Association between high-risk fertility behaviour and anaemia among urban Indian women (15-49 years).

BACKGROUND: Women in their reproductive age have tremendous health implications that affect their health and well-being. Anaemia is an indicator of inadequate dietary intake and poor health. Maternal malnutrition significantly impacts maternal and child health outcomes, increasing the mother's risk of dying during delivery. High-risk fertility behaviour is a barrier to reducing mother and child mortality. This study aims to examine the level of high-risk fertility behaviour and anaemia among ever-married urban Indian women and also examine the linkages between the both. METHODS: Based on the National Family Health Survey's fifth round of data, the study analyzed 44,225 samples of ever-married urban women. Univariate and bivariate analysis and binary logistic regression have been used for the analysis. RESULTS: Findings suggested that more than half (55%) of the urban women were anaemic, and about one-fourth (24%) of women had any high-risk fertility behaviour. Furthermore, the results suggest that 20% of women were more vulnerable to anaemia due to high-risk fertility behaviour. For the specific category, 19% and 28% of women were more likely to be anaemic due to single and multiple high-risk fertility. However, after controlling for sociodemographic factors, the findings showed a statistically significant link between high-risk fertility behaviour and anaemia. As a result, 16% of the women were more likely to be anaemic due to high-risk fertility behaviour, and 16% and 24% were more likely to be anaemic due to single and multiple high-risk fertility behaviour, respectively. CONCLUSIONS: The findings exposed that maternal high-risk fertility behaviour is a significant factor in raising the chance of anaemia in ever-married urban women of reproductive age in forms of the short birth interval, advanced maternal age, and advanced maternal age & higher order. Policy and choice-based family planning techniques should be employed to minimize the high-risk fertility behaviour among Indian urban women. This might aid in the reduction of the malnutrition status of their children.

A novel and improved selective media for the isolation and enumeration of Klebsiella species.

Bacterial pathogens are fostered in and transmitted through wastewater. Hence, monitoring their impact on sanitation and hygiene is imperative. As part of the monitoring process, culture-based methodologies are primarily used, which centre on the use of selective and differential media. Media available today are, at best, difficult to formulate and, at worst, prohibitively expensive. To address this lacuna, the study proposes a selective and differential medium for Klebsiella spp. Klebsiella blue agar (KBA) is completely selective against selected gram-positive bacteria (Bacillus spp., Staphylococcus aureus) and a few gram-negative bacteria (Acinetobacter baumanii, Serratia marcescens). On the other hand, it supports the growth of the chosen members of the Klebsiella pneumoniae species-complex with a characteristic green colouration. Methylene blue, tryptophan, and bile salt make up the selective components of KBA. Moreover, methylene blue, 0.6% NaCl, and glycerol render it differential. KBA was more selective than HiCrome™ Klebsiella Selective Agar Base (KSA) in replica plating experiments. KBA promoted only 157 CFUs against 209 CFUs in KSA when stamped with 253 CFUs grown on LB. The colonies so isolated were predominantly Klebsiella spp., on identification through colony polymerase chain reaction. Moreover, the differential nature of KBA distinguished Klebsiella aerogenes from other species. On the contrary, KSA lodged colonies indistinguishable from each other and Klebsiella spp. Due to its ease of formulation, high selectivity, differential nature, and cost-effective composition, KBA is a viable option for the routine culture of Klebsiella spp. in environmental and clinical settings. KEY POINTS: • Formulated a novel selective and differential media for Klebsiella spp., named Klebsiella Blue agar • Facile formulation methodology • Can be employed to isolate Klebsiella spp. from complex sources such as wastewater.

Bile Acid Tethered Docetaxel-Based Nanomicelles Mitigate Tumor Progression through Epigenetic Changes.

In this study, we describe the engineering of sub-100 nm nanomicelles (DTX-PC NMs) derived from phosphocholine derivative of docetaxel (DTX)-conjugated lithocholic acid (DTX-PC) and poly(ethylene glycol)-tethered lithocholic acid. Administration of DTX-PC NMs decelerate tumor progression and increase the mice survivability compared to Taxotere (DTX-TS), the FDA-approved formulation of DTX. Unlike DTX-TS, DTX-PC NMs do not cause any systemic toxicity and slow the decay rate of plasma DTX concentration in rodents and non-rodent species including non-human primates. We further demonstrate that DTX-PC NMs target demethylation of CpG islands of Sparcl1 (a tumor suppressor gene) by suppressing DNA methyltransferase activity and increase the expression of Sparcl1 that leads to tumor regression. Therefore, this unique system has the potential to improve the quality of life in cancer patients and can be translated as a next-generation chemotherapeutic.

Cholic Acid-Peptide Conjugates as Potent Antimicrobials against Interkingdom Polymicrobial Biofilms.

Interkingdom polymicrobial biofilms formed by Gram-positive Staphylococcus aureus and Candida albicans pose serious threats of chronic systemic infections due to the absence of any common therapeutic target for their elimination. Herein, we present the structure-activity relationship (SAR) of membrane-targeting cholic acid-peptide conjugates (CAPs) against Gram-positive bacterial and fungal strains. Structure-activity investigations validated by mechanistic studies revealed that valine-glycine dipeptide-derived CAP 3 was the most effective broad-spectrum antimicrobial against S. aureus and C. albicans CAP 3 was able to degrade the preformed single-species and polymicrobial biofilms formed by S. aureus and C. albicans, and CAP 3-coated materials prevented the formation of biofilms. Murine wound and catheter infection models further confirmed the equally potent bactericidal and fungicidal effect of CAP 3 against bacterial, fungal, and polymicrobial infections. Taken together, these results demonstrate that CAPs, as potential broad-spectrum antimicrobials, can effectively clear the frequently encountered polymicrobial infections and can be fine-tuned further for future applications.

Oral Delivery of Cholic Acid-Derived Amphiphile Helps in Combating Salmonella-Mediated Gut Infection and Inflammation.

A major impediment to developing effective antimicrobials against Gram-negative bacteria like Salmonella is the ability of the bacteria to develop resistance against existing antibiotics and the inability of the antimicrobials to clear the intracellular bacteria residing in the gastrointestinal tract. As the critical balance of charge and hydrophobicity is required for effective membrane-targeting antimicrobials without causing any toxicity to mammalian cells, herein we report the synthesis and antibacterial properties of cholic acid-derived amphiphiles conjugated with alkyl chains of varied hydrophobicity. Relative to other hydrophobic counterparts, a compound with hexyl chain (6) acted as an effective antimicrobial against different Gram-negative bacteria. Apart from its ability to permeate the outer and inner membranes of bacteria; compound 6 can cross the cellular and lysosomal barriers of epithelial cells and macrophages and kill the facultative intracellular bacteria without disrupting the mammalian cell membranes. Oral delivery of compound 6 was able to clear the Salmonella-mediated gut infection and inflammation, and was able to combat persistent, stationary, and multi-drug-resistant clinical strains. Therefore, our study reveals the ability of cholic acid-derived amphiphiles to clear intracellular bacteria and Salmonella-mediated gut infection and inflammation.

6-Shogaol induces caspase-independent paraptosis in cancer cells via proteasomal inhibition.

An α, ß-unsaturated carbonyl compound of ginger, 6-Shogaol (6S), induced extensive cytoplasmic vacuolation and cell death in breast cancer cell (MDA-MB-231) and non-small lung cancer (A549) cells. In the presence of autophagic inhibitors the cells continued to exhibit cytoplasmic vacuolation and cell death clearly distinguishing it from the classic autophagic process. 6S induced death did not exhibit the characteristic apoptotic features like caspase cleavage, phosphatidyl serine exposure and DNA fragmentation. The immunofluorescence with the Endoplasmic Reticulum (ER) resident protein, calreticulin indicated that the vacuoles were of ER origin, typical of paraptosis. This was supported by the increase in level of microtubule associated protein light chain 3B (LC3 I and LC3 II) and polyubiquitin binding protein, p62. The level of ER stress markers like polyubiquitinated proteins, Bip and CHOP also consistently increased. We have found that 6S inhibits the 26S proteasome. The proteasomal inhibitory activity was elucidated by a) molecular docking of 6S onto the active site of ß5 subunit and b) reduced fluorescence by the fluorogenic substrate of the chymotrypsin-like subunit. In conclusion these studies demonstrate for the first time that proteasomal inhibition by 6S induces cell death via paraptosis. So 6-shogaol may act as a template for anti-cancer lead discovery against the apoptosis resistant cancer cells.

Tethering of Chemotherapeutic Drug/Imaging Agent to Bile Acid-Phospholipid Increases the Efficacy and Bioavailability with Reduced Hepatotoxicity.

Weakly basic drugs display poor solubility and tend to precipitate in the stomach's acidic environment causing reduced oral bioavailability. Tracing of these orally delivered therapeutic agents using molecular probes is challenged due to their poor absorption in the gastrointestinal tract (GIT). Therefore, we designed a gastric pH stable bile acid derived amphiphile where Tamoxifen (as a model anticancer drug) is conjugated to lithocholic acid derived phospholipid (LCA-Tam-PC). In vitro studies suggested the selective nature of LCA-Tam-PC for cancer cells over normal cells as compared to the parent drug. Fluorescent labeled version of the conjugate (LCA-Tam-NBD-PC) displayed an increased intracellular uptake compared to Tamoxifen. We then investigated the antitumor potential, toxicity, and median survival in 4T1 tumor bearing BALB/c mice upon LCA-Tam-PC treatment. Our studies confirmed a significant reduction in the tumor volume, tumor weight, and reduced hepatotoxicity with a significant increase in median survival on LCA-Tam-PC treatment as compared to the parent drug. Pharmacokinetic and biodistribution studies using LCA-Tam-NBD-PC witnessed the enhanced gut absorption, blood circulation, and tumor site accumulation of phospholipid-drug conjugate leading to improved antitumor activity. Therefore, our studies revealed that conjugation of chemotherapeutic/imaging agents to bile acid phospholipid can provide a new platform for oral delivery and tracing of chemotherapeutic drugs.

Molecular Self-Assembly of Bile Acid-Phospholipids Controls the Delivery of Doxorubicin and Mice Survivability.

Lipid composition in general determines the drug encapsulation efficacy and release kinetics from liposomes that impact the clinical outcomes of cancer therapy. We synthesized three bile acid phospholipids by conjugating the phosphocholine headgroup to the 3'-hydroxyl group of benzylated lithocholic acid (LCA), deoxycholic acid (DCA), and cholic acid (CA); and investigated the impact of membrane rigidity on drug encapsulation efficacy, drug release kinetics, anticancer effects, and mice survival. Liposomes with a hydrodynamic diameter of 100-110 nm were subsequently developed using these phospholipids. Fluorescence-probe based quantification revealed a more fluidic nature of DCA-PC- and CA-PC-derived liposomes, whereas the LCA-PC-derived ones are rigid in nature. Doxorubicin encapsulation studies showed ∼75% encapsulation and ∼38% entrapment efficacy of doxorubicin using more fluidic DCA-PC and CA-PC derived liposomes as compared to ∼58% encapsulation and ∼18% entrapment efficacy in the case of LCA-PC derived liposomes. In vivo anticancer studies in the murine model confirmed that doxorubicin entrapped CA-PC liposomes compromise mice survival, whereas rigid drug entrapped LCA-PC-derived-liposomes increased mice survival with ∼2-fold decrease in tumor volume. Pharmacokinetic and biodistribution studies revealed an ∼1.5-fold increase in plasma drug concentration and an ∼4.0-fold rise in tumor accumulation of doxorubicin on treatment with drug entrapped LCA-PC liposomes as compared to doxorubicin alone. In summary, this study presents the impact of bile acid derived liposomes with different rigidities on drug delivery and mice survivability.

A positive feedback loop involving Erk5 and Akt turns on mesangial cell proliferation in response to PDGF.

Platelet-derived growth factor BB and its receptor (PDGFRß) play a pivotal role in the development of renal glomerular mesangial cells. Their roles in increased mesangial cell proliferation during mesangioproliferative glomerulonephritis have long been noted, but the operating logic of signaling mechanisms regulating these changes remains poorly understood. We examined the role of a recently identified MAPK, Erk5, in this process. PDGF increased the activating phosphorylation of Erk5 and tyrosine phosphorylation of proteins in a time-dependent manner. A pharmacologic inhibitor of Erk5, XMD8-92, abrogated PDGF-induced DNA synthesis and mesangial cell proliferation. Similarly, expression of dominant negative Erk5 or siRNAs against Erk5 blocked PDGF-stimulated DNA synthesis and proliferation. Inhibition of Erk5 attenuated expression of cyclin D1 mRNA and protein, resulting in suppression of CDK4-mediated phosphorylation of the tumor suppressor protein pRb. Expression of cyclin D1 or CDK4 prevented the dominant negative Erk5- or siErk5-mediated inhibition of DNA synthesis and mesangial cell proliferation induced by PDGF. We have previously shown that phosphatidylinositol 3-kinase (PI3-kinase) contributes to PDGF-induced proliferation of mesangial cells. Inhibition of PI3-kinase blocked PDGF-induced phosphorylation of Erk5. Since PI3-kinase acts through Akt, we determined the role of Erk5 on Akt phosphorylation. XMD8-92, dominant negative Erk5, and siErk5 inhibited phosphorylation of Akt by PDGF. Interestingly, we found inhibition of PDGF-induced Erk5 phosphorylation by a pharmacological inhibitor of Akt kinase and kinase dead Akt in mesangial cells. Thus our data unfold the presence of a positive feedback microcircuit between Erk5 and Akt downstream of PI3-kinase nodal point for PDGF-induced mesangial cell proliferation.

Extracellular Matrix Scaffold-Assisted Tumor Vaccines Induce Tumor Regression and Long-Term Immune Memory.

Injectable scaffold delivery is a strategy to enhance the efficacy of cancer vaccine immunotherapy. The choice of scaffold biomaterial is crucial, impacting both vaccine release kinetics and immune stimulation via the host response. Extracellular matrix (ECM) scaffolds prepared from decellularized tissues facilitate a pro-healing inflammatory response that promotes local cancer immune surveillance. Here, an ECM scaffold-assisted therapeutic cancer vaccine that maintains an immune microenvironment consistent with tissue reconstruction is engineered. Several immune-stimulating adjuvants are screened to develop a cancer vaccine formulated with decellularized small intestinal submucosa (SIS) ECM scaffold co-delivery. It is found that the STING pathway agonist cyclic di-AMP most effectively induces cytotoxic immunity in an ECM scaffold vaccine, without compromising key interleukin 4 (IL-4) mediated immune pathways associated with healing. ECM scaffold delivery enhances therapeutic vaccine efficacy, curing 50-75% of established E.G-7OVA lymphoma tumors in mice, while none are cured with soluble vaccine. SIS-ECM scaffold-assisted vaccination prolonged antigen exposure is dependent on CD8+ cytotoxic T cells and generates long-term antigen-specific immune memory for at least 10 months post-vaccination. This study shows that an ECM scaffold is a promising delivery vehicle to enhance cancer vaccine efficacy while being orthogonal to characteristics of pro-healing immune hallmarks.

Paraptosis: a unique cell death mode for targeting cancer.

Programmed cell death (PCD) is the universal process that maintains cellular homeostasis and regulates all living systems' development, health and disease. Out of all, apoptosis is one of the major PCDs that was found to play a crucial role in many disease conditions, including cancer. The cancer cells acquire the ability to escape apoptotic cell death, thereby increasing their resistance towards current therapies. This issue has led to the need to search for alternate forms of programmed cell death mechanisms. Paraptosis is an alternative cell death pathway characterized by vacuolation and damage to the endoplasmic reticulum and mitochondria. Many natural compounds and metallic complexes have been reported to induce paraptosis in cancer cell lines. Since the morphological and biochemical features of paraptosis are much different from apoptosis and other alternate PCDs, it is crucial to understand the different modulators governing it. In this review, we have highlighted the factors that trigger paraptosis and the role of specific modulators in mediating this alternative cell death pathway. Recent findings include the role of paraptosis in inducing anti-tumour T-cell immunity and other immunogenic responses against cancer. A significant role played by paraptosis in cancer has also scaled its importance in knowing its mechanism. The study of paraptosis in xenograft mice, zebrafish model, 3D cultures, and novel paraptosis-based prognostic model for low-grade glioma patients have led to the broad aspect and its potential involvement in the field of cancer therapy. The co-occurrence of different modes of cell death with photodynamic therapy and other combinatorial treatments in the tumour microenvironment are also summarized here. Finally, the growth, challenges, and future perspectives of paraptosis research in cancer are discussed in this review. Understanding this unique PCD pathway would help to develop potential therapy and combat chemo-resistance in various cancer.

Mitigation of biogenic methanethiol using bacteriophages in synthetic wastewater augmented with Pseudomonas putida.

Wastewater malodour is the proverbial 'elephant in the room' notwithstanding its severe implications on sanitation, health, and hygiene. The predominant malodorous compounds associated with wastewater treatment plants and toilets are volatile organic compounds, such as hydrogen sulphide, ammonia, methanethiol, and organic acids. Among them, methanethiol warrants more attention owing to its relatively low olfactory threshold and associated cytotoxicity. This requires an efficient odour-abatement method since conventional techniques are either cost-prohibitive or leave recalcitrant byproducts. Bacteriophage-based methodology holds promise, and the described work explores the potential. In this study, a non-lysogenous Pseudomonas putida strain is used as a model organism that produces methanethiol in the presence of methionine. Two double-stranded DNA phages of genome sizes > 10 Kb were isolated from sewage. ɸPh_PP01 and ɸPh_PP02 were stable at suboptimal pH, temperature, and at 10% chloroform. Moreover, they showed adsorption efficiencies of 53% and 89% in 12 min and burst sizes of 507 ± 187 and 105 ± 7 virions per cell, respectively. In augmented synthetic wastewater, ɸPh_PP01 and ɸPh_PP02 reduced methanethiol production by 52% and 47%, respectively, with the concomitant reduction in P. putida by 3 logs in 6 h. On extension of the study in P. putida spiked-sewage sample, maximum reduction in methanethiol production was achieved in 3 h, with 49% and 48% for ɸPh_PP01 and ɸPh_PP02, respectively. But at 6 h, efficiency reduced to 36% with both the phages. The study clearly demonstrates the potential of phages as biocontrol agents in the reduction of malodour in wastewater.

Corrigendum: Paraptosis: a unique cell death mode for targeting cancer.

[This corrects the article DOI: 10.3389/fphar.2023.1159409.].

Harnessing the probiotic properties and immunomodulatory effects of fermented food-derived Limosilactobacillus fermentum strains: implications for environmental enteropathy.

Introduction: Environmental enteropathy (EE), a chronic small intestine disease characterized by gut inflammation, is widely prevalent in low-income countries and is hypothesized to be caused by continuous exposure to fecal contamination. Targeted nutritional interventions using potential probiotic strains from fermented foods can be an effective strategy to inhibit enteric pathogens and prevent chronic gut inflammation. Methods: We isolated potential strains from fermented rice water and lemon pickle and investigated their cell surface properties, antagonistic properties, adhesion to HT-29 cells, and inhibition of pathogen adherence to HT-29 cells. Bacteriocin-like inhibitory substances (BLIS) were purified, and in vivo, survival studies in Caenorhabditis elegans infected with Salmonella enterica MW116733 were performed. We further checked the expression pattern of pro and anti-inflammatory cytokines (IL-6, IL8, and IL-10) in HT-29 cells supplemented with strains. Results: The strains isolated from rice water (RS) and lemon pickle (T1) were identified as Limosilactobacillus fermentum MN410703 and MN410702, respectively. Strains showed probiotic properties like tolerance to low pH (pH 3.0), bile salts up to 0.5%, simulated gastric juice at low pH, and binding to extracellular matrix molecules. Auto-aggregation of T1 was in the range of 85% and significantly co-aggregated with Klebsiella pneumoniae, S. enterica, and Escherichia coli at 48, 79, and 65%, respectively. Both strains had a higher binding affinity to gelatin and heparin compared to Bacillus clausii. Susceptibility to most aminoglycoside, cephalosporin, and macrolide classes of antibiotics was also observed. RS showed BLIS activity against K. pneumoniae, S. aureus, and S. enterica at 60, 48, and 30%, respectively, and the protective effects of BLIS from RS in the C. elegans infection model demonstrated a 70% survival rate of the worms infected with S. enterica. RS and T1 demonstrated binding efficiency to HT-29 cell lines in the 38-46% range, and both strains inhibited the adhesion of E. coli MDR and S. enterica. Upregulation of IL-6 and IL-10 and the downregulation of IL-8 were observed when HT-29 cells were treated with RS, indicating the immunomodulatory effects of the strain. Discussion: The potential strains identified could effectively inhibit enteric pathogens and prevent environmental enteropathy.

A localized hydrogel-mediated chemotherapy causes immunogenic cell death via activation of ceramide-mediated unfolded protein response.

Treatment of triple-negative breast cancer (TNBC) is challenging because of its "COLD" tumor immunosuppressive microenvironment (TIME). Here, we present a hydrogel-mediated localized delivery of a combination of docetaxel (DTX) and carboplatin (CPT) (called DTX-CPT-Gel therapy) that ensured enhanced anticancer effect and tumor regression on multiple murine syngeneic and xenograft tumor models. DTX-CPT-Gel therapy modulated the TIME by an increase of antitumorigenic M1 macrophages, attenuation of myeloid-derived suppressor cells, and increase of granzyme B+CD8+ T cells. DTX-CPT-Gel therapy elevated ceramide levels in tumor tissues that activated the protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK)-mediated unfolded protein response (UPR). This UPR-mediated activation of apoptotic cell death led to release of damage-associated molecular patterns, thereby activating the immunogenic cell death that could even clear the metastatic tumors. This study provides a promising hydrogel-mediated platform for DTX-CPT therapy that induces tumor regression and effective immune modulation and, therefore, can be explored further for treatment of TNBC.

Lytics broadcasting system: A novel approach to disseminate bacteriophages for disinfection and biogenic hydrogen sulphide removal tested in synthetic sewage.

Owing to their selective nature, bacteriophages are prospective in targeted wastewater disinfection. Other potential applications include the removal of biogenic malodour and the mitigation of corrosion in sewerage pipelines. Nevertheless, its applications are ridden with challenges, the most prominent of which is scaling up. Towards that end, effective methodologies are required for dispersing phages into wastewater. The study describes a device arbitrarily named Lytics Broadcasting System. In principle, the device contains phages that can be continuously dispersed into wastewater. The modified version is called Bacteriophage Amplification Reactor, which operates with both phages and their respective hosts, ensuring continual production and dissemination of phages. Both prototypes utilize 0.22 µm cellulose membranes as an interface through which phage diffuse passively and selectively owing to its smaller size and established through membrane-overlay method. In the study, previously reported bacteriophage φPh_Se01 and Salmonella enterica were used. A reduction of 3-4 log was achieved with both the prototypes after 48 h of operation in 1 L of augmented synthetic sewage. Subsequently, the biogenic H2S produced by Salmonella enterica was reduced by 64-74% indicating its utility for targeted disinfection and malodour mitigation of wastewater. This study aims to provide a framework for the development of scalable prototypes of Lytic Broadcasting Systems for real-world wastewater applications.

Escherichia coli ST155 as a production-host of three different polyvalent phages and their characterisation with a prospect for wastewater disinfection.

Bacteriophages are generally specific, and a cocktail of phages is needed to combat different bacterial targets. Their production usually requires pathogenic isolation hosts. We identified a novel strain, Escherichia coli ST155, that could serve as a production host for three different polyvalent phages (ϕPh_SE03, ϕPh_SD01, and ϕPh_EC01), thus superseding the use of individual isolation hosts. Upon propagation in E. coli ST155, the phages demonstrated differential intergeneric infectivity against Salmonella enterica, E. coli OP50, Shigella dysenteriae, E. coli MDR, and Acinetobacter baumannii. Phages were characterised based on morphology, latent period, burst size, the efficiency of plating, and restriction enzyme profile. Survival assay on Caenorhabditis elegans, the absence of Shiga toxin, and enterotoxigenic E. coli virulence genes indicated that E. coli ST155 could be non-pathogenic. Lack of antibiotic resistance and absence of functional prophages rendered the host suitable for environmental applications. As a proof-of-concept, phage ϕPh_SE03 was produced in ST155 by employing a unique Bacteriophage Amplification Reactor-Lytics Broadcasting System and was simultaneously disseminated into S. enterica augmented wastewater, which resulted in a 3-log reduction in 24 h. The study establishes the potential of E. coli ST155 as a phage production host thereby minimising the possibility of accidental release of pathogenic hosts into wastewater.

Targeting Vancomycin-Resistant Enterococci (VRE) Infections and Van Operon-Mediated Drug Resistance Using Dimeric Cholic Acid-Peptide Conjugates.

Emergence of vancomycin resistance in Gram-positive bacteria and the prevalence of vancomycin-resistant Enterococci (VRE) infections are highly alarming as very limited antibiotic options are available against VRE infections. Here, we present the synthesis of cholic acid-derived dimeric amphiphiles where two cholic acid moieties are tethered through carboxyl terminals using different alkylene spacers. Our investigations revealed that dimer 5 possessing a propylene spacer and glycine-valine peptides tethered on hydroxyl groups is the most effective antimicrobial against VRE. Dimer 5 can permeabilize bacterial membranes, generate reactive oxygen species, and clear preformed biofilms. We further demonstrate that dimer 5 downregulates vancomycin-mediated transcriptional activation of the vanHAX gene cluster and does not allow VSE to develop vancomycin resistance until 100 generations. Therefore, this study, for the first time, presents a bacterial membrane-targeting amphiphile that can mitigate VRE infections and inhibit the emergence of vancomycin resistance.

Advances in engineering of low molecular weight hydrogels for chemotherapeutic applications.

Chemotherapy is the primary option for the treatment of cancer, inflammation, and infectious diseases. Conventional drug delivery poses solubility and bioavailability challenges, systemic toxicity, non-specific targeting, and poor accumulation of chemotherapeutic drugs at the desired site. Nanotechnology has led to the development of various nanomaterials that have decreased the toxicity and increased the accumulation of drugs at the target site. Systemic administration of nanomaterials causes burst release and non-specific targeting of chemotherapeutics, leading to off-target organ toxicity. Drug delivery based on low molecular weight hydrogels (LMWHs) provides a suitable alternative for drug delivery due to their ability to entrap chemotherapeutic drugs. Injectable and biodegradable LMWHs allow the administration of chemotherapeutics with minimal invasion, allow the sustained release of chemotherapeutic drugs for long periods, and reduce the challenges of immunogenicity and low drug entrapment efficiency. Herein, we summarize the advances in the engineering of LMWHs for controlled and prolonged delivery of chemotherapeutics for cancer, infectious diseases, and inflammatory disorders.

Self-assembled supramolecular nanomicelles from a bile acid-docetaxel conjugate are highly tolerable with improved therapeutic efficacy.

Herein, we present the engineering of a supramolecular nanomicellar system that is composed of self-assembled units of the PEGylated lithocholic acid (LCA)-docetaxel (DTX) conjugate (LCA-DTX-PEG). We tethered a short polyethylene glycol unit to LCA and used an esterase-sensitive ester linkage between DTX and LCA. The LCA-DTX-PEG conjugate formed nanomicelles (LCA-DTX-PEG NMs) with ∼160 nm hydrodynamic diameter that are sensitive to cellular esterases and maximized the release of DTX under high esterase exposure. LCA-DTX-PEG NMs were found to be effective as the parent drug in breast cancer cells by stabilizing tubulin and arresting the cells in the G2/M phase. We determined the maximum tolerated dose (MTD) and systemic and vital organ toxicity of LCA-DTX-PEG NMs in mice, rats, and rabbits. LCA-DTX-PEG NMs showed a MTD of >160 mg kg-1 and are found to be safe in comparison with their parent FDA-approved drug formulation (Taxotere® or DTX-TS) that is highly toxic. LCA-DTX-PEG NMs effectively reduced the tumor volume and increased the survival of 4T1 tumor-bearing mice with improved blood circulation time of the drug and its higher accumulation in tumor tissues. Therefore, this study highlights the potential of PEGylated bile acid-drug conjugate based nanomicelles for the development of next generation cancer therapeutics.