Molecular mechanism of specific HLA-A mRNA recognition by the RNA-binding-protein hMEX3B to promote tumor immune escape.

Immunotherapy, including immune checkpoint inhibitors and adoptive cell transfer, has obtained great progress, but their efficiencies vary among patients due to the genetic and epigenetic differences. Human MEX3B (hMEX3B) protein is an RNA-binding protein that contains two KH domains at the N-terminus and a RING domain at its C-terminus, which has the activity of E3 ubiquitin ligase and is essential for RNA degradation. Current evidence suggests that hMEX3B is involved in many important biological processes, including tumor immune evasion and HLA-A regulation, but the sequence of substrate RNA recognized by hMEX3B and the functional molecular mechanisms are unclear. Here, we first screened the optimized hMEX3B binding sequence on the HLA-A mRNA and reported that the two tandem KH domains can bind with their substrate one hundred times more than the individual KH domains. We systematically investigated the binding characteristics between the two KH domains and their RNA substrates by nuclear magnetic resonance (NMR). Based on this information and the small-angle X-ray scattering (SAXS) data, we used molecular dynamics simulations to obtain structural models of KH domains in complex with their corresponding RNAs. By analyzing the models, we noticed that on the KH domains' variable loops, there were two pairs of threonines and arginines that can disrupt the recognition of the RNA completely, and this influence had also been verified both in vitro and in vivo. Finally, we presented a functional model of the hMEX3B protein, which indicated that hMEX3B regulated the degradation of its substrate mRNAs in many biological processes. Taken together, our research illustrated how the hMEX3B protein played a key role in translation inhibition during the immune response to tumor cells and provided an idea and a lead for the study of the molecular mechanism and function of other MEX3 family proteins.

Fecal calprotectin as a non-invasive marker for the prediction of post-necrotizing enterocolitis stricture.

PURPOSE: This study aimed to evaluate the clinical utility of fecal calprotectin (FC) levels during the necrotizing enterocolitis (NEC) episode to predict the onset of post-NEC intestinal stricture. METHODS: The medical records of patients with NEC treated from April 2020 to April 2022 were recorded for this study. FC was quantified at the acute phase of NEC. FC levels were compared in patients with or without intestinal stricture. Receiver operating characteristics (ROC) analysis was constructed to determine optimal cut-offs of FC for post-NEC intestinal stricture. RESULTS: A total of 50 infants with NEC were enrolled in this study and 14 (28%) of them eventually developed intestinal stricture. All children with intestinal stricture underwent one-stage surgery and all made it through the follow-up period alive. The median FC level was 1237.55 (741.25, 1378.80) ug/g in patients with intestinal stricture and it was significantly higher than that in the non-stricture group [158.30 (76.23, 349.13) ug/g, P < 0.001]. FC had good diagnostic accuracy for predicting intestinal stricture, according to ROC curve analysis, with an AUC area of 0.911. At an optimal cut-off value of 664.2 ug/g, sensitivity and specificity were 85.71% and 91.67%, respectively. CONCLUSION: As a non-invasive parameter, FC has excellent efficacy and accuracy in predicting post-NEC intestinal stricture. Increased FC levels at the acute phase of NEC were associated with the development of intestinal stricture.

Tricyclic Diterpenoids Selectively Suppress Androgen Receptor-Positive Prostate Cancer Cells.

Androgen receptor (AR) is a viable therapeutic target for lethal castration-resistant prostate cancer (CRPC), because the continued progression of CRPC is mainly driven by the reactivation of AR transcriptional activity. The current FDA-approved AR antagonists binding to ligand binding domain (LBD) become ineffective in CRPC with AR gene amplification, LBD mutation, and the evolution of LBD-truncated AR splice variants. Encouraged by the fact that tricyclic aromatic diterpenoid QW07 has recently been established as a potential N-terminal AR antagonist, this study aims to explore the structure-activity relationship of tricyclic diterpenoids and their potential to suppress AR-positive cell proliferation. Dehydroabietylamine, abietic acid, dehydroabietic acid, and their derivatives were selected, since they have a similar core structure as QW07. Twenty diterpenoids were prepared for the evaluation of their antiproliferative potency on AR-positive prostate cancer cell models (LNCaP and 22Rv1) using AR-null cell models (PC-3 and DU145) as comparisons. Our data indicated that six tricyclic diterpenoids possess greater potency than enzalutamide (FDA-approved AR antagonist) towards LNCaP and 22Rv1 AR-positive cells, and four diterpenoids are more potent than enzalutamide against 22Rv1 AR-positive cells. The optimal derivative possesses greater potency (IC50 = 0.27 µM) and selectivity than QW07 towards AR-positive 22Rv1 cells.

Modeling the effects of phosphorylation on phase separation of the FUS low-complexity domain.

Aggregation of the RNA-binding protein fused in sarcoma (FUS) is a hallmark of neurodegenerative diseases. Phosphorylation of Ser/Thr in the FUS low-complexity domain (FUS-LC) may regulate phase separation of FUS and prevent pathological aggregation in cells. However, many details of this process remain elusive to date. In this work, we systematically investigated the phosphorylation of FUS-LC and the underlying molecular mechanism by molecular dynamics (MD) simulations and free energy calculations. The results clearly show that phosphorylation can destroy the fibril core structure of FUS-LC by breaking interchain interactions, particularly contacts involving residues like Tyr, Ser, and Gln. Among the six phosphorylation sites, Ser61 and Ser84 may have more important effects on the stability of the fibril core. Our study reveals structural and dynamic details of FUS-LC phase separation modulated by phosphorylation.

Core Structure-Activity Relationship Studies of 5,7,20-O-Trimethylsilybins in Prostate Cancer Cell Models.

Silibinin, also known as silybin, is isolated from milk thistle (Silybum marianum). Silibinin has been demonstrated to be a good lead compound due to its potential to prevent and treat prostate cancer. Its moderate potency and poor pharmacokinetic profile hindered it from moving forward to therapeutic use. Our research group has been working on optimizing silibinin for the potential treatment of castration-resistant prostate cancer. Our previous studies established 5,7,20-O-trimethylsilybins as promising lead compounds as they can selectively suppress androgen receptor (AR)-positive LNCaP cell proliferation. Encouraged by the promising data, the present study aims to investigate the relationships between the core structure of 5,7,20-O-trimethylsilybin and their antiproliferative activities towards AR-positive (LNCaP) and AR-negative prostate cancer cell lines (PC-3 and DU145). The structure-activity relationships among the four different core structures (including flavanonol-type flavonolignan (silibinin), flavone-type flavonolignan (hydnocarpin D), chalcone-type flavonolignan, and taxifolin (a flavonolignan precursor) indicate that 5,7,20-O-trimethylsilybins are the most promising scaffold to selectively suppress AR-positive LNCaP prostate cancer cell proliferation. Further investigation on the antiproliferative potency of their optically enriched versions of the most promising 5,7,20-O-trimethylsilybins led to the conclusion that (10R,11R) derivatives (silybin A series) are more potent than (10S,11S) derivatives (silybin B series) in suppressing AR positive LNCaP cell proliferation.

Multi-scale analysis of nickel ion tolerance mechanism for thermophilic Sulfobacillus thermosulfidooxidans in bioleaching.

Bioleaching is intensively investigated for recovering valuable metals such as Li, Co, Ni and Cu. Nickel ion stress threatens the health of microorganisms when Ni2+ starts to accumulate in the leachate during the bioleaching of materials that are rich in Ni, such as spent lithium-ion batteries. The possible mechanisms underlying the response of S. thermosulfidooxidans to nickel ion stress were analyzed using a multi-scale approach. Under the condition of nickel ion stress, high concentrations of nickel ions were immobilized by extracellular polymeric substances, while concentrations of nickel ions inside the cells remained low. The intracellular adenosine triphosphate (ATP) concentration and H+-ATPase activity increased to maintain normal cell growth and metabolic activities. Scavenging abilities of S. thermosulfidooxidans for hydrogen peroxide and superoxide anion were enhanced to reduce oxidative damage induced by nickel ion stress. There were 734 differentially expressed genes identified by RNA-seq under nickel ion stress. Most of them were involved in oxidative phosphorylation, glutathione metabolism and genetic information processing, responsible for intracellular energy utilization, intracellular antioxidant capacity and DNA damage repair, respectively. The results of this study are of major significance for in-depth understanding of the mechanisms of acidophilic microorganisms' resistance to metal ions.

Synthesis and biological evaluation of niclosamide PROTACs.

Roughly 268,000 new cases of prostate cancer and 34,000 deaths from prostate cancer are projected by the American Cancer Society to occur in the United States in 2022. Androgen receptor is a key protein in the proliferation and survival of prostate cancer cells and has been revealed to be overexpressed in 30% to 50% of castration-resistant prostate cancer patients. One promising approach to reducing the level of this protein is Proteolysis Targeting Chimeras (PROTACs) that is an emerging drug discovery technology. PROTACs are hetero-bifunctional molecules where one end binds to a protein of interest and the other to an E3 ligase ligand, initiating the Ubiquitin-Proteasome Pathway for protein degradation. Two PROTACs with niclosamide as androgen receptor ligand and VHL-032 as the E3 ligase ligand have been designed and synthesized for suppressing proliferation of androgen receptor-positive prostate cancer cells via degrading androgen receptor. The in vitro antiproliferative assessment suggested that they can selectively suppress PC-3, LNCaP, and 22Rv1 prostate cancer cell proliferation, but cannot inhibit DU145 cell proliferation. However, the mechanism of both compounds in suppressing prostate cancer cell proliferation is not through the AR PROTAC mechanism because they did not degrade AR in our Western Blotting assay up to 1 µM.

Strategies for anti-oxidative stress and anti-acid stress in bioleaching of LiCoO2 using an acidophilic microbial consortium.

High metal ion concentrations and low pH cause severely inhibit the activity of an acidophilic microbial consortium (AMC) in bioleaching. This work investigated the effects of exogenous spermine on biofilm formation and the bioleaching efficiency of LiCoO2 by AMC in 9K medium. After the addition of 1 mM spermine, the activities of glutathione peroxidase and catalase increased, while the amount of H2O2, intracellular reactive oxygen species (ROS) and malondialdehyde in AMC decreased. These results indicated that the ability of AMC biofilm to resist oxidative stress introduced by 3.5 g/L Li+ and 30.1 g/L Co2+ was improved by spermine. The activity of glutamate decarboxylase was promoted to restore the intracellular pH buffering ability of AMC. Electrochemical measurements showed that the oxidation rate of pyrite was increased by exogenous spermine. As a result, high bioleaching efficiencies of 97.1% for Li+ and 96.1% for Co2+ from a 5.0% (w v-1) lithium cobalt oxide powder slurry were achieved. This work demonstrated that Tafel polarization can be used to monitor the AMC biofilm's ability of uptaking electrons from pyrite during bioleaching. The corrosion current density increased with 1 mM spermine, indicating enhanced electron uptake by the biofilm from pyrite.

Forecasting Network Interface Flow Using a Broad Learning System Based on the Sparrow Search Algorithm.

In this paper, we propose a broad learning system based on the sparrow search algorithm. Firstly, in order to avoid the complicated manual parameter tuning process and obtain the best combination of hyperparameters, the sparrow search algorithm is used to optimize the shrinkage coefficient (r) and regularization coefficient (λ) in the broad learning system to improve the prediction accuracy of the model. Second, using the broad learning system to build a network interface flow forecasting model. The flow values in the time period [T-11,T] are used as the characteristic values of the traffic at the moment T+1. The hyperparameters outputted in the previous step are fed into the network to train the broad learning system network traffic prediction model. Finally, to verify the model performance, this paper trains the prediction model on two public network flow datasets and real traffic data of an enterprise cloud platform switch interface and compares the proposed model with the broad learning system, long short-term memory, and other methods. The experiments show that the prediction accuracy of this method is higher than other methods, and the moving average reaches 97%, 98%, and 99% on each dataset, respectively.

Multi-Center Analysis of Predictive Factors of Enteral Autonomy and Risk Factors of Complications of Pediatric Intestinal Failure in China.

OBJECTIVES: The aim of this study was to identify predictors for enteral autonomy and intestinal failure (IF)-related complications and evaluate the outcomes of a multi-center pediatric cohort in China. METHODS: The medical records of pediatric patients with IF treated at four medical centers in China from January 1, 2012 to November 31, 2020 were retrospectively reviewed. Enteral autonomy was defined as sustained growth and cessation of parenteral nutrition for >90 days. Multivariate logistic regression analysis was used to identify factors predictive of enteral autonomy and the risk factors of complications, such as IF-associated liver disease (IFALD) and catheter-related bloodstream infection (CRBSI). RESULTS: The study cohort of 92 pediatric patients with IF included 71 (77%) who underwent surgery and 21 (23%) who received non-surgical treatment. Eventually, 63 (68.5%) patients achieved enteral autonomy by the end of the follow-up period. Multivariate logistic regression analysis indicated that longer duration of parenteral nutrition (PN), sepsis, and non-breastfeeding were risk factors for enteral autonomy. When considering the detailed intraoperative data, the presence of an ileocecal valve (ICV) and greater residual small bowel (RSB) length were reaffirmed as predictors of achieving enteral autonomy. Medium/long-chain (MCT/LCT) lipids or sepsis were identified as negative predictors for IFALD. Univariate analysis revealed that the use of MCT/LCT lipids was associated with a greater likelihood of CRBSI. CONCLUSION: In this cohort, enteral autonomy was achieved at a percentage of 68.5%, and the risk factors for not achieving enteral autonomy were a longer duration of PN, sepsis, and non-breastfeeding. The presence of an ICV and a greater RSB length were important predictors of achieving enteral autonomy.

5-Substituted 3, 3', 4', 7-tetramethoxyflavonoids - A novel class of potent DNA triplex specific binding ligands.

Herein, we present a class of potent triplex DNA binding ligands derived from the natural product quercetin, which is the first of its kind that has ever been reported in the literature. The binding of 5-substituted quercetin derivatives (3, 3', 4', 7-tetramethoxyflavonoids) to triplex and duplex DNA was investigated using several biophysical tools, including thermal denaturation monitored by UV, circular dichroism, differential scanning calorimetry, and isothermal titration calorimetry. Experimental data reveal that several 5-substituted 3, 3', 4', 7-tetramethoxyflavonoids have remarkable effects on binding to DNA triple helices, and they do not influence the double-helical DNA structures. A few derivatives such as compounds 5 and 7 have comparable (if not better) binding affinities to neomycin, a well-known DNA triplex binding ligand, under the same conditions. The amino-containing side chains at the 5-position of 3, 3', 4', 7-tetramethoxyflavonoids are crucial for the observed binding affinity and specificity.

Risk factors for the occurrence and recurrence of acute cerebellar ataxia: a retrospective observational study.

OBJECTIVE: There is little evidence to support a correlation between abdominal surgery and acute cerebellar ataxia (ACA). We reviewed the records of children with ACA treated at our institution to analyze risk factors for ACA. METHODS: Clinical data of 442 children with ACA treated at Children's Hospital of Nanjing Medical University between November 2015 and June 2019 were retrospectively analyzed. Univariate and multivariate analyses were performed to determine risk factors for the occurrence and recurrence of ACA. RESULTS: In total, 442 children with ACA were included in this study. Multivariate logistic regression analysis showed age (p = 0.009), infection (p < 0.001), vaccination (p < 0.001), head trauma (p < 0.001), intussusception surgery (IS) (p < 0.001), operation for indirect inguinal hernia (p < 0.001), and operation for congenital gastrointestinal malformation (p < 0.001) were independent risk factors for ACA occurrence. Univariate analysis showed that only IS (p < 0.001) was associated with ACA recurrence. CONCLUSIONS: Surgeons should be aware that age, infection, vaccination, head trauma, and history of abdominal surgery are associated with ACA, while IS is a risk factor for ACA recurrence.

Effects of cadmium sulfide nanoparticles on sulfate bioreduction and oxidative stress in Desulfovibrio desulfuricans.

Sulfate-containing wastewater has a serious threat to the environment and human health. Microbial technology has great potential for the treatment of sulfate-containing wastewater. It was found that nano-photocatalysts could be used as extracellular electron donors to promote the growth and metabolic activity of non-photosynthetic microorganisms. However, nano-photocatalysts could also induce oxidative stress and damage cells. Therefore, the interaction mechanism between photosynthetic nanocatalysts and non-photosynthetic microorganisms is crucial to determine the regulatory strategies for microbial wastewater treatment technologies. In this paper, the mechanism and regulation strategy of cadmium sulfide nanoparticles (CdS NPs) on the growth of sulfate-reducing bacteria and the sulfate reduction process were investigated. The results showed that the sulfate reduction efficiency could be increased by 6.4% through CdS NPs under light conditions. However, the growth of Desulfovibrio desulfuricans C09 was seriously inhibited by 55% due to the oxidative stress induced by CdS NPs on cells. The biomass and sulfate reduction efficiency could be enhanced by 6.8% and 5.9%, respectively, through external addition of humic acid (HA). At the same time, the mechanism of the CdS NPs strengthening the sulfate reduction process by sulfate bacteria was also studied which can provide important theoretical guidance and technical support for the development of microbial technology combined with extracellular electron transfer (EET) for the treatment of sulfate-containing wastewater.

3-O-Carbamoyl-5,7,20-O-trimethylsilybins: Synthesis and Preliminary Antiproliferative Evaluation.

To search for novel androgen receptor (AR) modulators for the potential treatment of castration-resistant prostate cancer (CRPC), naturally occurring silibinin was sought after as a lead compound because it possesses a moderate potency towards AR-positive prostate cancer cells and its chemical scaffold is dissimilar to all currently marketed AR antagonists. On the basis of the structure-activity relationships that we have explored, this study aims to incorporate carbamoyl groups to the alcoholic hydroxyl groups of silibinin to improve its capability in selectively suppressing AR-positive prostate cancer cell proliferation together with water solubility. To this end, a feasible approach was developed to regioselectively introduce a carbamoyl group to the secondary alcoholic hydroxyl group at C-3 without causing the undesired oxidation at C2-C3, providing an avenue for achieving 3-O-carbamoyl-5,7,20-O-trimethylsilybins. The application of the synthetic method can be extended to the synthesis of 3-O-carbamoyl-3',4',5,7-O-tetramethyltaxifolins. The antiproliferative potency of 5,7,20-O-trimethylsilybin and its nine 3-carbamoyl derivatives were assessed in an AR-positive LNCaP prostate cancer cell line and two AR-null prostate cancer cell lines (PC-3 and DU145). Our preliminary bioassay data imply that 5,7,20-O-trimethylsilybin and four 3-O-carbamoyl-5,7,20-O-trimethylsilybins emerge as very promising lead compounds due to the fact that they can selectively suppress AR-positive LNCaP cell proliferation. The IC50 values of these five 5,7,20-O-trimethylsilybins against the LNCaP cells fall into the range of 0.11-0.83 µM, which exhibit up to 660 times greater in vitro antiproliferative potency than silibinin. Our findings suggest that carbamoylated 5,7,20-O-trimethylsilybins could serve as a natural product-based scaffold for new antiandrogens for lethal castration-resistant prostate cancer.

Gestational diabetes mellitus is associated with the neonatal gut microbiota and metabolome.

BACKGROUND: Gestational diabetes mellitus (GDM) is a metabolic disease that occurs in pregnant women and increases the risk for the development of diabetes. The relationship between GDM and meconium microbiota and metabolome remains incompletely understood. METHODS: Four hundred eighteen mothers (147 women with GDM and 271 normal pregnant women) and their neonates from the GDM Mother and Child Study were included in this study. Meconium microbiota were profiled by 16S rRNA gene sequencing. Meconium and maternal serum metabolome were examined by UPLC-QE. RESULTS: Microbial communities in meconium were significantly altered in neonates from the GDM mothers. A reduction in alpha diversity was observed in neonates of GDM mothers. At the phylum level, the abundance of Firmicutes and Proteobacteria changed significantly in neonates of GDM mothers. Metabolomic analysis of meconium showed that metabolic pathways including taurine and hypotaurine metabolism, pyrimidine metabolism, beta-alanine metabolism, and bile acid biosynthesis were altered in GDM subjects. Several changed metabolites varying by the similar trend across the maternal serum and neonatal meconium were observed. CONCLUSION: Altogether, these findings suggest that GDM could alter the serum metabolome and is associated with the neonatal meconium microbiota and metabolome, highlighting the importance of maternal factors on early-life metabolism.

An amide mimic of desTHPdactylolide: Total synthesis and antiproliferative evaluation.

(-)-Zampanolide is a unique microtubule stabilizing agent (MSA) with covalent-binding mechanism and low nanomolar anitproliferative potency towards multi-drug resistant cancer cells. MSAs have a special connection with prostate cancer by inhibiting androgen receptor nuclear translocation. Zampanolide and the structurally related dactylolide have thus been sought after by us as lead compounds for development of anti-prostate cancer agents. DesTHPdactylolide is a simplified mimic of dactylolide and has previously been synthesized by us in both configurations, with the (17R) configuration being more potent in suppressing prostate cancer cell proliferation. The current study aims to synthesize an amide mimic of (17R) desTHPdactylolide that was anticipated to be metabolically more stable than (17R) desTHPdactylolide. To this end, the amide mimic has been successfully synthesized through a 26-step transformation from 2-butyn-1-ol. Our WST-1 cell proliferation assay in five human prostate cancer cell models indicated that the lactam moiety can serve as a bioisostere for the lactone in desTHPdactylolide.

Comp34 displays potent preclinical antitumor efficacy in triple-negative breast cancer via inhibition of NUDT3-AS4, a novel oncogenic long noncoding RNA.

The abnormal PI3K/AKT/mTOR pathway is one of the most common genomic abnormalities in breast cancers including triple-negative breast cancer (TNBC), and pharmacologic inhibition of these aberrations has shown activity in TNBC patients. Here, we designed and identified a small-molecule Comp34 that suppresses both AKT and mTOR protein expression and exhibits robust cytotoxicity towards TNBC cells but not nontumorigenic normal breast epithelial cells. Mechanically, long noncoding RNA (lncRNA) AL354740.1-204 (also named as NUDT3-AS4) acts as a microRNA sponge to compete with AKT1/mTOR mRNAs for binding to miR-99s, leading to decrease in degradation of AKT1/mTOR mRNAs and subsequent increase in AKT1/mTOR protein expression. Inhibition of lncRNA-NUDT3-AS4 and suppression of the NUDT3-AS4/miR-99s association contribute to Comp34-affected biologic pathways. In addition, Comp34 alone is effective in cells with secondary resistance to rapamycin, the best-known inhibitor of mTOR, and displays a greater in vivo antitumor efficacy and lower toxicity than rapamycin in TNBC xenografted models. In conclusion, NUDT3-AS4 may play a proproliferative role in TNBC and be considered a relevant therapeutic target, and Comp34 presents promising activity as a single agent to inhibit TNBC through regulation of NUDT3-AS4 and miR-99s.

1-Chromonyl-5-Imidazolylpentadienone Demonstrates Anti-Cancer Action against TNBC and Exhibits Synergism with Paclitaxel.

Curcumin has been well studied for its anti-oxidant, anti-inflammatory, and anti-cancer action. Its potential as a therapy is limited due to its low bioavailability and rapid metabolism. To overcome these challenges, investigators are developing curcumin analogs, nanoparticle formulations, and combining curcumin with other compounds or dietary components. In the present study, we used a 1-chromonyl-5-imidazolylpentadienone named KY-20-22 that contains both the pharmacophore of curcumin and 1,4 benzopyrone (chromone) moiety typical for flavonoids, and also included specific moieties to enhance the bioavailability. When we tested the in vitro effect of KY-20-22 in triple-negative breast cancer (TNBC) cell lines, we found that it decreased the cell survival and colony formation of MDA-MB-231 and MDA-MB-468 cells. An increase in mitochondrial reactive oxygen species was also observed in TNBC cells exposed to KY-20-22. Furthermore, KY-20-22 decreased epithelial-mesenchymal formation (EMT) as evidenced by the modulation of the EMT markers E-cadherin and N-cadherin. Based on the fact that KY-20-22 regulates interleukin-6, a cytokine involved in chemotherapy resistance, we combined it with paclitaxel and found that it synergistically induced anti-proliferative action in TNBC cells. The results from this study suggested that 1-chromonyl-5-imidazolylpentadienone KY-20-22 exhibited anti-cancer action in MDA-MB-231 and MDA-MB-468 cells. Future studies are required to evaluate the anti-cancer ability and bioavailability of KY-20-22 in the TNBC animal model.

New Zampanolide Mimics: Design, Synthesis, and Antiproliferative Evaluation.

Zampanolide is a promising microtubule-stabilizing agent (MSA) with a unique chemical structure. It is superior to the current clinically used MSAs due to the covalent nature of its binding to ß-tubulin and high cytotoxic potency toward multidrug-resistant cancer cells. However, its further development as a viable drug candidate is hindered by its limited availability. More importantly, conversion of its chemically fragile side chain into a stabilized bioisostere is envisioned to enable zampanolide to possess more drug-like properties. As part of our ongoing project aiming to develop its mimics with a stable side chain using straightforward synthetic approaches, 2-fluorobenzyl alcohol was designed as a bioisosteric surrogate for the side chain based on its binding conformation as confirmed by the X-ray structure of tubulin complexed with zampanolide. Two new zampanolide mimics with the newly designed side chain have been successfully synthesized through a 25-step chemical transformation for each. Yamaguchi esterification and intramolecular Horner-Wadsworth-Emmons condensation were used as key reactions to construct the lactone core. The chiral centers at C17 and C18 were introduced by the Sharpless asymmetric dihydroxylation. Our WST-1 cell proliferation assay data in both docetaxel-resistant and docetaxel-naive prostate cancer cell lines revealed that compound 6 is the optimal mimic and the newly designed side chain can serve as a bioisostere for the chemically fragile N-acetyl hemiaminal side chain in zampanolide.

Prospective study reveals a microbiome signature that predicts the occurrence of post-operative enterocolitis in Hirschsprung disease (HSCR) patients.

Hirschsprung disease (HSCR) is a birth defect with an approximate incidence of 1/5,000 live births, and up to one-third of HSCR patients develop Hirschsprung-associated enterocolitis (HAEC), the leading cause of HSCR-related death. Very little is known about the pathogenesis, prevention, and early diagnosis of HAEC. Here, we used a prospective study to investigate the enteric microbiome composition at the time of surgery as a predictor for developing postoperative HAEC. We identified a microbiome signature containing 21 operational taxonomic units (OTUs) that can potentially predict postoperative HAEC with ~85% accuracy. Furthermore, we identified exclusive breastfeeding as a novel protective factor for total HAEC (i.e., preoperative and postoperative HAEC combined). In addition, we discovered that breastfeeding was associated with a lowered risk for HAEC potentially mediated by modulating the gut microbiome composition characterized by a lower abundance of Gram-negative bacteria and lower LPS concentrations. In conclusion, modulating the gut microbiome by encouraging breastfeeding might prevent HAEC progression in HSCR patients.