BACKGROUND: In triple-negative breast cancer (TNBC) therapy, insufficient tumor infiltration by lymphocytes significantly hinders the efficacy of immune checkpoint inhibitors. We have previously demonstrated that Hainanenin-1 (HN-1), a host defense peptide (HDP) identified from Hainan frog skin, induces breast cancer apoptosis and boots anti-tumor immunity via unknown mechanism.
METHODS: We used in vitro experiments to observe immunogenic cell death (ICD) indicators in HN-1-treated TNBC cell lines, a mouse tumor model to verify HN-1 promotion of mice anti-tumor immune response, and an in vitro drug sensitivity test of patient-derived breast cancer cells to verify the inhibitory effect of HN-1.
RESULTS: HN-1 induced ICD in TNBC in a process during which damage-associated molecular patterns (DAMPs) were released that could further increase the anti-tumor immune response. The secretion level of interleukin 2 (IL-2), IL-12, and interferon γ in the co-culture supernatant was increased, and dendritic cells (DCs) were activated via a co-culture with HN-1-pretreated TNBC cells. As a result, HN-1 increased the infiltration of anti-tumor immune cells (DCs and T lymphocytes) in the mouse model bearing both 4T1 and EMT6 tumors. Meanwhile, regulatory T cells and myeloid-derived suppressor cells were suppressed. In addition, HN-1 induced DNA damage, and double-strand DNA release in the cytosol was significantly enhanced, indicating that HN-1 might stimulate ICD via activation of STING pathway. The knockdown of STING inhibited HN-1-induced ICD. Of note, HN-1 exhibited inhibitory effects on patient-derived breast cancer cells under three-dimensional culture conditions.
CONCLUSIONS: Collectively, our study demonstrated that HN-1 could be utilized as a potential compound that might augment immunotherapy effects in patients with TNBC.

The intestine defends against pathogenic microbial invasion via the secretion of host defense peptides (HDPs). Nutritional immunomodulation can stimulate the expression of endogenous HDPs and enhance the body\'s immune defense, representing a novel non-antibiotic strategy for disease prevention. The project aims to explore the regulatory mechanism of protegrin-1 (PG-1) expression using sodium phenylbutyrate (PBA) by omics sequencing technology and further investigate the role of key regulatory genes on intestinal health. The results showed that PBA promoted PG-1 expression in intestinal epithelial cells based on cell density through epidermal growth factor receptor (EGFR) and G protein-coupled receptor (GPR43). Transcriptome sequencing and microRNA sequencing revealed that C-X-C motif chemokine receptor 2 (CXCR2) exhibited interactions with PG-1. Pre-treatment cells with a CXCR2 inhibitor (SB225002) effectively suppressed the induction of PG-1 by PBA. Furthermore, SB225002 significantly suppressed the gene expression of HDPs in the jejunum of mice without influencing on the morphology, number of goblet cells, and proliferation of the intestine. CXCR2 inhibition significantly reduced the expression of HDPs during E. coli infection, and resulted in the edema of jejunal epithelial cells. The 16S rDNA analysis of cecal contents showed that the E. coli and SB225002 treatments changed gut microbiota diversity and composition at different taxonomic levels. Correlation analysis suggested a potential regulatory relationship between gut microbiota and HDPs. To that end, a gene involved in the HDP expression, CXCR2, has been identified in the study, which contributes to improving intestinal immune function. PBA may be used as a functional additive to regulate intestinal mucosal function, thereby enhancing the health of the intestinal and host.

The infections associated with implantable medical devices can greatly affect the therapeutic effect and impose a heavy financial burden. Therefore, it is of great significance to develop antimicrobial biomaterials for the prevention and mitigation of healthcare-associated infections. Here, a facile construction of antimicrobial surface via one-step co-deposition of peptide polymer and dopamine is reported. The co-deposition of antimicrobial peptide polymer DLL60 BLG40 with dopamine (DA) on the surface of thermoplastic polyurethane (TPU) provides peptide polymer-modified TPU surface (TPU-DLL60 BLG40 ). The antimicrobial test shows that the TPU-DLL60 BLG40 surfaces of the sheet and the catheter both exhibit potent killing of 99.9% of methicillin-resistant Staphylococcus aureus (MRSA) and Escherichia coli (E. coli). In addition, the TPU-DLL60 BLG40 surface also exhibits excellent biocompatibility. This one-step antimicrobial modification method is fast and efficient, implies promising application in surface antimicrobial modification of implantable biomaterials and medical devices.

Host defense peptides (HDPs) are primary components of the innate immune system with diverse biological functions, such as antibacterial ability and immunomodulatory function. HDPs are produced and released by immune and epithelial cells against microbial invasion, which are widely distributed in humans, animals, plants, and microbes. Notably, there are great differences in endogenous HDP distribution and expression in humans and animals. Moreover, HDP expression could be regulated by exogenous substances, such as nutrients, and different physiological statuses in health and disease. In this review, we systematically assessed the regulation of expression and mechanism of endogenous HDPs from nutrition and disease perspectives, providing a basis to identify the specificity and regularity of HDP expression. Furthermore, the regulation mechanism of HDP expression was summarized systematically, and the differences in the regulation between nutrients and diseases were explored. From this review, we provide novel ideas targeted the immune regulation of HDPs for protecting host health in nutrition and practical and effective new ideas using the immune regulation theory for further research on protecting host health from pathogenic infection and excessive immunity diseases under the global challenge of the antibiotic-abuse-induced series of problems, including food security and microbial resistance.

Focal bacterial infections are often difficult to treat due to the rapid emergence of antibiotic-resistant bacteria, high risk of relapse, and severe inflammation at local lesions. To address multidrug-resistant skin and soft tissue infections, a bacteria-absorbing sponge was prepared to involve a \"trap-and-kill\" mechanism. The system describes a guanidinium-rich lipopeptide functionalized lyotropic liquid-crystalline hydrogel with bicontinuous cubic networks. Amphiphilic lipopeptides can be spontaneously anchored to the lipid-water interface, exposing their bacterial targeting sequences to enhance antibacterial trapping/killing activity. Computational simulations supported our structural predictions, and the sponge was confirmed to successfully remove ∼98.8% of the bacteria in the medium. Release and degradation behavior studies indicated that the bacteria-absorbing sponge could degrade, mediate enzyme-responsive lipopeptide release, or generate ∼200 nm lipopeptide nanoparticles with environmental erosion. This implies that the sponge can effectively capture and isolate high concentrations of bacteria at the infected site and then sustainably release antimicrobial lipopeptides into deep tissues for the eradication of residual bacteria. In the animal experiment, we found that the antibacterial performance of the bacterial-absorbing sponge was significant, which demonstrated not only a long-term inhibition effect to disinfect and avoid bacterial rebound, but also a unique advantage to protect tissue from bacterial attack. STATEMENT OF SIGNIFICANCE: Host defense peptides/peptidomimetics (HDPs) have shown potential for the elimination of focal bacterial infections, but the application of their topical formulations suffers from time-consuming preparation processes, indistinctive toxicity reduction effects, and inefficient bacterial capture ability. To explore new avenues for the development of easily prepared, low-toxicity and high-efficiency topical antimicrobials, a guanidinium-rich lipopeptide was encapsulated in a lyotropic liquid-crystalline hydrogel (denoted as \"bacteria-absorbing sponge\") to achieve complementary superiorities. The superior characteristic of the bacteria-absorbing sponge involves a \"trap-and-kill\" mechanism, which undergoes not only a long-term inhibition effect to disinfect and avoid bacterial rebound, but also effective bacterial capture and isolating action to confine bacterial diffusion and protect tissues from bacterial attack.

Resistin, a cysteine-rich protein, expressed in adipocytes, was initially proposed as a link between obesity and diabetes in mice. In humans, resistin is considered to be a pro-inflammatory molecule expressed in immune cells, which plays a regulatory role in many chronic inflammatory diseases, metabolic diseases, infectious diseases, and cancers. However, increasing evidence shows that resistin functions as a host defense peptide of innate immunity, in terms of its wide-spectrum anti-microbial activity, modulation of immunity, and limitation of microbial product-induced inflammation. To date, the understanding of resistin participating in host defense mechanism is still limited. The review aims to summarize current knowledge about the biological properties, functions, and related mechanisms of resistin in host defense, which provides new insights into the pleiotropic biological function of resistin and yields promising strategies for developing new antimicrobial therapeutic agents.

It is an urgent need to tackle drug-resistance microbial infections that are associated with implantable biomedical devices. Host defense peptide-mimicking polymers have been actively explored in recent years to fight against drug-resistant microbes. Our recent report on lithium hexamethyldisilazide-initiated superfast polymerization on amino acid N-carboxyanhydrides enables the quick synthesis of host defense peptide-mimicking peptide polymers. Here we reported a facile and cost-effective thermoplastic polyurethane (TPU) surface modification of peptide polymer (DLL: BLG = 90 : 10) using plasma surface activation and substitution reaction between thiol and bromide groups. The peptide polymer-modified TPU surfaces exhibited board-spectrum antibacterial property as well as effective contact-killing ability in vitro. Furthermore, the peptide polymer-modified TPU surfaces showed excellent biocompatibility, displaying no hemolysis and cytotoxicity. In vivo study using methicillin-resistant Staphylococcus aureus (MRSA) for subcutaneous implantation infectious model showed that peptide polymer-modified TPU surfaces revealed obvious suppression of infection and great histocompatibility, compared to bare TPU surfaces. We further explored the antimicrobial mechanism of the peptide polymer-modified TPU surfaces, which revealed a surface contact-killing mechanism by disrupting the bacterial membrane. These results demonstrated great potential of the peptide-modified TPU surfaces for practical application to combat bacterial infections that are associated with implantable materials and devices.

Currently, implant-related bone infection characterized by aggravated infection-induced inflammatory responses and osteolysis, remains a severe challenge in orthopedic surgery, especially in patients with osteoporosis. Attempts to control such responses using biomaterials with combined immunomodulatory and anti-bacterial properties may provide novel strategies. Herein, DJK-5, a class of host defense peptides (HDPs) with established antimicrobial and immunomodulatory functions, was introduced into porous Ti alloy. Our results indicated that the DJK-5 immobilized surfaces showed intrinsically multifunctional properties, including antibacterial ability, anti-inflammation, biocompatibility and osteolysis-inhibiting properties. The results demonstrated that the antibacterial efficiency of DJK-5 functionalized surfaces was over 90 % for both Gram-positive and Gram-negative bacteria. Specifically, DJK-5 functionalized samples also possessed the excellent anti-bacterial activity against a mixture of bacterial strains, including S. aureus, S. epidermidis and P. aeruginosa, with an antibacterial rate against mixed bacteria reaching 91.36 %, as well as reduced biofilm formation. The remarkable anti-bacterial efficacy was likely based on the direct anti-bacterial effect of DJK-5, which destroyed the integrity of bacteria membranes, leading to the leakage of intracellular materials. Additionally, the immobilized DJK-5 surfaces could indirectly kill bacteria through promoted macrophage capacity to bacteria uptake. Furthermore, DJK-5 functionalized surfaces suppressed inflammatory reaction by decreasing the release of pro-inflammatory factors and increasing the secretions of anti-inflammatory factors, and thereby impeded the activation of NF-κB signal pathway, which resulted in the disruption of the actin rings and decreased Tracp5b expressions. Based on these promising findings, the multi-functional DJK-5 immobilized titanium represents an efficient alternative to realize better osseointegration in sever implant-associated bacterial infections.

Poly(2-oxazoline)s have excellent biocompatibility and have been used as FDA-approved indirect food additives. The inert property of the hydrophilic poly(2-oxazoline)s suggests them as promising substitutes for poly(ethylene glycol) (PEG) in various applications such as anti-biofouling agents. It was recently reported that poly(2-oxazoline)s themselves have antimicrobial properties as synthetic mimics of host defense peptides. These studies revealed the bioactive properties of poly(2-oxazoline)s as a new class of functional peptide mimics, by mimicking host defense peptides to display potent and selective antimicrobial activities against methicillin-resistant Staphylococcus aureus both in vitro and in vivo, without concerns about antimicrobial resistance. The high structural diversity, facile synthesis, and potent and tunable antimicrobial properties underscore the great potential of poly(2-oxazoline)s as a class of novel antimicrobial agents in dealing with drug-resistant microbial infections and antimicrobial resistance.

Zika virus (ZIKV) is a mosquito-borne virus belonging to the genus Flavivirus and has reemerged in recent years with epidemic potential. ZIKV infection may result in severe syndromes such as neurological complications and microcephaly in newborns. Therefore, ZIKV has become a global public health threat and currently there is no approved specific drug for its treatment. Animal venoms are important resources of novel drugs. Cathelicidin-BF (BF-30) is a defensive peptide identified from Bungarus fasciatus snake venom and has been shown to be an excellent template for applicable peptide design. In this study, we found that ZY13, one of the peptidic analogs of BF-30, inhibits ZIKV infection in vitro and in vivo. Mechanistic studies revealed that ZY13 can directly inactivate ZIKV and reduce the production of infectious virions. Further studies also indicated that administration of ZY13 strengthen the host antiviral immunity via AXL-SOCS (suppressor of cytokine signaling protein) pathway. Additionally, the results of mouse experiment suggest that ZY13 efficiently restrict ZIKV infection and improve the growth defects of ZIKV-infected mouse pups. Together, our findings not only demonstrate that ZY13 might be a candidate for anti-ZIKV drug, but also indicated the importance of animal venom peptides as templates for antivirals development.