Disseminated Talaromyces marneffei infection initially presenting as cutaneous and subcutaneous lesion in an HIV-Negative renal transplant recipient: a case report and literature review.

BACKGROUND: The incidence of Talaromyces marneffei (T. marneffei) infection has increased in recent years with the development of organ transplantation and the widespread use of immunosuppressive agents. However, the lack of clinical suspicion leading to delay or misdiagnosis is an important reason for the high mortality rate in non-human immunodeficiency virus (HIV) and non-endemic population. Herein, we report a case of disseminated T. marneffei infection in a non-HIV and non-endemic recipient after renal transplant, who initially presented with skin rashes and subcutaneous nodules and developed gastrointestinal bleeding. CASE PRESENTATION: We describe a 54-year-old renal transplantation recipient presented with scattered rashes, subcutaneous nodules and ulcerations on the head, face, abdomen, and right upper limb. The HIV antibody test was negative. The patient had no obvious symptoms such as fever, cough, etc. Histopathological result of the skin lesion sites showed chronic suppurative inflammation with a large number of fungal spores. Subsequent fungal culture suggested T. marneffei infection. Amphotericin B deoxycholate was given for antifungal treatment, and there was no deterioration in the parameters of liver and kidney function. Unfortunately, the patient was soon diagnosed with gastrointestinal bleeding, gastrointestinal perforation and acute peritonitis. Then he rapidly developed multiple organ dysfunction syndrome and abandoned treatment. CONCLUSIONS: The risk of fatal gastrointestinal bleeding can be significantly increased in kidney transplant patients with T. marneffei infection because of the long-term side effects of post-transplant medications. Strengthening clinical awareness and using mNGS or mass spectrometry technologies to improve the detection rate and early diagnosis of T. marneffei are crucial for clinical treatment in non-HIV and non-endemic population.

Comprehensive overview of different medicinal parts from Morus alba L.: chemical compositions and pharmacological activities.

Morus alba L., a common traditional Chinese medicine (TCM) with a centuries-old medicinal history, owned various medicinal parts like Mori folium, Mori ramulus, Mori cortex and Mori fructus. Different medical parts exhibit distinct modern pharmacological effects. Mori folium exhibited analgesic, anti-inflammatory, hypoglycemic action and lipid-regulation effects. Mori ramulus owned anti-bacterial, anti-asthmatic and diuretic activities. Mori cortex showed counteraction action of pain, inflammatory, bacterial, and platelet aggregation. Mori fructus could decompose fat, lower blood lipids and prevent vascular sclerosis. The main chemical components in Morus alba L. covered flavonoids, phenolic compounds, alkaloids, and amino acids. This article comprehensively analyzed the recent literature related to chemical components and pharmacological actions of M. alba L., summarizing 198 of ingredients and described the modern activities of different extracts and the bioactive constituents in the four parts from M. alba L. These results fully demonstrated the medicinal value of M. alba L., provided valuable references for further comprehensive development, and layed the foundation for the utilization of M. alba L.

Spin-Phonon Coupling in Iron-Doped Ultrathin Bismuth Halide Perovskite Derivatives.

Spin in semiconductors facilitates magnetically controlled optoelectronic and spintronic devices. In metal halide perovskites (MHPs), doping magnetic ions is proven to be a simple and efficient approach to introducing a spin magnetic momentum. In this work, we present a facile metal ion doping protocol through the vapor-phase metal halide insertion reaction to the chemical vapor deposition (CVD)-grown ultrathin Cs3BiBr6 perovskites. The Fe-doped bismuth halide (Fe:CBBr) perovskites demonstrate that the iron spins are successfully incorporated into the lattice, as revealed by the spin-phonon coupling below the critical temperature Tc around 50 K observed through temperature-dependent Raman spectroscopy. Furthermore, the phonons exhibit significant softening under an applied magnetic field, possibly originating from magnetostriction and spin exchange interaction. The spin-phonon coupling in Fe:CBBr potentially provides an efficient way to tune the spin and lattice parameters for halide perovskite-based spintronics.

Spatially Resolved Anion Diffusion and Tunable Waveguides in Bismuth Halide Perovskites.

Bismuth halide perovskites are widely regarded as nontoxic alternatives to lead halide perovskites for optoelectronics and solar energy harvesting applications. With a tailorable composition and intriguing optical properties, bismuth halide perovskites are also promising candidates for tunable photonic devices. However, robust control of the anion composition in bismuth halide perovskites remains elusive. Here, we established chemical vapor deposition and anion exchange protocols to synthesize bismuth halide perovskite nanoflakes with controlled dimensions and variable compositions. In particular, we demonstrated the gradient bromide distribution by controlling the anion exchange and diffusion processes, which is spatially resolved by time-of-flight secondary ion mass spectrometry. Moreover, the optical waveguiding properties of bismuth halide perovskites can be modulated by flake thicknesses and anion compositions. With a unique gradient anion distribution and controllable optical properties, bismuth halide perovskites provide new possibilities for applications in optoelectronic devices and integrated photonics.

Dual amplification for PEC ultrasensitive aptasensing of biomarker HER-2 based on Z-scheme UiO-66/CdIn2S4 heterojunction and flower-like PtPdCu nanozyme.

As an important prognostic indicator in breast cancer, human epithelial growth factor receptor-2 (HER-2) is of importance for assessing prognosis of breast cancer patients, whose accurate and facile analysis are imperative in clinical diagnosis and treatment. Herein, photoactive Z-scheme UiO-66/CdIn2S4 heterojunction was constructed by a hydrothermal method, whose optical property and photoactivity were critically investigated by a range of techniques, combined by elucidating the interfacial charge transfer mechanism. Meanwhile, PtPdCu nanoflowers (NFs) were fabricated by a simple aqueous wet-chemical method, whose peroxidase (POD)-mimicking catalytic activity was scrutinized by representative tetramethylbenzidine (TMB) oxidation in H2O2 system. Taken together, the UiO-66/CdIn2S4 based photoelectrochemical (PEC) aptasensor was established for quantitative analysis of HER-2, where the detection signals were further magnified through catalytic precipitation reaction towards 4-chloro-1-naphthol (4-CN) oxidation (assisted by the PtPdCu NFs nanozyme). The PEC aptasensor presented a broader linear range within 0.1 pg mL-1-0.1 µg mL-1 and a lower limit of detection of 0.07 pg mL-1. This work developed a new PEC aptasensor for ultrasensitive determination of HER-2, holding substantial promise for clinical diagnostics.

Subcutaneous implantation of nodular goiter after transoral endoscopic thyroidectomy vestibular approach: A case study and review of literature.

BACKGROUND: Extrathyroid implantation or dissemination of thyroid tissue secondary to a thyroid procedure is rare. Most of these belonged to thyroid carcinoma with metastatic potential and uncommon for benign pathologies. METHODS: We report the case of a 31-year-old female who was identified to have multiple subcutaneous implantation of thyroid tissue 5 years after transoral endoscopic thyroidectomy vestibular approach. A comprehensive literature search on implantation of thyroid tissue secondary to thyroid procedures was performed. RESULTS: Accidental tearing of the capsule during previous surgery may lead to the subcutaneous implantation. Through literature review, a total 29 articles with 47 patients were identified. 33.3% were benign lesions, and implantation was mostly secondary to fine needle aspiration biopsy (46.5%). CONCLUSIONS: Subcutaneous or port site implantation after endoscopic thyroid surgery may occur in benign thyroid pathologies and therefore, oncologic principles must be strictly followed during surgery regardless of its histopathological nature.

Upfront surgery for stage IIIA/B non-small cell lung cancer: retrospective cohort study.

BACKGROUND: Stage III non-small cell lung cancer is a heterogeneous disease. Several international guidelines recommend neoadjuvant treatment before surgery; however, upfront surgery is the preferred approach for technically resectable non-small cell lung cancer in East Asia. The aim of this retrospective study was to evaluate the long-term outcomes of curative-intent upfront surgery in stage IIIA/B non-small cell lung cancer. METHODS: Patients who underwent curative-intent upfront surgery with stage cIIIA/B non-small cell lung cancer were identified. The clinical and pathological variables and survival outcomes were evaluated. RESULTS: Overall, 664 patients were identified, of whom 320 (48.8%) had N2 disease, 66.7% were males, 49.4% had a smoking history, and 61.2% had lung adenocarcinoma. Lobectomy was the most performed surgical procedure (84.9%). A total of 40 patients (6.02%) had positive margins (R1/R2). The grade III adverse event rate was 2.0% (13 of 664). The median follow-up was 30.6 (range 1.9-97.7) months. At follow-up, the mortality rate was 13.3% (88 of 664) and 37.2% of patients (247 of 664) had recurrence. Lung (101 of 247 (40.9%)) and brain (53 of 247 (21.5%)) were the most common sites of recurrence. The median overall survival was 60.0 (95% c.i. 51.5 to 67.6) months, with overall survival probability at 1, 2, 3, and 5 years being 89.6%, 77.8%, 67.2%, and 49.0% respectively. The R0 cohort showed an improved median overall survival compared with the R1/R2 cohort (67.4 versus 26.5 months respectively; P = greater than 0.001). The multivariable analysis revealed that age greater than or equal to 65 years (HR 1.51, 95% c.i. 1.08 to 2.12; reference = age less than 65 years), tumour size (greater than or equal to 5 cm (HR 2.13, 95% c.i. 1.41 to 3.21) and greater than or equal to 3 cm but less than 5 cm (HR 1.15, 95% c.i. 0.78 to 1.71); reference = less than 3 cm), and adjuvant treatment (chemotherapy (HR 0.69, 95% c.i. 0.49 to 0.96) and targeted therapy (HR 0.30, 95% c.i. 0.12 to 0.76); reference = none) significantly predicted overall survival. CONCLUSION: Upfront surgery is an option for the management of stage IIIA/B non-small cell lung cancer.

Tubule-specific cyclin-dependent kinase 12 knockdown potentiates kidney injury through transcriptional elongation defects.

Direct tubular injury caused by several medications, especially chemotherapeutic drugs, is a common cause of AKI. Inhibition or loss of cyclin-dependent kinase 12 (CDK12) triggers a transcriptional elongation defect that results in deficiencies in DNA damage repair, producing genomic instability in a variety of cancers. Notably, 10-25% of individuals developed AKI after treatment with a CDK12 inhibitor, and the potential mechanism is not well understood. Here, we found that CDK12 was downregulated in the renal tubular epithelial cells in both patients with AKI and murine AKI models. Moreover, tubular cell-specific knockdown of CDK12 in mice enhanced cisplatin-induced AKI through promotion of genome instability, apoptosis, and proliferative inhibition, whereas CDK12 overexpression protected against AKI. Using the single molecule real-time (SMRT) platform on the kidneys of CDK12RTEC+/- mice, we found that CDK12 knockdown targeted Fgf1 and Cast through transcriptional elongation defects, thereby enhancing genome instability and apoptosis. Overall, these data demonstrated that CDK12 knockdown could potentiate the development of AKI by altering the transcriptional elongation defect of the Fgf1 and Cast genes, and more attention should be given to patients treated with CDK12 inhibitors to prevent AKI.

Toward Controlled Synthesis of 2D Crystals by CVD: Learning from the Real-Time Crystal Morphology Evolutions.

The rich morphology of 2D materials grown through chemical vapor deposition (CVD), is a distinctive feature. However, understanding the complex growth of 2D crystals under practical CVD conditions remains a challenge due to various intertwined factors. Real-time monitoring is crucial to providing essential data and enabling the use of advanced tools like machine learning for unraveling these complexities. In this study, we present a custom-built miniaturized CVD system capable of observing and recording 2D MoS2 crystal growth in real time. Image processing converts the real-time footage into digital data, and machine learning algorithms (ML) unveil the significant factors influencing growth. The machine learning model successfully predicts CVD growth parameters for synthesizing ultralarge monolayer MoS2 crystals. It also demonstrates the potential to reverse engineer CVD growth parameters by analyzing the as-grown 2D crystal morphology. This interdisciplinary approach can be integrated to enhance our understanding of controlled 2D crystal synthesis through CVD.

Autoinducer-2 promotes the colonization of Lactobacillus rhamnosus GG to improve the intestinal barrier function in a neonatal mouse model of antibiotic-induced intestinal dysbiosis.

BACKGROUND: Human health is seriously threatened by antibiotic-induced intestinal disorders. Herein, we aimed to determine the effects of Autoinducer-2 (AI-2) combined with Lactobacillus rhamnosus GG (LGG) on the intestinal barrier function of antibiotic-induced intestinal dysbiosis neonatal mice. METHODS: An antibiotic-induced intestinal dysbiosis neonatal mouse model was created using antibiotic cocktails, and the model mice were randomized into the control, AI-2, LGG, and LGG + AI-2 groups. Intestinal short-chain fatty acids and AI-2 concentrations were detected by mass spectrometry and chemiluminescence, respectively. The community composition of the gut microbiota was analyzed using 16S rDNA sequencing, and biofilm thickness and bacterial adhesion in the colon were assessed using scanning electron microscopy. Transcriptome RNA sequencing of intestinal tissues was performed, and the mRNA and protein levels of HCAR2 (hydroxycarboxylic acid receptor 2), claudin3, and claudin4 in intestinal tissues were determined using quantitative real-time reverse transcription PCR and western blotting. The levels of inflammatory factors in intestinal tissues were evaluated using enzyme-linked immunosorbent assays (ELISAs). D-ribose, an inhibitor of AI-2, was used to treat Caco-2 cells in vitro. RESULTS: Compared with the control, AI-2, and LGG groups, the LGG + AI-2 group showed increased levels of intestinal AI-2 and proportions of Firmicutes and Lacticaseibacillus, but a reduced fraction of Proteobacteria. Specifically, the LGG + AI-2 group had considerably more biofilms and LGG on the colon surface than those of other three groups. Meanwhile, the combination of AI-2 and LGG markedly increased the concentration of butyric acid and promoted Hcar2, claudin3 and claudin4 expression levels compared with supplementation with LGG or AI-2 alone. The ELISAs revealed a significantly higher tumor necrosis factor alpha (TNF-α) level in the control group than in the LGG and LGG + AI-2 groups, whereas the interleukin 10 (IL-10) level was significantly higher in the LGG + AI-2 group than in the other three groups. In vitro, D-ribose treatment dramatically suppressed the increased levels of Hcar2, claudin3, and claudin4 in Caco-2 cells induced by AI-2 + LGG. CONCLUSIONS: AI-2 promotes the colonization of LGG and biofilm formation to improve intestinal barrier function in an antibiotic-induced intestinal dysbiosis neonatal mouse model.

tRF3-IleAAT reduced extracellular matrix synthesis in diabetic kidney disease mice by targeting ZNF281 and inhibiting ferroptosis.

It is well established that the synthesis of extracellular matrix (ECM) in mesangial cells is a major determinant of diabetic kidney disease (DKD). Elucidating the major players in ECM synthesis may be helpful to provide promising candidates for protecting against DKD progression. tRF3-IleAAT is a tRNA-derived fragment (tRF) produced by nucleases at tRNA-specific sites, which is differentially expressed in the sera of patients with diabetes mellitus and DKD. In this study we investigated the potential roles of tRFs in DKD. Db/db mice at 12 weeks were adapted as a DKD model. The mice displayed marked renal dysfunction accompanied by significantly reduced expression of tRF3-IleAAT and increased ferroptosis and ECM synthesis in the kidney tissues. The reduced expression of tRF3-IleAAT was also observed in high glucose-treated mouse glomerular mesangial cells. We administered ferrostatin-1 (1 mg/kg, once every two days, i.p.) to the mice from the age of 12 weeks for 8 weeks, and found that inhibition of the onset of ferroptosis significantly improved renal function, attenuated renal fibrosis and reduced collagen deposition. Overexpression of tRF3-IleAAT by a single injection of AAV carrying tRF3-IleAAT via caudal vein significantly inhibited ferroptosis and ECM synthesis in DKD model mice. Furthermore, we found that the expression of zinc finger protein 281 (ZNF281), a downstream target gene of tRF3-IleAAT, was significantly elevated in DKD models but negatively regulated by tRF3-IleAAT. In high glucose-treated mesangial cells, knockdown of ZNF281 exerted an inhibitory effect on ferroptosis and ECM synthesis. We demonstrated the targeted binding of tRF3-IleAAT to the 3'UTR of ZNF281. In conclusion, tRF3-IleAAT inhibits ferroptosis by targeting ZNF281, resulting in the mitigation of ECM synthesis in DKD models, suggesting that tRF3-IleAAT may be an attractive therapeutic target for DKD.

Tubular TMEM16A promotes tubulointerstitial fibrosis by suppressing PGC-1α-mediated mitochondrial homeostasis in diabetic kidney disease.

Tubulointerstitial fibrosis (TIF) plays a crucial role in the progression of diabetic kidney disease (DKD). However, the underlying molecular mechanisms remain obscure. The present study aimed to examine whether transmembrane member 16A (TMEM16A), a Ca2+-activated chloride channel, contributes to the development of TIF in DKD. Interestingly, we found that TMEM16A expression was significantly up-regulated in tubule of murine model of DKD, which was associated with development of TIF. In vivo inhibition of TMEM16A channel activity with specific inhibitors Ani9 effectively protects against TIF. Then, we found that TMEM16A activation induces tubular mitochondrial dysfunction in in vivo and in vitro models, with the evidence of the TMEM16A inhibition with specific inhibitor. Mechanically, TMEM16A mediated tubular mitochondrial dysfunction through inhibiting PGC-1α, whereas overexpression of PGC-1α could rescue the changes. In addition, TMEM16A-induced fibrogenesis was dependent on increased intracellular Cl-, and reducing intracellular Cl- significantly blunted high glucose-induced PGC-1α and profibrotic factors expression. Taken together, our studies demonstrated that tubular TMEM16A promotes TIF by suppressing PGC-1α-mediated mitochondrial homeostasis in DKD. Blockade of TMEM16A may serve as a novel therapeutic approach to ameliorate TIF.

Programming Peptide Liquid Crystal Media to Acquire Independent Sets of Residual Dipolar Couplings and Enantiodiscrimination in Multiple Solvent Systems.

Multiple independent sets of residual dipolar couplings (RDCs) acquired by relying on different alignment media show the great potential for de novo structure determination of organic compounds. However, this methodology is severely compromised by the limited availability of multialignment media. In this work, an engineering strategy was developed to program the oligopeptide amphiphiles (OPAs) to create different peptide liquid crystal (LC) media for the acquisition of independent sets of RDCs. With no need for de novo design on peptide sequences, the molecular alignment can be simply modulated by varying the length of the hydrophobic tails within OPAs. Relying on these programmed peptide LC media, five independent sets of RDCs were extracted in a highly efficient and accurate manner. Because of the similar bulk composition of OPAs, this approach offers the significant advantage in circumventing the possible incompatibilities of analytes with one or several different alignment media, therefore avoiding the analysis complication. Notably, these peptide LC media show enantiodifferentiating properties, and the enantiodiscriminating capabilities could also be optimized through the programmed strategy. Furthermore, we show that these media are compatible with different polar solvents, allowing the possible de novo structure elucidation of organic compounds with varied polarities and solubilities.

UPLC-Q-TOF-MS, network analysis, and molecular docking to investigate the effect and active ingredients of tea-seed oil against bacterial pathogens.

Object: This research intended to probe the antibacterial effect and pharmacodynamic substances of Tea-Seed Oil (TSO) through the use of ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) analysis, network analysis, and molecular docking. Methods: The major chemical components in the methanol-extracted fractions of TSO were subjected to UPLC-Q-TOF-MS. Network pharmacology and molecular docking techniques were integrated to investigate the core components, targets, and potential mechanisms of action through which the TSO exert their antibacterial properties. To evaluate the inhibitory effects, the minimum inhibitory concentration and diameter of the bacteriostatic circle were calculated for the potential active ingredients and their equal ratios of combinatorial components (ERCC) against Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, and Candida albicans. Moreover, the quantification of the active constituents within TSO was achieved through the utilization of high-performance liquid chromatography (HPLC). Results: The methanol-extracted fractions contained a total of 47 chemical components, predominantly consisting of unsaturated fatty acids and phenolic compounds. The network pharmacology analysis and molecular docking analysis revealed that various components, including gallocatechin, gallic acid, epigallocatechin, theophylline, chlorogenic acid, puerarin, and phlorizin, have the ability to interact with critical core targets such as serine/threonine protein kinase 1 (AKT1), epidermal growth factor receptor (EGFR), a monoclonal antibody to mitogen-activated protein kinase 14 (MAPK14), HSP90AA1, and estrogen receptor 1 (ESR1). Furthermore, these components can modulate the phosphatidylinositol-3-kinase protein kinase B (PI3K-AKT), estrogen, MAPK and interleukin 17 (IL-17) signaling pathways, hereby exerting antibacterial effects. In vitro validation trials have found that seven components, namely gallocatechin, gallic acid, epigallocatechin, theophylline, chlorogenic acid, puerarin, and phloretin, displayed substantial inhibitory effects on E. coli, S. aureus, P. aeruginosa, and C. albicans, and are typically present in tea oil, with a total content ranging from 15.87∼24.91 µg·g-1. Conclusion: The outcomes of this investigation possess the possibility to expand our knowledge base concerning the utilization of TSO, furnish a theoretical framework for the exploration of antibacterial drugs and cosmetics derived from inherently occurring TSO, and establish a robust groundwork for the advancement and implementations of TOS products within clinical settings.

Sublobar resection reduces the risk of postoperative cognitive dysfunction compared with lobectomy.

OBJECTIVES: Sublobar resection, including wedge resection and segmentectomy, is non-inferior to lobectomy in early-stage non-small cell lung cancer treatment. We aimed to compare the risk of postoperative cognitive dysfunction (POCD) between sublobar resection and lobectomy. METHODS: We conducted a prospective cohort study. Patients with sublobar resection or lobectomy were divided into the sublobar group or the lobar group, respectively. Cognition was assessed before and after surgery with Montreal Cognitive Assessment and Minimum Mental State Examination tests. POCD is defined as Z score of Montreal Cognitive Assessment change ≤-1.96. Propensity score matching (PSM) was performed to make demographics well-balanced between the 2 groups. RESULTS: A total of 335 patients were enrolled. Both the postoperative 1-day POCD rate (sublobar 5.5% vs lobar 18.2%, P < 0.001) and the postoperative 1-month POCD rate (sublobar 7.9% vs lobar 21.8%, P < 0.001) were significantly lower in the sublobar group compared with lobar group, with demographics unbalanced between the 2 groups. In the 133 demographics-matched pairs obtained by PSM, both the postoperative 1-day POCD rate (sublobar 5.3% vs lobar 17.3%, P = 0.005) and the postoperative 1-month POCD rate (sublobar 8.3% vs lobar 18.8%, P = 0.018) remained significantly lower in the sublobar group than in the lobar group. The incidences of postoperative 1-day (P = 0.109) and postoperative 1-month (P = 0.026) Minimum Mental State Examination abnormity were also lower in the sublobar group than in the lobar group but only the latter was with statistical significance after PSM. CONCLUSIONS: Sublobar resection has an advantage over lobectomy in preventing POCD. Our findings might be a reference for selecting the most suitable type of resection for non-small-cell lung cancer patients.

Programming lipopeptide nanotherapeutics for tandem treatment of postsurgical infection and melanoma recurrence.

Tumor recurrence and chronic bacterial infection constitute two major criteria in postsurgical intervention for malignant melanoma. One plausible strategy is the equipment of consolidation therapy after surgery, which relies on adjuvants to eliminate the residual tumor cells and inhibit bacterial growth. Until now, a number of proof-of-concept hybrid nanoadjuvants have been proposed to combat tumor recurrence and postsurgical bacterial infection, which may suffer from the potential bio-unsafety or involve complex design and synthesis. The batch-to-batch inconsistencies in drug composition further delay the clinical trials. To circumvent these issues, herein we develop a programmable strategy to generate lipopeptide nanotherapeutics with identical constitution for tandem intervention of postsurgical bacterial infection and cancer recurrence of melanoma. Increasing the number of hydrophobic linoleic acid within lipopeptides has been found to be a simple and practical strategy to improve the therapeutic outcomes for both tumor cells and bacteria. Self-assembled lipopeptide nanotherapeutics with two linoleic acid molecules possesses excellent antitumor activity and antimicrobial function toward both susceptible strains and drug-resistant bacteria. Arising from the incorporation of unsaturated linoleic acid, the unavoidable hemolysis of cationic peptide drugs was effectively alleviated. In vivo therapeutic abilities of postsurgical infection and tumor recurrence were investigated in BALB/c nude mice bearing a B16-F10 tumor model, with an incomplete surgical resection and in situ infection by methicillin-resistant Staphylococcus aureus (MRSA). Self-assembled lipopeptide nanotherapeutics could effectively inhibit cancer cell growth and bacterial infection, as well as promote wound healing. The easily scalable large-scale production, broad-spectrum antitumor and antibacterial bioactivities as well as fixed component endows lipopeptide nanotherapeutics as promising adjuvants for clinically postsurgical therapy of melanoma.

Satellite cell-derived exosome-mediated delivery of microRNA-23a/27a/26a cluster ameliorates the renal tubulointerstitial fibrosis in mouse diabetic nephropathy.

Renal tubulointerstitial fibrosis (TIF) is considered as the final convergent pathway of diabetic nephropathy (DN) without effective therapies currently. MiRNAs play a key role in fibrotic diseases and become promising therapeutic targets for kidney diseases, while miRNA clusters, formed by the cluster arrangement of miRNAs on chromosomes, can regulate diverse biological functions alone or synergistically. In this study, we developed clustered miR-23a/27a/26a-loaded skeletal muscle satellite cells-derived exosomes (Exos) engineered with RVG peptide, and investigated their therapeutic efficacy in a murine model of DN. Firstly, we showed that miR-23a-3p, miR-26a-5p and miR-27a-3p were markedly decreased in serum samples of DN patients using miRNA sequencing. Meanwhile, we confirmed that miR-23a-3p, miR-26a-5p and miR-27a-3p were primarily located in proximal renal tubules and highly negatively correlated with TIF in db/db mice at 20 weeks of age. We then engineered RVG-miR-23a/27a/26a cluster loaded Exos derived from muscle satellite cells, which not only enhanced the stability of miR-23a/27a/26a cluster, but also efficiently delivered more miR-23a/27a/26a cluster homing to the injured kidney. More importantly, administration of RVG-miR-23a/27a/26a-Exos (100 µg, i.v., once a week for 8 weeks) significantly ameliorated tubular injury and TIF in db/db mice at 20 weeks of age. We revealed that miR-23a/27a/26a-Exos enhanced antifibrotic effects by repressing miRNA cluster-targeting Lpp simultaneously, as well as miR-27a-3p-targeting Zbtb20 and miR-26a-5p-targeting Klhl42, respectively. Knockdown of Lpp by injection of AAV-Lpp-RNAi effectively ameliorated the progression of TIF in DN mice. Taken together, we established a novel kidney-targeting Exo-based delivery system by manipulating the miRNA-23a/27a/26a cluster to ameliorate TIF in DN, thus providing a promising therapeutic strategy for DN.

Aucubin inhibits hepatic stellate cell activation through stimulating Nrf2/Smad7 axis.

AIM: Liver fibrosis may develop into end-stage liver disease if left unprevented. The study is attempting to identify a compound to ameliorate liver fibrosis progression with high efficiency and low toxicity, as well as to analyze its potential molecular mechanism. METHODS: The drug screening was performed using human hepatic stellate cell line LX-2 for identifying the compound as collagen I inhibitor. Primary Human hepatic stellate cells and LX-2 cell line were used to detect the antifibrotic function activity and molecular mechanism analysis in vitro. The CCl4-induced mouse experimental model was used to measure the amelioration in liver fibrosis. RESULTS: This study identified Aucubin, a natural compound, as a candidate for anti-liver fibrosis. Besides, Aucubin could inhibit the collagen I and α-SMA expressions in LX-2 cells and primary human hepatic stellate cells, as well as the cell proliferation. In terms of mechanism, Aucubin could upregulate Smad7 in hepatic stellate cells in a dose-dependent manner and block TGF-ß signaling. We also found that Nrf2 might be a direct target for the action of Aucubin, whose activation was necessary for Smad7 upregulation. In an in-vivo mouse model, Aucubin efficiency ameliorated the progression of CCl4-induced liver fibrosis, and reduced the hepatic levels of collagen deposition, transaminase and inflammatory cytokines. CONCLUSION: Capable of inhibiting the activation of hepatic stellate cells in vitro and in vivo, Aucubin may be a potential therapeutic candidate for liver fibrosis, which is dependent on the suppression of TGF-ß signaling through stimulating Nrf2/Smad7 axis.

Protective Effect of Unfractionated Heparin on Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome in Neonatal Mice via the JAK2/STAT3 Signaling Pathway.

BACKGROUND: Neonatal acute respiratory distress syndrome (ARDS) is a clinical disorder characterized by excessive acute inflammatory response in lung parenchyma and has high morbidity and mortality. However, the therapeutic treatments are still lacking. The aim of this study is to evaluate the role of unfractionated heparin in neonatal ARDS and explore the underlying mechanism of its effects. METHODS: To conduct the ARDS model, the mouse pups were treated by intraperitoneal injection of lipopolysaccharide (LPS) (10 mg/kg). For unfractionated heparin intervention group, C57BL/6 mouse pups received a single subcutaneous injection of unfractionated heparin (400 IU/kg) 30 minutes prior to LPS. The survival rate was recorded for each group. Histological analysis was used to evaluate lung injury. MPO (myeloperoxidase) concentration level in lung tissues and extracellular histones in serum were detected by enzyme linked immunosorbent assay (ELISA). A commercially available kit was used to detect inflammatory cytokine levels in serum. Real time quantitative polymerase chain reaction (qPCR) and western blot were used to detect the mRNA and protein in the JAK2/STAT3 signaling pathway, respectively. RESULTS: Intervention of unfractionated heparin significantly increased the survival rate of mouse pups with ARDS, restored lung architecture, inhibited neutrophil infiltration as evidenced by reduced MPO concentration, and attenuated the LPS-induced inflammatory responses, characterized by the down-regulation of proinflammatoy factors and up-regulation of anti-inflammatory factor when compared with the ARDS group. In addition, the concentration of extracellular histones, which have been proven to be mediated in the pathogenesis of ARDS, was diminished by unfractionated heparin. Moreover, the protein expressions of p-JAK2 (Y1007/1008) and p-STAT3 (Y705) in the ARDS group were remarkably up-regulated, which were reversed by unfractionated heparin. CONCLUSIONS: Unfractionated heparin protects LPS-induced ARDS via inhibiting JAK2/STAT3 pathway in neonatal mice, which might present a novel therapeutic target for ARDS of neonates.