation supported increased tricarboxylic acid cycle activity and decreased hypoxia signaling corroborated by metabolomics. Cuproptotic tumors showed decreased angiogenesis but were sensitive to Sunitinib and Sorafenib. Cuproptotic level in ccRCC cell lines showed robust negative correlation with copper ionophore Elesclomol. All findings support a respiratory subtype of ccRCC identified by cuproptosis.

The significance of the complex bacterial ecosystem in the human body and the impediment of the mammalian membrane against many antibiotics together emphasize the necessity to develop antimicrobial agents with precise antimicrobial and cell-penetrating activities. A simple and feasible method for generating dual-function antimicrobial peptides inspired by highly hydrophobic peptide pheromone and cationic cell-penetrating peptides is presented. Furthermore, the extension of the peptide candidate library is achieved by modifying the charged domain. The bacteria-selective peptides L1, L2, L10, and L11 kill Streptococcus agalactiae by disrupting the membrane structure, and the targeted mechanism is suggested where the peptides offset the entrapment of S. agalactiae rather than of other bacteria. Moreover, L2 and L10 possess intracellular antibacterial activity and carrier property, which is mainly dependent on endocytosis. Given their suitable biocompatibility, high tolerance, no drug resistance, and effective antimicrobial capacity in a mouse mastitis model, L2 and L10 can be powerful weapons against S. agalactiae pathogen infection.

By studying the principles of self-assembly and combining the structural parameters required for the asymmetric distribution of antimicrobial peptides (AMPs), we newly designed and screened the high-activity and low-toxicity AMP F2I-LL. This peptide can form a supramolecular hydrogel with a nanofiber microstructure in a simulated physiological environment (phosphate buffered saline), which exhibits broad-spectrum antibacterial activity. Compared with monomeric peptides, the introduction of a self-assembly strategy not only improved the bactericidal titer but also enhanced the serum stability of AMPs. Mechanistic studies showed that the positive charge enriched on the surface of the nanofiber was conducive to its rapid binding to the negatively charged part of the outer membrane of bacteria and further entered the inner membrane, increasing its permeability and ultimately leading to cell membrane rupture and death. This work provides insights into the design of nanopeptides with broad-spectrum antibacterial activity and provides new results for the development of biomedicine.

Antibiotic resistance is emerging as a hot issue with the abuse and overuse of antibiotics, and the shortage of effective antimicrobial agents against multidrug resistant bacteria creates a huge problem to treat the threatening nosocomial skin and soft tissue infection. Antimicrobial peptides (AMPs) exhibite enormous potential as one of the most promising candidates of antibiotic to fight against pathogenic infections because of its unique membrane penetration mechanism to kill pathogens, whereas the clinical application of AMPs still faces the challenges of production cost, stability, safety, and design strategy. Herein, a series of Trp-rich peptides was designed following the principle of paired Trp plated at the ith and ith+4 position on the backbone of peptides, based on the template (VKKX)4, where X represents W, A, or L, to study the effect of intramolecular aromatic interactions on the bioactivity of AMPs. Through comparing the antimicrobial performance, hemolysis, cytotoxicity, and stability, VW5 which is equipped with the characters of direct antimicrobial efficacy (GM=1.68μM) and physical destruction of bacterial membrane (SEM and electron microscopy) stood out from the engineering peptides. VW5 also performed well in mice models, which could significantly decrease the bacterial colony (VW5 vs infection group, 12.72±2.26 vs 5.52±2.01×109CFU/abscess), the area of dermo-necrosis (VW5 vs infection group, 0.74±0.29 vs 1.86±0.98mm2) and the inflammation cytokine levels at the abscess site without causing toxicity to the skin. Overall, this study provides a strategy and template to diminish the randomness in the exploration and design of novel peptides.

Antimicrobial peptides are believed to be promising bio-preservatives to prevent microbial spoilage through food processing and preservation. With the aim of developing short peptides with broad-spectrum antimicrobial activity and revealing their potential antimicrobial mechanism, a novel class of dodecapeptides were designed by introducing Trp into the hydrophilic face of RI12, a truncated α-helical peptide of porcine myeloid antimicrobial peptide-36 (PMAP-36). The antimicrobial activity study indicated that Trp endowed the peptides with higher antimicrobial potency, and the net charge of +5 was sufficient for the dodecapeptides to exert antimicrobial action. Taking hemolytic activity into consideration, the most promising peptide RI12[K3W] (RLWKIGKVLKWI-NH2) was screened with high antimicrobial activity and non-toxicity. The antimicrobial mechanism study revealed that RI12[K3W] possessed the ability to bind to LPS components and enhance membrane permeability, which was verified by membrane penetration assays. Flow cytometry and electron microscopy further confirmed that RI12[K3W] killed bacterial cells primarily by membrane damage. The results guide the potential application of antimicrobial peptides in the food industry as food preservatives to prevent bacterial contamination.

There has recently been great concern regarding antibiotics due to potential drug resistance and the impact of antibiotics on the environment. Antimicrobial peptides are believed to have potential as novel antimicrobial agents to address the problems of antibiotics. Herein, we report a set of Trp-rich dodecapeptides derived from PMAP-36 that are based on the peptide folding principle and the amino acid characteristics. An effective peptide design template, (WXYX)3, where X represents Arg or Lys and Y represents hydrophobic or neutral amino acid, was summarized with the distribution of Trp at H-bond formation sites along the α-helical structure. The template peptide 6 (3W-2), with low amphipathicity, displayed strong antimicrobial activity against laboratory strains and clinical isolates while showing no cytotoxicity. Furthermore, 6 was able to suppress the emergence of antimicrobial resistance. Membrane permeabilization assays and microscope observations revealed the potent membrane-disruptive mechanism o...

The significance of the complex bacterial ecosystem in the human body and the impediment of the mammalian membrane against many antibiotics together emphasize the necessity to develop antimicrobial agents with precise antimicrobial and cell-penetrating activities. A simple and feasible method for generating dual-function antimicrobial peptides inspired by highly hydrophobic peptide pheromone and cationic cell-penetrating peptides is presented. Furthermore, the extension of the peptide candidate library is achieved by modifying the charged domain. The bacteria-selective peptides L1, L2, L10, and L11 kill

Due to compromised immune system, fungal infection incidences have markedly increased in the last few decades. Pathogenic fungi have developed resistance to the clinically available antifungal agents. Antifungal resistance poses a great challenge to clinical treatment and has stimulated the demand for novel antifungal agents. A promising alternative to the treatment of fungal diseases is the use of antimicrobial peptides (AMPs). However, the antifungal activities of AMPs have not been fully determined. Therefore, this study aimed at designing and screening α-helical peptides with potential antifungal activities. The effects of key physicochemical parameters on antifungal activities were also investigated. A series of lengthened and residue-substituted derivatives of the template peptide KV, a hexapeptide truncated from the α-helical region of porcine myeloid antimicrobial peptide-36, were designed and synthesized. Enhancement of hydrophobicity by introducing aromatic hydrophobic amino acids (tryptophan and phenylalanine) significantly increased the efficacies of the peptides against Candida albicans strains, including fluconazole-resistant isolates. Increased hydrophobicity also elevated the toxic properties of these peptides. RF3 with moderate hydrophobicity exhibited potent anticandidal activities (GM = 6.96 μM) and modest hemolytic activities (HC10 > 64 μM). Additionally, repeated exposure to a subinhibitory concentration of RF3 did not induce resistance development. The antifungal mechanisms of RF3 were due to membrane disruptions and induction of reactive oxygen species production. Such a dual-targeted mechanism was active against drug-resistant fungi. These results show the important role of hydrophobicity and provide new insights into designing and developing antifungal peptides. Meanwhile, the successful design of RF3 highlights the potential utility of AMPs in preventing the spread of drug-resistant fungal infections.

Renal cell carcinoma (RCC) is a common cancer of the urinary system. The potential therapeutic effects of certain natural products against renal cell carcinoma have been reported both in vivo and in vitro, but no reviews have been published classifying and summarizing the mechanisms of action of various natural products. In this study, we used PubMed and Google Scholar to collect and screen the recent literature on natural products with anti-renal-cancer effects. The main mechanisms of action of these products include the induction of apoptosis, inhibition of angiogenesis, inhibition of metastasis and reduction of drug resistance. In total, we examined more than 30 natural products, which include kahweol acetate, honokiol, englerin A and epigallocatechin-3-gallate, among others, have demonstrated a variety of anti-renal-cancer effects. In conclusion, natural products may have a wider application in kidney cancer than previously believed and are potential candidates for treatment in RCC.

There is an urgent need to develop novel antibacterial agents able to eradicate drug-resistant Gram-negative pathogens such as Pseudomonas aeruginosa. Antimicrobial hybrids have emerged as a promising strategy to combat bacterial resistance, as a stand-alone drug but also as an adjuvant in combination with existing antibiotics. Herein, we report for the first time the synthesis and biological evaluation of polymyxin-aminoglycoside heterodimers composed of polymyxin B3 covalently linked to tobramycin via an aliphatic hydrocarbon linker. The polymyxin B3–tobramycin hybrids demonstrate potent activity against carbapenem-resistant as well as multidrug- or extensively drug-resistant (MDR/XDR) P. aeruginosa clinical isolates. Furthermore, the most potent hybrid was able to synergize with currently used antibiotics against wild-type and MDR/XDR P. aeruginosa but also against Acinetobacter baumannii as well. The promising biological activity described herein warrants additional studies into design and development...

Antimicrobial peptides (AMPs), critical components of the innate immune system, are widely distributed throughout the animal and plant kingdoms. They can protect against a broad array of infection-causing agents, such as bacteria, fungi, parasites, viruses, and tumor cells, and also exhibit immunomodulatory activity. AMPs exert antimicrobial activities primarily through mechanisms involving membrane disruption, so they have a lower likelihood of inducing drug resistance. Extensive studies on the structure-activity relationship have revealed that net charge, hydrophobicity, and amphipathicity are the most important physicochemical and structural determinants endowing AMPs with antimicrobial potency and cell selectivity. This review summarizes the recent advances in AMPs development with respect to characteristics, structure-activity relationships, functions, antimicrobial mechanisms, expression regulation, and applications in food, medicine, and animals.

A series of 16 short proline-rich lipopeptides (SPRLPs) were constructed to mimic longer naturally existing proline-rich antimicrobial peptides. Antibacterial assessment revealed that lipopeptides containing hexadecanoic acid (C 16 ) possess optimal antibacterial activity relative to others with shorter lipid components. SPRLPs were further evaluated for their potential to serve as adjuvants in combination with existing antibiotics to enhance antibacterial activity against drug-resistant Pseudomonas aeruginosa . Out of 16 prepared SPRLPs, C 12 -PRP was found to significantly potentiate the antibiotics minocycline and rifampin against multidrug- and extensively drug-resistant (MDR/XDR) P. aeruginosa clinical isolates. This nonhemolytic C 12 -PRP is comprised of the heptapeptide sequence PRPRPRP-NH 2 acylated to dodecanoic acid (C 12 ) at the N terminus. The adjuvant potency of C 12 -PRP was apparent by its ability to reduce the MIC of minocycline and rifampin below their interpretative susceptibility breakpoints against MDR/XDR P. aeruginosa . An attempt to optimize C 12 -PRP through peptidomimetic modification was performed by replacing all l - to d -amino acids. C 12 -PRP demonstrated that it was amenable to optimization, since synergism with minocycline and rifampin were retained. Moreover, C 12 -PRP displayed no cytotoxicity against human liver carcinoma HepG2 and human embryonic kidney HEK-293 cell lines. Thus, the SPRLP C 12 -PRP is a lead adjuvant candidate that warrants further optimization. The discovery of agents that are able to resuscitate the activity of existing antibiotics against drug-resistant Gram-negative pathogens, especially P. aeruginosa , is of great clinical interest.

Drug efflux mechanisms interact synergistically with the outer membrane permeability barrier of Gram-negative bacteria, leading to intrinsic resistance that presents a major challenge for antibiotic drug development. Efflux pump inhibitors (EPIs) which block the efflux of antibiotics synergize antibiotics, but the clinical development of EPI/antibiotic combination therapy to treat multidrug-resistant (MDR) Gram-negative infections has been challenging. This is in part caused by the inefficiency of current EPIs to penetrate the outer membrane and resist efflux. We demonstrate that conjugation of a tobramycin (TOB) vector to EPIs like NMP, paroxetine, or DBP enhances synergy and efficacy of EPIs in combination with tetracycline antibiotics against MDR Gram-negative bacteria including Pseudomonas aeruginosa. Besides potentiating tetracycline antibiotics, TOB-EPI conjugates can also suppress resistance development to the tetracycline antibiotic minocycline, thereby providing a strategy to develop more effective adjuvants to rescue tetracycline antibiotics from resistance in MDR Gram-negative bacteria.

Antimicrobial peptides (AMPs) have recently attracted a great deal of attention as promising antibiotic candidates, but some obstacles such as toxicity and high synthesis cost must be addressed before developing them further. For developing short peptides with improved cell selectivity, we designed a series of modified PMAP-36 analogues. Antimicrobial assays showed that decreasing chain length in a certain range retained the high antimicrobial activity of the parental peptide and reduced hemolysis. The 18-mer peptide RI18 exhibited excellent antimicrobial activity against both bacteria and fungi, and its hemolytic activity was observably lower than PMAP-36 and melittin. The selectivity indexes of RI18 against bacteria and fungi were improved approximately 19-fold and 108-fold, respectively, compared to PMAP-36. In addition, serum did not affect the antibacterial activity of RI18 against E. coli but inhibited the antifungal efficiency against C. albicans. Flow cytometry and electron microscopy observation revealed that RI18 killed microbial cells primarily by damaging membrane integrity, leading to whole cell lysis. Taken together, these results suggest that RI18 has potential for further therapeutic research against frequently-encountered bacteria and fungi. Meanwhile, modification of AMPs is a promising strategy for developing novel antimicrobials to overcome drug-resistance.

Peptidomimetic modification is a common route of optimization for biologically active peptides. Previous studies in our group have shown that conjugation of amphiphilic tobramycin to other antibacterials enhance their latent outer membrane permeabilizing and efflux blocking activity toward Gram-negative pathogens including Pseudomonas aeruginosa. Herein, we describe the antimicrobial adjuvant properties of amphiphilic lysine ligated to tobramycin. The most potent amphiphilic lysine-tobramycin conjugate 3 potentiated the antibacterial efficacy of 8 clinically used antibiotics against wild type, multidrug- and extensively drug-resistant P. aeruginosa isolates from Canadian hospitals whereas amphiphilic lysine 4 did not. Antibiotics that are synergistic with conjugate 3 included moxifloxacin, ciprofloxacin, erythromycin, chloramphenicol, trimethoprim, novobiocin, linezolid, and fosfomycin. Out of these 8 antibiotics, novobiocin showed highest synergy.