Gender differences in the association between dietary protein intake and constipation: findings from NHANES.

Purpose: Dietary factors play a crucial role in the development and management of chronic constipation, yet the relationship between dietary protein intake and constipation remains underexplored. This study aims to investigate the association between dietary protein intake and the prevalence of constipation among American adults, with a focus on potential gender differences, using large-scale national data. Materials and methods: Data from 14,048 participants aged 20 and above (7,072 men and 6,976 women) from the National Health and Nutrition Examination Survey (NHANES) 2005-2010 were analyzed. The Bristol Stool Form Scale's types 1 (separate hard lumps, resembling nuts) and 2 (sausage-shaped, but lumpy) were used to define constipation. A 24-h dietary recall technique was used to measure dietary protein intake. After controlling for covariates, the association between protein consumption and constipation risk was examined using multivariable logistic regression, smooth curve fitting, and testing for gender interaction effects. We then further determined the threshold effect between dietary protein intake and constipation risk. Results: Constipation was present in 7.49% of people overall, with a higher proportion among women (10.19%) than among males (4.82%). In men, higher protein intake was significantly associated with a lower rate of constipation. However, in women, higher protein intake correlated with an increased risk of constipation, and the interaction between gender was significant (P for interaction = 0.0298). These results were corroborated by smooth curve fits, which also demonstrated a dose-response effect. Further threshold effect analysis showed that the turning points of dietary protein intake differed between male and female participants (119.42 gm/day for men; 40.79 gm/day for women). Conclusion: The association between dietary protein intake and constipation was different in different genders with threshold effect. For men, moderately increasing protein intake could be beneficial, while for women, exceeding a certain level may increase the risk of constipation. These insights are crucial for guiding dietary protein recommendations for different genders and have significant clinical implications.

Deep Clustering: A Comprehensive Survey.

Cluster analysis plays an indispensable role in machine learning and data mining. Learning a good data representation is crucial for clustering algorithms. Recently, deep clustering (DC), which can learn clustering-friendly representations using deep neural networks (DNNs), has been broadly applied in a wide range of clustering tasks. Existing surveys for DC mainly focus on the single-view fields and the network architectures, ignoring the complex application scenarios of clustering. To address this issue, in this article, we provide a comprehensive survey for DC in views of data sources. With different data sources, we systematically distinguish the clustering methods in terms of methodology, prior knowledge, and architecture. Concretely, DC methods are introduced according to four categories, i.e., traditional single-view DC, semi-supervised DC, deep multiview clustering (MVC), and deep transfer clustering. Finally, we discuss the open challenges and potential future opportunities in different fields of DC.

Late-stage peptide modification and macrocyclization enabled by tertiary amine catalyzed tryptophan allylation.

Late-stage modification of peptides could potentially endow peptides with significant bioactivity and physicochemical properties, and thereby provide novel opportunities for peptide pharmaceutical studies. Since tryptophan (Trp) bears a unique indole ring residue and plays various critical functional roles in peptides, the modification methods for tryptophan were preliminarily developed with considerable progress via transition-metal mediated C-H activation. Herein, we report an unprecedented tertiary amine catalyzed peptide allylation via the SN2'-SN2' pathway between the N1 position of the indole ring of Trp and Morita-Baylis-Hillman (MBH) carbonates. Using this method that proceeds under mild conditions, we demonstrated an extremely broad scope of Trp-containing peptides and MBH carbonates to prepare a series of peptide conjugates and cyclic peptides. The reaction is amenable to either solid-phase (on resin) or solution-phase conditions. In addition, the modified peptides can be further conjugated with other biomolecules at Trp, providing a new handle for bioconjugation.

Alkenyl oxindole is a novel PROTAC moiety that recruits the CRL4DCAF11 E3 ubiquitin ligase complex for targeted protein degradation.

Alkenyl oxindoles have been characterized as autophagosome-tethering compounds (ATTECs), which can target mutant huntingtin protein (mHTT) for lysosomal degradation. In order to expand the application of alkenyl oxindoles for targeted protein degradation, we designed and synthesized a series of heterobifunctional compounds by conjugating different alkenyl oxindoles with bromodomain-containing protein 4 (BRD4) inhibitor JQ1. Through structure-activity relationship study, we successfully developed JQ1-alkenyl oxindole conjugates that potently degrade BRD4. Unexpectedly, we found that these molecules degrade BRD4 through the ubiquitin-proteasome system, rather than the autophagy-lysosomal pathway. Using pooled CRISPR interference (CRISPRi) screening, we revealed that JQ1-alkenyl oxindole conjugates recruit the E3 ubiquitin ligase complex CRL4DCAF11 for substrate degradation. Furthermore, we validated the most potent heterobifunctional molecule HL435 as a promising drug-like lead compound to exert antitumor activity both in vitro and in a mouse xenograft tumor model. Our research provides new employable proteolysis targeting chimera (PROTAC) moieties for targeted protein degradation, providing new possibilities for drug discovery.

Poly(amino acid)-based drug delivery nanoparticles eliminate Methicillin resistant Staphylococcus aureus via tunable release of antibiotic.

Bacterial infections threaten public health, and novel therapeutic strategies critically demand to be explored. Herein, poly(amino acid) (PAA)-based drug delivery nanoparticles (NPs) were designed for eliminating Methicillin resistant Staphylococcus aureus (MRSA) via tunable release of antibiotic. Using N-acryloyl amino acids (valine, valine methyl ester, aspartic acid, serine) as monomers, four kinds of amphiphilic PAAs were synthesized via photoinduced electron/energy transfer-reversible addition fragmentation chain-transfer (PET-RAFT) polymerization and were further assembled into nano-sized delivery systems. Their assemble behavior was drove mainly by hydrophobic/hydrophilic interaction, which determined the particle size, efficacy of drug loading and release; but numerous hydrogen bonding (HB) interaction also played an important role in regulating morphologies of the NPs and enriching drug-binding capacity. By changing the HB- and hydrophobic-interaction of the PAAs, the particle sizes (240.7 nm-302.7 nm), the drug loading efficiency (9.57%-19.76%), and the Rifampicin (Rif) release rate (49.6%-69.7%) of the PAA-based NPs could be tunable. Specially, the antimicrobial properties of the Rif-loaded NPs are found to be related to the release of Rif, which was determined by its hydrophobic interaction with hydrophobic blocks and HB interaction with hydrophilic blocks. These studies provide a new outlook for the design of delivery systems for the therapy of bacterial infection.

LINC00472 Regulates Ferroptosis of Neurons in Alzheimer's Disease via FOXO1.

INTRODUCTION: The objective of the study was to explore the molecular mechanism of long noncoding RNA (lncRNA) LINC00472 in Alzheimer's disease (AD) and identify potential novel targets for AD therapy. METHOD: Ferroptosis-related lncRNAs were screened by GEO database. AD mouse model was constructed for in vivo experiments. The content of Aß protein and tau protein hyperphosphorylation were examined in hippocampal tissue samples of mice. Subsequently, HT22 cells were induced with Aß25-35 to establish a neuronal injury model of AD in vitro. The expression of FOXO1, a key gene for ferroptosis, was verified by overexpressing/knocking down the LINC00472. The effects of LINC00472 on ROS and lipid peroxidation content, GPX4, and tau protein in AD model cells were examined by ROS assay, MDA assay, Western blot, and qRT-PCR. Subsequently, the expression of iron ion, FTH, TfRC, and Fpn protein were detected in AD cells. RESULTS: The level of FOXO1 was positively correlated with the degree of AD. In vivo experiments showed that the expression of Aß and tau hyperphosphorylated were significantly reduced in the inhibitor group and iron was significantly reduced relative to the AD group. In the AD cell model, the content of lipid peroxide was upregulated, GPX4 protein and mRNA were decreased, and phosphorylation of tau protein was enhanced in the AD cell model relative to the control group. Whereas knocking down LINC00472 inhibited the upregulation of lipid peroxide, decreased the level of GPX4, and enhanced tau protein phosphorylation, and reduced iron accumulation in AD cells. CONCLUSIONS: LINC00472 affects ferroptosis in AD by regulating iron accumulation in neuronal cells.

Novel Peptide DR3penA as a Low-Toxicity Antirenal Fibrosis Agent by Suppressing the TGF-ß1/miR-212-5p/Low-Density Lipoprotein Receptor Class a Domain Containing 4/Smad Axis.

Renal fibrosis is a complex pathological process that contributes to the development of chronic kidney disease due to various risk factors. Conservative treatment to curb progression without dialysis or renal transplantation is widely applicable, but its effectiveness is limited. Here, the inhibitory effect of the novel peptide DR3penA (DHα-(4-pentenyl)-AlaNPQIR-NH2), which was developed by our group, on renal fibrosis was assessed in cells and mice with established fibrosis and fibrosis triggered by transforming growth factor-ß1 (TGF-ß1), unilateral ureteral obstruction, and repeated low-dose cisplatin. DR3penA preserved renal function and ameliorated renal fibrosis at a dose approximately 100 times lower than that of captopril, which is currently used in the clinic. DR3penA also significantly reduced existing fibrosis and showed similar efficacy after subcutaneous or intraperitoneal injection. Mechanistically, DR3penA repressed TGF-ß1 signaling via miR-212-5p targeting of low-density lipoprotein receptor class a domain containing 4, which interacts with Smad2/3. In addition to having good pharmacological effects, DR3penA could preferentially target injured kidneys and exhibited low toxicity in acute and chronic toxicity experiments. These results unveil the advantages of DR3penA regarding efficacy and toxicity, making it a potential candidate compound for renal fibrosis therapy.

FePd Nanozyme- and SKN-Encapsulated Functional Lipid Nanoparticles for Cancer Nanotherapy via ROS-Boosting Necroptosis.

Cell necroptosis has presented great potential, acting as an effective approach against tumor apoptotic resistance, and it could be further enhanced via accompanying reactive oxygen species (ROS) overexpression. However, whether overproduced ROS assists the necroptotic pathway remains unclear. Thus, iron-palladium nanozyme (FePd NZ)- and shikonin (SKN)-encapsulated functional lipid nanoparticles (FPS-LNPs) were designed to investigate the ROS overexpression-enhanced SKN-induced necroptosis. In this system, SKN acts as an effective necroptosis inducer for cancer cells, and FePd NZ, a sensitive Fenton reaction catalyst, produces extra-intracellular ROS to reinforce the necroptotic pathway. Both in vitro and in vivo antitumor evaluation revealed that FPS-LNPs presented the best tumor growth inhibition efficacy compared with FP-LNPs or SKN-LNPs alone. Meanwhile, induced necroptosis by FPS-LNPs can further trigger the release of damage-associated molecular patterns (DAMPs) and antigens from dying tumor cells to activate the innate immune response. Taking biosafety into consideration, this study has provided a potential nanoplatform for cancer nanotherapy via inducing necroptosis to avoid apoptosis resistance and activate CD8+ T cell immune response.

Poly(d-amino acid) Nanoparticles Target Staphylococcal Growth and Biofilm Disassembly by Interfering with Peptidoglycan Synthesis.

d-Amino acids are signals for biofilm disassembly. However, unexpected metabolic pathways severely attenuate the utilization of d-amino acids in biofilm disassembly, resulting in unsatisfactory efficiency. Herein, three-dimensional poly(d-amino acid) nanoparticles (NPs), which possess the ability to block intracellular metabolism, are constructed with the aim of disassembling the biofilms. The obtained poly(α-N-acryloyl-d-phenylalanine)-block-poly(ß-N-acryloyl-d-aminoalanine NPs (denoted as FA NPs) present α-amino groups and α-carboxyl groups of d-aminoalanine on their surface, which guarantees that FA NPs can effectively insert into bacterial peptidoglycan (PG) via the mediation of PG binding protein 4 (PBP4). Subsequently, the FA NPs trigger the detachment of amyloid-like fibers that connect to the PG and reduce the number of polysaccharides and proteins in extracellular polymeric substances (EPS). Finally, FA NPs damage the structural stability of EPS and lead to the disassembly of the biofilm. Based on this feature, FA NPs significantly enhance the killing efficacy of encapsulated sitafloxacin sesquihydrate (Sita) by facilitating the penetration of Sita within the biofilm, achieving complete elimination of Staphylococcal biofilm in mice. Therefore, this study strongly demonstrates that FA NPs can effectively improve biofilm disassembly efficacy and provide great potential for bacterial biofilm infection treatment.

Fufangxiaopi formula alleviates DSS-induced colitis in mice by inhibiting inflammatory reaction, protecting intestinal barrier and regulating intestinal microecology.

ETHNOPHARMACOLOGICAL RELEVANCE: Fufangxiaopi Formula (FF) is a modified form of Sishen Wan, traditionally used for treating diarrhea. The application of FF for treating ulcerative colitis (UC) has achieved desirable outcomes in clinical settings. However, the underlying mechanism of the effect of FF on UC is yet to be determined. AIM OF STUDY: This study aimed to evaluate the protective effect and underlying mechanism of FF on mice with dextran sodium sulfate (DSS)-induced colitis. MATERIALS AND METHODS: In vivo, the efficacy of FF on the symptoms associated with DSS-induced colitis in mice was clarified by observing the body weight change, colon length, DAI score, and H&E staining. The release of inflammatory mediators in mouse colon tissues was detected by ELISA and MPO, and the contents of TLR4/NF-κB signaling pathway and MAPK signaling pathway-related proteins, as well as intestinal barrier-related proteins, were detected in mouse colon tissues by western blot method. Changes in the content of barrier proteins in mouse colon tissues were detected by immunofluorescence. 16S rRNA sequencing and FMT were performed to clarify the effects of FF on intestinal flora. In vitro, the effect of FF-containing serum on LPS-induced inflammatory mediator release from RAW264.7 cells were detected by qRT-PCR. The contents of TLR4/NF The effects of FF-containing serum on B signaling pathway and MAPK signaling pathway related proteins in RAW264.7 cells and intestinal barrier related proteins in Caco-2 cells were detected by western blot. The effects of FF-containing serum on LPS-induced nuclear translocation of p65 protein in RAW264.7 cells and barrier-associated protein in Caco-2 cells were detected by immunofluorescence. RESULTS: In vivo studies showed that FF could significantly alleviate the symptoms of UC, including reducing colon length, weight loss, clinical score, and colon tissue injury in mice. FF could significantly reduce the secretion of proinflammatory cytokines by suppressing the activation of the TLR4/NF-κB and MAPK signaling pathways. Moreover, FF could protect the integrity of intestinal barriers by significantly increasing claudin-3, occludin, and ZO-1 expression levels. 16S rRNA sequencing and FMT elucidate that FF can alleviate symptoms associated with colitis in mice by interfering with intestinal flora. In vitro studies showed that FF drug-containing serum could significantly inhibit proinflammatory responses and attenuate the secretion of iNOS, IL-1ß, TNF-α, IL-6, and COX-2 by suppressing the activation of TLR4/NF-κB and MAPK signaling pathways in RAW264.7 cells. Furthermore, FF could protect the Caco-2 cell epithelial barrier. CONCLUSION: FF could alleviate DSS-induced colitis in mice by maintaining the intestinal barrier, inhibiting the activation of TLR4/NF-κB and MAPK signaling pathways, reducing the release of proinflammatory factors, and regulating intestinal microecology.

Asiaticoside ameliorates DSS-induced colitis in mice by inhibiting inflammatory response, protecting intestinal barrier and regulating intestinal microecology.

Ulcerative colitis (UC) is one of the most prevalent inflammatory bowel diseases and poses a serious threat to human health. Currently, safe and effective preventive measures are unavailable. In this study, the protective effects of asiaticoside (AS) on dextran sodium sulfate (DSS)-induced colitis in mice and the underlying molecular mechanism were investigated. In this experiment, colitis was induced in mice with DSS. Subsequently, the role of AS in colitis and its underlying mechanisms were examined using H&E staining, immunofluorescence staining, western blot, Elisa, FMT, and other assays. The results showed that AS significantly attenuated the related symptoms of DSS-induced colitis in mice. In addition, AS inhibited the activation of signaling pathways TLR4/NF-κB and MAPK reduced the release of inflammatory factors, thereby attenuating the inflammatory response in mice. AS administration also restored the permeability of the intestinal barrier by increasing the levels of tight junction-associated proteins (claudin-3, occludin, and ZO-1). In addition, AS rebalanced the intestinal flora of DSS-treated mice by increasing the diversity of the flora. AS can alleviate DSS-induced ulcerative colitis in mice by maintaining the intestinal barrier, thus inhibiting the signaling pathways TLR4/NF-κB and MAPK activation, reducing the release of inflammatory factors, and regulating intestinal microecology.

Synthesis of Isoquinuclidines via Dearomative Diels-Alder Reaction of Cyclic Amidines with Indoles.

The development and utilization of new dienes and dienophiles for the controlled synthesis of isoquinuclidines is highly appealing. Herein, we describe a novel strategy for diastereoselective synthesis of indoline-fused isoquinuclidines via copper-catalyzed dearomative Diels-Alder reaction of cyclic amidines with indoles. This protocol avoids the use of unstable DHPs and activated alkenes, offering a more efficient and selective approach to synthesize isoquinuclidines.

GSH/pH Cascade-Responsive Nanoparticles Eliminate Methicillin-Resistant Staphylococcus aureus Biofilm via Synergistic Photo-Chemo Therapy.

Bacterial biofilm infection threatens public health, and efficient treatment strategies are urgently required. Phototherapy is a potential candidate, but it is limited because of the off-targeting property, vulnerable activity, and normal tissue damage. Herein, cascade-responsive nanoparticles (NPs) with a synergistic effect of phototherapy and chemotherapy are proposed for targeted elimination of biofilms. The NPs are fabricated by encapsulating IR780 in a polycarbonate-based polymer that contains disulfide bonds in the main chain and a Schiff-base bond connecting vancomycin (Van) pendants in the side chain (denoted as SP-Van@IR780 NPs). SP-Van@IR780 NPs specifically target bacterial biofilms in vitro and in vivo by the mediation of Van pendants. Subsequently, SP-Van@IR780 NPs are decomposed into small size and achieve deep biofilm penetration due to the cleavage of disulfide bonds in the presence of GSH. Thereafter, Van is then detached from the NPs because the Schiff base bonds are broken at low pH when SP@IR780 NPs penetrate into the interior of biofilm. The released Van and IR780 exhibit a robust synergistic effect of chemotherapy and phototherapy, strongly eliminate the biofilm both in vitro and in vivo. Therefore, these biocompatible SP-Van@IR780 NPs provide a new outlook for the therapy of bacterial biofilm infection.

Drug delivery systems for enhanced tumour treatment by eliminating intra-tumoral bacteria.

Cancer remains one of the serious threats to human health. The relationship between bacteria and various tumours has been widely reported in recent years, and studies on intra-tumoral bacteria have become important as intra-tumoral bacteria directly affect the tumorigenesis, progression, immunity and metastatic processes. Therefore, eliminating these commensal intra-tumoral bacteria while treating tumour is expected to be a potential strategy to further enhance the clinical outcome of tumour therapy. Drug delivery systems (DDSs) are widely used to deliver antibiotics and chemotherapeutic drugs for antibacterial and anticancer applications, respectively. Thus, this review firstly provides a comprehensive summary of the association between intra-tumoral bacteria and a host of tumours, followed by a description of advanced DDSs for improving the therapeutic efficacy of cancer treatment through the elimination of intra-tumoral bacteria. It is hoped that this review will provide guidelines for the therapeutic and "synergistic antimicrobial and antitumour" drug delivery strategy.

M335, a novel small-molecule STING agonist activates the immune response and exerts antitumor effects.

In the context of antitumor immune responses, the activation of the stimulator of interferon genes (STING) assumes a critical role and imparts enhanced immunogenicity. An effective strategy for exogenously activating the immune system involves the utilization of STING agonists, and prior investigations primarily concentrated on modifying endogenous cyclic dinucleotides (CDNs) to achieve this. Nevertheless, the practical utility of CDNs was restricted due to limitations associated with their physicochemical attributes and administration protocols. In this article, we present the discovery of a novel small-molecule agonist denoted as M335, identified through high-throughput screening using surface plasmon resonance (SPR). M335 demonstrates the ability to activate the TBK1-IRF3-IFN axis in a STING-dependent manner in vitro. Through experimentation on mouse models bearing tumors, we observed that the administration of M335 resulted in the activation of immune cells. Notably, significant antitumor effects were achieved with both intratumoral and intraperitoneal administration of M335. These findings suggest the potential of M335 as a promising agent for cancer immunotherapy, which will promote the development of STING agonists in anti-tumor applications.

Design and synthesis of dual BRD4/Src inhibitors for treatment of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an extremely aggressive tumor with limited treatment options and effectiveness. Dual-target inhibitors capable of simultaneously suppressing invasion may represent a promising therapeutic approach for TNBC. In this work, we developed a series of dual BRD4/Src inhibitors by connecting JQ1 and dasatinib using various linkers and evaluated their efficacy against TNBC both in vitro and in vivo. Among these compounds, HL403 demonstrated IC50 values of 133 nM for BRD4 inhibition and 4.5 nM for Src inhibition. Most importantly, HL403 not only exhibited potent anti-proliferative capabilities, but also effectively suppressed the invasion of MDA-MB-231 cells in vitro. Finally, the anti-tumor efficacy of HL403 was validated in a mouse MDA-MB-231 xenograft tumor model, achieving a tumor growth inhibition rate (TGI) of 70.7 %, which was superior to the combination of JQ1 and dasatinib (TGI = 54.0 %). Our research provides a promising and feasible new strategy for improving the treatment of TNBC.

Enhancing near-infrared II photodynamic therapy with nitric oxide for eradicating multidrug-resistant biofilms in deep tissues.

Nitric oxide (NO) enhanced photodynamic therapy (PDT) is a promising approach to overcome drug tolerance and resistance to biofilm but is limited by its short excitation wavelengths and low yield of reactive oxygen species (ROS). Herein, we develop a compelling degradable polymer-based near-infrared II (NIR-II, 1000-1700 nm) photosensitizer (PNIR-II), which can maintain 50 % PDT efficacy even under a 2.6 cm tissue barrier. Remarkably, PNIR-II is synthesized by alternately connecting the electron donor thiophene to the electron acceptors diketopyrrolopyrrole (DPP) and boron dipyrromethene (BODIPY), where the intramolecular charge transfer properties can be tuned to increase the intersystem crossover rate and decrease the internal conversion rate, thereby stabilizing the NIR-II photodynamic rather than photothermal effect. For exerting a combination therapy to eradicate multidrug-resistant biofilms, PNIR-II is further assembled into nanoparticles (NPs) with a synthetic glutathione-triggered NO donor polymer. Under 1064 nm laser radiation, NPs precisely release ROS and NO that triggered by over-expressed GSH in the biofilm microenvironment, thereby forming more bactericidal reactive nitrogen species (RNS) in vitro and in vivo in the mice model that orderly destroy biofilm of multidrug-resistant Staphylococcus aureus cultures from clinical patients. It thus provides a new outlook for destroy the biofilm of deep tissues.

Enantioselective Synthesis of N-N Amide-Pyrrole Atropisomers via Paal-Knorr Reaction.

The catalytic asymmetric construction of monoheteroaryl N-N axially chiral compounds and chiral five-membered aryl-based scaffolds remains challenging. Herein, we present a highly efficient enantioselective synthesis of monoheteroaryl N-N atropisomers via an asymmetric Paal-Knorr reaction, affording a diverse array of N-N amide-pyrrole atropisomers with excellent enantioselectivities. Gram-scale synthesis and post-transformations of the product demonstrated the synthesis utility of this method. Racemization experiments confirmed the configurational stability of these N-N axially chiral products. This study not only provides the first de novo cyclization example for accessing an asymmetric monoheteroaryl N-N scaffold but also offers a new member of the N-N atropisomer family with potential synthetic and medicinal applications.

The Peptide DHα-(4-pentenyl)-ANPQIR-NH2 Exhibits Antifibrotic Activity in Multiple Pulmonary Fibrosis Models Induced by Particulate and Soluble Chemical Fibrogenic Agents.

Interstitial lung diseases (ILDs) are a group of restrictive lung diseases characterized by interstitial inflammation and pulmonary fibrosis. The incidence of ILDs associated with exposure to multiple hazards such as inhaled particles, fibers, and ingested soluble chemicals is increasing yearly, and there are no ideal drugs currently available. Our previous research showed that the novel and low-toxicity peptide DHα-(4-pentenyl)-ANPQIR-NH2 (DR3penA) had a strong antifibrotic effect on a bleomycin-induced murine model. Based on the druggability of DR3penA, we sought to investigate its effects on respirable particulate silicon dioxide (SiO2)- and soluble chemical paraquat (PQ)-induced pulmonary fibrosis in this study by using western blot, quantitative reverse-transcription polymerase chain reaction (RT-qPCR), immunofluorescence, H&E and Masson staining, immunohistochemistry, and serum biochemical assays. The results showed that DR3penA alleviated the extent of fibrosis by inhibiting the expression of fibronectin and collagen I and suppressed oxidative stress and epithelial-mesenchymal transition (EMT) in vitro and in vivo. Further study revealed that DR3penA may mitigate pulmonary fibrosis by negatively regulating the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway and mitogen-activated protein kinase (MAPK) pathway. Unexpectedly, through the conversion of drug bioavailability under different routes of administration, DR3penA exerted antifibrotic effects equivalent to those of the positive control drug pirfenidone (PFD) at lower doses. In summary, DR3penA may be a promising lead compound for various fibrotic ILDs. SIGNIFICANCE STATEMENT: Our study verified that DHα-(4-pentenyl)-ANPQIR-NH2 (DR3penA) exhibited positive antifibrotic activity in pulmonary fibrosis induced by silicon dioxide (SiO2) particles and soluble chemical paraquat (PQ) and demonstrated a low-dose advantage compared to the small-molecule drug pirfenidone (PFD). The peptide DR3penA can be further developed for the treatment of multiple fibrotic lung diseases.

Endometriosis and epithelial ovarian cancer: a two-sample Mendelian randomization analysis.

Endometriosis, a prevalent condition, has long been recognized as a chronic and debilitating ailment affecting an estimated 1790 million women worldwide. Observational studies have established a correlation between endometriosis and ovarian cancer. Thus, we endeavored to employ Two-Sample Mendelian Randomization, utilizing summary statistics from a Genome-Wide Association Study of endometriosis and epithelial ovarian cancer, with genetic markers serving as proxies for epithelial ovarian cancer. The analysis revealed a significant correlation between these entities, with an odds ratio (OR) of 1.23 (95% CI 1.11-1.36). Upon histotype-specific examination, robust evidence emerged for an association of endometriosis with the risk of endometrioid carcinoma (OR 1.49, 95% CI 1.24-1.81), clear cell carcinoma (OR 2.56, 95% CI 1.75-3.73), and low malignant potential tumors (OR 1.28, 95% CI 1.08-1.53). These findings provide a theoretical framework for prospective investigations aimed at enhancing the potential therapeutic efficacy of managing endometriosis in averting the onset and progression of ovarian cancer.