Natural rubber latex-based biomaterials for drug delivery and regenerative medicine: Trends and directions.

Natural Rubber Latex (NRL) has shown to be a promising biomaterial for use as a drug delivery system to release various bioactive compounds. It is cost-effective, easy to handle, biocompatible, and exhibits pro-angiogenic and pro-healing properties for both soft and hard tissues. NRL releases compounds following burst and sustained release kinetics, exhibiting first-order release kinetics. Moreover, its pore density can be adjusted for tailored kinetics profiles. In addition, biotechnological applications of NRL in amblyopia, smart mattresses, and neovaginoplasty have demonstrated success. This comprehensive review explores NRL's diverse applications in biotechnology and biomedicine, addressing challenges in translating research into clinical practice. Organized into eight sections, the review emphasizes NRL's potential in wound healing, drug delivery, and metallic nanoparticle synthesis. It also addresses the challenges in enhancing NRL's physical properties and discusses its interactions with the human immune system. Furthermore, examines NRL's potential in creating wearable medical devices and biosensors for neurological disorders. To fully explore NRL's potential in addressing important medical conditions, we emphasize throughout this review the importance of interdisciplinary research and collaboration. In conclusion, this review advances our understanding of NRL's role in biomedical and biotechnological applications, offering insights into its diverse applications and promising opportunities for future development.

Insights into taxadiene synthase catalysis and promiscuity facilitated by mutability landscape and molecular dynamics.

MAIN CONCLUSION: Protein modeling, carbocation docking, and molecular dynamics along with structure-based mutability landscapes provided insight into taxadiene synthase catalysis (first step of the anticancer Taxol biosynthesis), protein structure-function correlations, and promiscuity. Plant terpenes belong to one of the largest and most diverse classes of natural products. This diversity is driven by the terpene synthase enzyme family which comprises numerous different synthases, several of which are promiscuous. Taxadiene synthase (TXS) is a class I diterpene synthase that catalyzes the first step in the biosynthesis pathway of the diterpene Taxol, an anticancer natural product produced by the Taxus plant. Exploring the molecular basis of TXS catalysis and its promiscuous potential garnered interest as a necessary means for understanding enzyme evolution and engineering possibilities to improve Taxol biosynthesis. A catalytically active closed conformation TXS model was designed using the artificial intelligence system, AlphaFold, accompanied by docking and molecular dynamics simulations. In addition, a mutability landscape of TXS including 14 residues was created to probe for structure-function relations. The mutability landscape revealed no mutants with improved catalytic activity compared to wild-type TXS. However, mutations of residues V584, Q609, V610, and Y688 showed high degree of promiscuity producing cembranoid-type and/or verticillene-type major products instead of taxanes. Mechanistic insights into V610F, V584M, Q609A, and Y688C mutants compared to the wild type revealed the trigger(s) for product profile change. Several mutants spanning residues V584, Q609, Y688, Y762, Q770, and F834 increased production of taxa-4(20),11(12)-diene which is a more favorable substrate for Taxol production compared to taxa-4(5),11(12)-diene. Finally, molecular dynamics simulations of the TXS reaction cascade revealed residues involved in ionization, carbocation stabilization, and cyclization ushering deeper understanding of the enzyme catalysis mechanism.

COPD Assessment Test and risk of readmission in patients with bronchiectasis: a prospective cohort study.

Introduction: Readmission following bronchiectasis exacerbation is a common and challenging clinical problem and few simple predictive tools exist. The COPD Assessment Test (CAT) is an easy-to-use questionnaire. This study aims to evaluate the predictive value of CAT scores in determining the risk of readmission in patients with bronchiectasis exacerbation. Methods: We conducted a prospective cohort study in 106 bronchiectasis patients admitted with exacerbation. All patients completed the CAT at admission and at discharge. Patients were followed-up for 12 months to collect data on readmission. The area under the curve was used to measure the predictive value of CAT at admission, CAT at discharge and change in CAT for readmission due to bronchiectasis exacerbation. Results: 46 patients were readmitted for bronchiectasis exacerbation within 12 months. High CAT at admission was an independent risk factor for readmission within 12 months in patients with acute exacerbation of bronchiectasis (hazard ratio 3.201, 95% CI 1.065-9.624; p<0.038) after adjustment for confounding variables. The cut-off value of CAT at admission and CAT at discharge to predict 12-month readmission in patients with acute exacerbation of bronchiectasis was 23.5 (sensitivity 62.2%, specificity 83.6%) and 15.5 (sensitivity 52.2%, specificity 87.0%). Conclusions: CAT at admission is a strong predictor of readmission in patients with bronchiectasis exacerbation.

Emulsion template fabricated heterogeneous bilayer gelatin-based scaffolds with sustained-delivery of lycium barbarum glycopeptide for periodontitis treatment.

Periodontitis is a chronic inflammatory disease raising the risks of tooth-supporting structures destruction and even tooth loss. The way to reconstruct periodontal bone tissues in inflammatory microenvironment has been long in demand for periodontitis treatment. In this study, the lycium barbarum glycopeptide (LbGP) loaded gelatin-based scaffolds were fabricated for periodontitis treatment. Gelatin microspheres with suitable size were prepared by emulsification and gathered by oxidized sodium alginate to prepare heterogeneous bilayer gelatin-based scaffolds, and then they were loaded with LbGP. The prepared scaffolds possessed interconnected porous microstructures, good degradation properties, sufficient mechanical properties, sustained release behavior and well biocompatibility. In vitro experiments suggested that the LbGP loaded gelatin-based scaffolds could inhibit the expression of inflammatory factors (IL-1ß, IL-6, and TNF-α), promote the expression of anti-inflammatory factor (IL-10), and the expression of osteogenic markers (BMP2, Runx2, ALP, and OCN) in PDLSCs under the LPS-stimulated inflammatory microenvironment. Moreover, in rat periodontitis models, the LbGP gelatin-based scaffolds would reduce the alveolar bone resorption of rats, increase the collagen fiber content of periodontal membrane, alleviate local inflammation and improve the expression of osteogenesis-related factors. Therefore, the LbGP loaded gelatin-based scaffolds in this study will provide a potential therapeutic strategy for periodontitis treatment.

Long-term Change of Low Anterior Resection Syndrome in Survivors of Rectal Cancer: Longitudinal Follow-up of a Randomized Controlled Trial.

BACKGROUND: Postoperative bowel dysfunction, also known low anterior resection syndrome, is common in rectal cancer survivors and significantly impacts quality of life. Although long-term longitudinal follow-up is lacking, improvement of the syndrome is commonly believed to happen only within the first two years. OBJECTIVE: This study aims to depict the longitudinal evolvement of low anterior resection syndrome beyond 3 years and explores factors associated with the change. DESIGN: Longitudinal long-term follow-ups were performed for the single center with the largest cohort within the multi-center FOWARC randomized controlled trial. SETTING: A quaternary referral center. PATIENTS: Individuals diagnosed with rectal cancer who received long-course neoadjuvant chemotherapy or chemoradiotherapy, followed by sphincter-preserving radical proctectomy. MAIN OUTCOME MEASUREMENTS: Change of low anterior resection syndrome score and stoma status. RESULTS: Of the 220 patients responding to the first follow-up at a median of 39 months, 178 (80.9%) responded to the second follow-up after a median of 83 months. During the interval, mean low anterior resection syndrome score improved from 29.5 (95% confidence interval [CI] 28.3-30.7) to 18.6 (95% CI 16.6-20.6). 56 (31.5%) patients reported improvement from major to no/minor severity, and 6 (3.4%) patients had new stoma due to severe bowel dysfunction. Neoadjuvant radiation (p = 0.016) was independently and negatively associated with improvement of the score. LIMITATIONS: Loss of follow-up during the long-term follow-ups. CONCLUSION: Most rectal cancer survivors with low anterior resection syndrome continued to improve beyond 3 years after proctectomy. Neoadjuvant radiation was negatively associated with long-term improvement of low anterior resection syndrome. See Video Abstract.

Reconstruction and analysis of transient evolution images of laser-produced plasma plumes.

We introduce a method for the analysis and simulation of transient images of laser-produced plasma (LPP) plumes. This method comprises three steps: (i) calculating the two-dimensional distribution of plasma parameters using a radiation hydrodynamics model, (ii) constructing radiation paths through ray tracing, and (iii) solving the radiation transport equation along these paths. In our simulations, we have meticulously considered factors that could influence the imaging results, including the quantum efficiency to different radiation wavelengths, the imaging lens' transmittance, the target surface's reflectivity, and the absorption, emission, and scattering quantum effect of the detector processes occurring in the plasma. We applied this method to analyze and simulate the transient images of aluminum plasma plumes in a background air environment at a pressure of 2000 Pa. The results demonstrate that our method not only produces simulated images that align with experimental results but also provides a reliable distribution of plasma state parameters and clearly identifies the ion species radiating in different bands. Given its capability in transient image reconstruction and its adaptability as a tool for spectral simulation and analysis of LPPs, we believe this method holds significant potential for spectral diagnostics in fields such as laser-induced breakdown spectroscopy, extreme ultraviolet lithography sources, and high-energy-density physics, among others.

Hyaluronic acid-functionalized DDAB/PLGA nanoparticles for improved oral delivery of magnolol in the treatment of ulcerative colitis.

Dysfunction of the mucosal barrier as well as local inflammation are major challenges in the treatment of ulcerative colitis (UC). Mag, a natural compound derived from traditional Chinese medicine, has been shown to have anti-inflammatory and mucosal protection properties. However, its poor gastrointestinal stability as well as its insufficient accumulation in inflamed colonic lesions limit its potential use as an alternative therapeutic drug in UC. The present research involved the design and preparation of a hybrid nanoparticle system (LPNs) specifically targeting macrophages at the colonic site. This was achieved by electrostatically adsorbing HA onto positively charged lipid-polymer hybrid nanoparticles (HA-LPNs). The prepared HA-LPNs exhibited a rounded morphology and a narrow size distribution. In vitro, the anti-inflammatory efficacy of Mag-HA-LPNs (which control levels of the pro-inflammatory cytokines NO, IL-6 and TNF-α) was assessed in RAW 264.7 cells. Analysis by flow cytometry and fluorescence microscopy demonstrated increased cellular uptake through HA/CD44 interaction. As expected, Mag-HA-LPNs was found to effectively increased colon length and reduced DAI scores in DSS-treated mice. This effect was achieved by regulating the inflammatory cytokines level and promoting the restoration of the colonic mucosal barrier through increased expression of Claudin-1, ZO-1 and Occludin. In this study, we developed an efficient and user-friendly delivery method for the preparation of HA-functionalized PLGA nanoparticles, which are intended for oral delivery of Mag. The findings suggest that these HA-LPNs possess the potential to serve as a promising approach for direct drug delivery to the colon for effective treatment of UC.

Kinetics of extracting valuable components from Ti-bearing blast furnace slag by acidolysis with sulphuric acid.

Ti-bearing blast furnace slag is a kind of solid waste produced by Pangang Group Company through the blast furnace smelting method. A variety of valuable components can be extracted from the Ti-bearing blast furnace slag after acidolysis with concentrated sulphuric acid. In order to study the kinetics of acidolysis, this paper investigated the effects of the acidolysis temperature, acid-slag ratio and raw material particle size on the overall extraction rate of Ti4+, Mg2+ and Al3+ components at different reaction times, and simulated the acidolysis process by using the unreacted shrinking core model. The results showed that the acidolysis process was controlled by internal diffusion with an apparent activation energy of 19.05 kJ mol-1 and the semi-empirical kinetic equation of the acidolysis process was obtained.

Human papillomavirus E7 protein induces homologous recombination defects and PARPi sensitivity.

PURPOSE: Cervical cancer is a common gynecological malignancy, pathologically associated with persistent infection of high-risk types of human papillomavirus (HPV). Previous studies revealed that HPV-positive cervical cancer displays genomic instability; however, the underlying mechanism is not fully understood. METHODS: To investigate if DNA damage responses are aggravated in precancerous lesions of HPV-positive cervical epithelium, cervical tissues were biopsied and cryosectioned, and subjected to immunofluorescent staining. Cloned HA-tagged E6 and E7 genes of HPV16 subtype were transfected into HEK293T or C33A cells, and indirect immunofluorescent staining was applied to reveal the competency of double strand break (DSB) repair. To test the synthetic lethality of E7-indued HRD and PARP inhibitor (PARPi), we expressed E7 in C33A cells in the presence or absence of olaparib, and evaluated cell viability by colony formation. RESULTS: In precancerous lesions, endogenous DNA lesions were elevated along with the severity of CIN grade. Expressing high-risk viral factor (E7) in HPV-negative cervical cells did not impair checkpoint activation upon genotoxic insults, but affected the potential of DSB repair, leading to homologous recombination deficiency (HRD). Based on this HPV-induced genomic instability, the viability of E7-expressing cells was reduced upon exposure to PARPi in comparison with control cells. CONCLUSION: In aggregate, our findings demonstrate that HPV-E7 is a potential driver for genome instability and provides a new angle to understand its role in cancer development. The viral HRD could be employed to target HPV-positive cervical cancer via synthetic lethality.

The clinical characteristics of non-cystic fibrosis bronchiectasis patients with positive serum tumor markers: a retrospective study.

BACKGROUND: Serum tumor markers (STM), extensively used for the diagnosis, monitoring and prognostic assessment of tumors, can be increased in some non-malignant lung diseases. To date, there is a paucity of studies regarding the clinical characteristics of non-cystic fibrosis bronchiectasis patients with positive STMs. OBJECTIVE: To investigate the clinical characteristics and indicators of bronchiectasis with positive STMs. METHODS: The clinical data of 377 bronchiectasis patients was retrospectively collected from January 2017 to December 2019 from Beijing Chaoyang Hospital. Patients were divided into the STM negative group, the single STM positive group and the ≥2 STMs positive group according to the number of the positive STMs. The clinical characteristics are described and compared separately. The multivariate logistic regression analysis model was used to investigate the indicators regarding positive STMs. RESULTS: Patients in the ≥2 STMs positive group were older (P = 0.015), had higher mMRC scores (P < 0.001) and developed higher fever (P = 0.027). Additionally, these patients also had lower Albumin/Globulin Ratio (A/G), albumin (ALB), prealbumin (PAB) (P < 0.001, P < 0.001, P < 0.001, respectively) and higher CRP, ESR and Fbg (P < 0.001, P < 0.001 and P < 0.001, respectively). Age (OR 1.022, 95%CI 1.003-1.042; P = 0.026) and the number of affected lobes (OR 1.443, 95%CI 1.233-1.690; P < 0.001) were independently associated with one and ≥ 2 positive STMs in bronchiectasis patients. CONCLUSION: The ≥2 positive STMs are associated with a higher inflammation status and severer radiologic manifestations in bronchiectasis patients.

Potential Roles of Nr4a3-Mediated Inflammation in Immunological and Neurological Diseases.

As a protein of the orphan nuclear receptor Nr4a family, Nr4a3 has no identified natural ligands. However, its biological activity can be mediated by inducing conformational changes through interactions with specific certain small molecules and receptors. Nr4a3 is activated as an early stress factor under various pathological conditions and plays a regulatory role in various tissues and cells, participating in processes such as cell differentiation, apoptosis, metabolism, and homeostasis. At present, research on the role of Nr4a3 in the pathophysiology of inflammation is considerably limited, especially with respect to its role in the central nervous system (CNS). In this review, we discuss the role of Nr4a3 in multiple sclerosis, Alzheimer's disease, retinopathy, Parkinson's disease, and other CNS diseases. This review shows that Nr4a3 has considerable potential as a therapeutic target in the treatment of CNS diseases. We provide a theoretical basis for the targeted therapy of CNS diseases and neuroinflammation, among other conditions.

New insights on the role of microRNAs in retinal Müller glial cell function.

MicroRNAs belong to the family of non-coding RNAs that participate in cell proliferation, cell death and development. The Müller glial cells are the inherent and specific neuroglia cells in the retinal organisation and play significant roles in retinal neuroprotection, organisational maintenance, inflammation and immunity, regeneration, and the occurrence and development of retinal diseases. However, only a few studies report the underlying mechanism of how miRNAs drive the function of Müller glial cells in the development of retinal diseases. This review aims to summarise the roles of miRNAs in retinal Müller glial cell function, including gliogenesis, inflammation and immunity, regeneration, the development of retinal diseases, and retinal development. This review may point out a novel miRNA-based insight into retinal repair and regeneration. MiRNAs in Müller glial cells may be considered a diagnostic and therapeutic target in the process of retinal repair and regeneration.

Amphotericin B-loaded natural latex dressing for treating Candida albicans wound infections using Galleria mellonella model.

Amphotericin B (AmB) is the gold standard for antifungal drugs. However, AmB systemic administration is restricted because of its side effects. Here, we report AmB loaded in natural rubber latex (NRL), a sustained delivery system with low toxicity, which stimulates angiogenesis, cell adhesion and accelerates wound healing. Physicochemical characterizations showed that AmB did not bind chemically to the polymeric matrix. Electronic and topographical images showed small crystalline aggregates from AmB crystals on the polymer surface. About 56.6% of AmB was released by the NRL in 120 h. However, 33.6% of this antifungal was delivered in the first 24 h due to the presence of AmB on the polymer surface. The biomaterial's excellent hemo- and cytocompatibility with erythrocytes and human dermal fibroblasts (HDF) confirmed its safety for dermal wound application. Antifungal assay against Candida albicans showed that AmB-NRL presented a dose-dependent behavior with an inhibition halo of 30.0 ± 1.0 mm. Galleria mellonella was employed as an in vivo model for C. albicans infection. Survival rates of 60% were observed following the injection of AmB (0.5 mg.mL-1) in G. mellonella larvae infected by C. albicans. Likewise, AmB-NRL (0.5 mg.mL-1) presented survival rates of 40%, inferring antifungal activity against fungus. Thus, NRL adequately acts as an AmB-sustained release matrix, which is an exciting approach, since this antifungal is toxic at high concentrations. Our findings suggest that AmB-NRL is an efficient, safe, and reasonably priced ($0.15) dressing for the treatment of cutaneous fungal infections.

Anti-noise UWFBG-array enhanced DAS system using double-pulse-based time-domain adaptive delay interference: publisher's note.

This publisher's note contains a correction to Opt. Lett.48, 1814 (2023)10.1364/OL.486149.

Recent advances and perspectives on natural latex serum and its fractions for biomedical applications.

Advances and the discovery of new biomaterials have opened new frontiers in regenerative medicine. These biomaterials play a key role in current medicine by improving the life quality or even saving the lives of millions of people. Since the 2000s, Natural Rubber Latex (NRL) has been employed as wound dressings, mechanical barrier for Guided Bone Regeneration (GBR), matrix for drug delivery, and grafting. NRL is a natural polymer that can stimulate cell proliferation, neoangiogenesis, and extracellular matrix (ECM) formation. Furthermore, it is well established that proteins and other biologically active molecules present in the Natural Latex Serum (NLS) are responsible for the biological properties of NRL. NLS can be obtained from NRL by three main methods, namely (i) Centrifugation (fractionation of NRL in distinct fractions), (ii) Coagulation and sedimentation (coagulating NRL to separate the NLS from rubber particles), and (iii) Alternative extraction process (elution from NRL membrane). In this review, the chemical composition, physicochemical properties, toxicity, and other biological information such as osteogenesis, vasculogenesis, adhesion, proliferation, antimicrobial behavior, and antitumoral activity of NLS, as well as some of its medical instruments and devices are discussed. The progress in NLS applications in the biomedical field, more specifically in cell cultures, alternative animals, regular animals, and clinical trials are also discussed. An overview of the challenges and future directions of the applications of NLS and its derivatives in tissue engineering for hard and soft tissue regeneration is also given.

Engineering a Plant Polyketide Synthase for the Biosynthesis of Methylated Flavonoids.

Homoeriodictyol and hesperetin are naturally occurring O-methylated flavonoids with many health-promoting properties. They are produced in plants in low abundance and as complex mixtures of similar compounds that are difficult to separate. Synthetic biology offers the opportunity to produce various flavonoids in a targeted, bottom-up approach in engineered microbes with high product titers. However, the production of O-methylated flavonoids is currently still highly inefficient. In this study, we investigated and engineered a combination of enzymes that had previously been shown to support homoeriodictyol and hesperetin production in Escherichia coli from fed O-methylated hydroxycinnamic acids. We determined the crystal structures of the enzyme catalyzing the first committed step of the pathway, chalcone synthase from Hordeum vulgare, in three ligand-bound states. Based on these structures and a multiple sequence alignment with other chalcone synthases, we constructed mutant variants and assessed their performance in E. coli toward producing methylated flavonoids. With our best mutant variant, HvCHS (Q232P, D234 V), we were able to produce homoeriodictyol and hesperetin at 2 times and 10 times higher titers than reported previously. Our findings will facilitate further engineering of this enzyme toward higher production of methylated flavonoids.

Tumor abnormal protein as a promising biomarker for screening solid malignancies and monitoring recurrence and metastasis.

Background: Tumor abnormal protein (TAP), the sugar chain protein released by tumor cells during metabolism, allows the development of a technique that exploits aggregated tumor-associated abnormal sugar chain signals in diagnosing malignancies. Clinically, we have found that TAP detection can well predict some malignancies, but several physicians have not paid attention, and related studies have been minimal. Methods: We evaluated TAP's ability to distinguish between malignancies and benign diseases by receiver operating characteristic (ROC) curve analysis and studied the possibility of monitoring malignancy progression by evaluating TAP levels in follow-up. We used Kaplan-Meier survival curves and Cox proportional hazard regression models to investigate the relationship between TAP and prognosis. Results: TAP levels were higher in whole solid malignancies and every type of solid malignancy than in benign patients. ROC curve analysis showed that TAP levels aid in distinguishing between malignancies and benign diseases. TAP levels decreased in patients with complete remission (CR) after treatment and increased in patients with relapse from CR. Patients with metastases had higher TAP levels than non-CR patients without metastases. There was no difference in overall survival among patients with different TAP levels, and multivariate analysis suggested that TAP was not an independent risk factor for solid malignancies. Conclusion: TAP is an effective screening biomarker for many solid malignancies that can be used to monitor the progression of malignancies but not to prognosticate.

Antitumor effect of tubeimoside-I on murine colorectal cancers through PKM2-dependent pyroptosis and immunomodulation.

Induction of cancer cell death is an established treatment strategy, but chemotherapy drug-mediated apoptosis can be evaded by many tumors. Pyroptosis is a type of inflammatory programmed cell death (PCD) that is important for organism immunity. Tubeimoside-I (TBMS1) is a plant-derived component that exhibits antitumor activity. However, it is unclear how TBMS1 induces pyroptosis to inhibit colorectal cancer (CRC). In this study, we demonstrated that TBMS1 is able to induce pyroptosis in murine CRC cells and releases pro-inflammatory cytokines. Mechanistically, we found that TBMS1 inhibits CRC cell proliferation and migration and induces pyroptosis by activating caspase-3 and cleaving gasdermin E (GSDME) through the inhibition of PKM2. In the animal experiments, TBMS1 attenuated the weight of solid tumors, increased the proportion of CD8+ cytotoxic T cells, and reduced the content of M2-type macrophages in the spleen of tumor-bearing mice. Furthermore, TBMS1 inhibited M2-type polarization by blocking STAT6 pathway activation in RAW 264.7 cells. To sum up, our findings suggest that TBMS1 triggers pyroptosis in CRC by acting on the PKM2/caspase-3/GSDME signaling pathway. Additionally, it modulates the antitumor immune response in CRC murine models. This study provides a promising basis for the potential use of TBMS1 in treating CRC.

Self-Assembled Construction of Ion-Selective Nanobarriers in Electrolyte Membranes for Redox Flow Batteries.

Ion-conducting membranes (ICMs) with high selectivity are important components in redox flow batteries. However it is still a challenge to break the trade-off between ion conductivity and ion selectivity, which can be resolved by the regulation of their nanostructures. Here, polyoxometalate (POM)-hybridized block copolymers (BCPs) are used as self-assembled additives to construct proton-selective nanobarriers in the ICM matrix to improve the microscopic structures and macroscopic properties of ICMs. Benefiting from the co-assembly behavior of BCPs and POMs and their cooperative noncovalent interactions with the polymer matrix, ∼50 nm ellipsoidal functional nanoassemblies with hydrophobic vanadium-shielding cores and hydrophilic proton-conducting shells are constructed in the sulfonated poly(ether ether ketone) matrix, which leads to an overall enhancement of proton conductivity, proton selectivity, and cell performance. These results present a self-assembly route to construct functional nanostructures for the modification of polymer electrolyte membranes toward emerging energy technologies.