Empagliflozin and liraglutide ameliorate HFpEF in mice via augmenting the Erbb4 signaling pathway.

Heart failure with preserved ejection fraction (HFpEF) is closely associated with metabolic derangement. Sodium glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) exert anti-HFpEF effects, but the underlying mechanisms remain unclear. In this study, we explored the anti-HFpEF effects of empagliflozin and liraglutide and the underlying molecular mechanisms in a mouse model of HFpEF. This model was established by high-fat diet (HFD) feeding plus Nω-nitro-L-arginine methyl ester (L-NAME) treatment. The mice were treated with empagliflozin (20 mg·kg-1·d-1, i.g.) or liraglutide (0.3 mg·kg-1·d-1, i.p.) or their combination for 4 weeks. At the end of the experimental protocol, cardiac function was measured using ultrasound, then mice were euthanized and heart, liver, and kidney tissues were collected. Nuclei were isolated from frozen mouse ventricular tissue for single-nucleus RNA-sequencing (snRNA-seq). We showed that administration of empagliflozin or liraglutide alone or in combination significantly improved diastolic function, ameliorated cardiomyocyte hypertrophy and cardiac fibrosis, as well as exercise tolerance but no synergism was observed in the combination group. Furthermore, empagliflozin and/or liraglutide lowered body weight, improved glucose metabolism, lowered blood pressure, and improved liver and kidney function. After the withdrawal of empagliflozin or liraglutide for 1 week, these beneficial effects tended to diminish. The snRNA-seq analysis revealed a subcluster of myocytes, in which Erbb4 expression was down-regulated under HFpEF conditions, and restored by empagliflozin or liraglutide. Pseudo-time trajectory analysis and cell-to-cell communication studies confirmed that the Erbb4 pathway was a prominent pathway essential for both drug actions. In the HFpEF mouse model, both empagliflozin and liraglutide reversed Erbb4 down-regulation. In rat h9c2 cells, we showed that palmitic acid- or high glucose-induced changes in PKCα and/or ERK1/2 phosphorylation at least in part through Erbb4. Collectively, the single-cell atlas reveals the anti-HFpEF mechanism of empagliflozin and liraglutide, suggesting that Erbb4 pathway represents a new therapeutic target for HFpEF. Effects and mechanisms of action of empagliflozin and liraglutide in HFpEF mice. HFpEF was induced with a high-fat diet and L-NAME for 15 weeks, and treatment with empagliflozin and liraglutide improved the HFpEF phenotype. Single nucleus RNA sequencing (snRNA-seq) was used to reveal the underlying mechanism of action of empagliflozin and liraglutide.

Nonlinear optical response of heme solutions.

Heme is the prosthetic group for cytochrome that exists in nearly all living organisms and serves as a vital component of human red blood cells (RBCs). Tunable optical nonlinearity in suspensions of RBCs has been demonstrated previously, however, the nonlinear optical response of a pure heme (without membrane structure) solution has not been studied to our knowledge. In this work, we show optical nonlinearity in two common kinds of heme (i.e., hemin and hematin) solutions by a series of experiments and numerical simulations. We find that the mechanism of nonlinearity in heme solutions is distinct from that observed in the RBC suspensions where the nonlinearity can be easily tuned through optical power, concentration, and the solution properties. In particular, we observe an unusual phenomenon wherein the heme solution exhibits negative optical nonlinearity and render self-collimation of a focused beam at specific optical powers, enabling shape-preserving propagation of light to long distances. Our results may have potential applications in optical imaging and medical diagnosis through blood.

Exploring the molecular mechanism of berberine for treating diabetic nephropathy based on network pharmacology.

BACKGROUND AND PURPOSE: Diabetic nephropathy (DN) is a prevalent complication of diabetes mellitus characterized by hyperglycemia, hyperlipidemia, albuminuria and edema. Increasing evidence indicated that berberine (BBR) could alleviate the occurrence and development of DN. However, the molecular mechanism underlying the beneficial effects of BBR in the treatment of DN remains unclear. METHODS: The online public databases were chosen to screen the relevant targets of BBR and DN and the screened overlapped targets were analyzed by GO enrichment analysis, KEGG enrichment analysis and protein-protein interaction network analysis. The interaction between BBR and the key proteinwas verified by molecular docking and cellularthermalshiftassay. Additionally, the expression of key proteins and related indicators of DN were verified by immunofluorescence and western blot in vitro and in vivo. RESULTS: We successfully identified 92 overlapped targets of BBR and DN based on network pharmacology. Notably, VEGFR2 was identified to be the main target of BBR. Meanwhile, we found that BBR exhibited a high binding affinity to VEGFR2 protein, as confirmed by molecular docking and CETSA. This binding led to interfering with the PI3K/AKT/mTOR signaling pathway. In addition, we found that BBR could inhibit the abnormal proliferation of mesangial cells and reduce the expression of downstream pathway protein in vitro and in vivo. Finally, BBR was found to effectively lower the level of blood glucose and improve kidney function in mice, highlighting its potential as a therapeutic agent for the treatment of DN. CONCLUSION: Berberine interfered the PI3K/AKT/mTOR signaling pathway via targeting VEGFR2 protein, further led to the inhibition of abnormal proliferation of mesangial cells and ultimately resulted in improved renal function.

Multiple flatbands and localized states in photonic super-Kagome lattices.

We demonstrate multiple flatbands and compact localized states (CLSs) in a photonic super-Kagome lattice (SKL) that exhibits coexistence of singular and nonsingular flatbands within its unique band structure. Specifically, we find that the upper two flatbands of an SKL are singular-characterized by singularities due to band touching with their neighboring dispersive bands at the Brillouin zone center. Conversely, the lower three degenerate flatbands are nonsingular and remain spectrally isolated from other dispersive bands. The existence of such two distinct types of flatbands is experimentally demonstrated by observing stable evolution of the CLSs with various geometrical shapes in a laser-written SKL. We also discuss the classification of the flatbands in momentum space, using band-touching singularities of the Bloch wave functions. Furthermore, we validate this classification in real space based on unit cell occupancy of the CLSs in a single SKL plaquette. These results may provide insights for the study of flatband transport, dynamics, and nontrivial topological phenomena in other relevant systems.

Gain optimization of an erbium-ytterbium co-doped amplifier via a Si3N4 photonic platform.

Erbium-doped waveguide amplifiers enable the integration of various active functions on a silicon platform. Er3+ can provide the basis for efficient optical amplification of photonic integrated circuits, but the gain is limited by cooperative upconversion leading to doping concentration limitations and insufficient optimization of the waveguide structure. In this paper, an erbium-ytterbium co-doped Al2O3 amplifier has been innovatively implemented on a low loss Si3N4 waveguide by careful design and optimization with the finite difference method. A more accurate and comprehensive theoretical model of erbium-ytterbium co-doping is established, with consideration of upconversions, energy transfer, amplified spontaneous radiation and propagation loss to perform optimization of the high-gain erbium-ytterbium co-doped waveguide amplifier. The optimized waveguide amplifier achieves a small-signal gain of more than 36 dB at 1550 nm under Er3+ concentration of 3 × 1020 cm-3 and Yb3+ concentration of 3 × 1021 cm-3. Endowing Si3N4 photonic integrated circuits with gain can enable the miniaturization of various on-chip based active devices.

A multifunctional surgical suture with electroactivity assisted by oligochitosan/gelatin-tannic acid for promoting skin wound healing and controlling scar proliferation.

Surgical wound closure is accomplished most frequently with sutures, optimally proceeding rapidly and without complication. However, surgical sutures can trigger foreign body reactions and incite abnormal collagen deposition. Sustained inflammation can result in abnormal wound healing with hypertrophic scar formation. Therefore, evolution of suture material to inhibit inflammation and scar formation is of great clinical significance. In the present study, commercial 3-0 PPDO [poly(p-dioxanone)] suture was used as the base material and modified by adding two layers: a drug-loaded layer and an electroactive layer. The former layer was curcumin (Cur) encapsulated by PLGA [poly (lactic-co-glycolic acid)] and the latter layer was composed of oligochitosan-gelatin/tannic acid/polypyrrole (OCS-GE/TA/PPy). The multifunctional sutures, named S@LC@CGTP, had desirable sustained-drug release properties in vitro where Cur could be released for 8 days due to the action of PLGA. The three-dimensional network structure of OCS-GE/TA ensured S@LC@CGTP against surface cracking and maintained electrical. Furthermore, using an in vivo experiment, S@LC@CGTP could attenuate inflammation and promote scar-free wound healing according to suppression of infiltrating inflammatory cells, down-regulation of TGF-ß1 and collagen type I expression, and improved collagen arrangement. Cumulatively, we indicated that S@LC@CGTP suture material has great potential to facilitate optimal, nearly scarless healing of surgical incisions.

Photonic Realization of a Generic Type of Graphene Edge States Exhibiting Topological Flat Band.

Cutting a honeycomb lattice (HCL) ends up with three types of edges (zigzag, bearded, and armchair), as is well known in the study of graphene edge states. Here, we propose and demonstrate a distinctive twig-shaped edge, thereby observing new edge states using a photonic platform. Our main findings are (i) the twig edge is a generic type of HCL edge complementary to the armchair edge, formed by choosing the right primitive cell rather than simple lattice cutting or Klein edge modification; (ii) the twig edge states form a complete flat band across the Brillouin zone with zero-energy degeneracy, characterized by nontrivial topological winding of the lattice Hamiltonian; (iii) the twig edge states can be elongated or compactly localized at the boundary, manifesting both flat band and topological features. Although realized here in a photonic graphene, such twig edge states should exist in other synthetic HCL structures. Moreover, our results may broaden the understanding of graphene edge states, as well as new avenues for realization of robust edge localization and nontrivial topological phases based on Dirac-like materials.

Molecular mechanism of GSDMD mediated glomerular endothelial cells pyroptosis: An implying in the progression of diabetic nephropathy.

Diabetic nephropathy (DN), a chronic progressive kidney disease, is the most prevalent microvascular complication associated with diabetes which causes the end-stage renal disease. Glomerular endothelial cells (GECs) are one of the inherent cells of the glomerulus and are particularly susceptible to be damaged by glucose, lipids and inflammatory factors. Numerous studies indicated that GECs injury was a critical pathological event in the early stages of DN. Previous studies have shown that podocyte pyroptosis occurred through the classical caspase-1 pathway, leading to kidney injury. However, the occurrence of pyroptosis in GECs and the underlying mechanism remain unclear. In this study, we investigated the pyroptosis of GECs during DN and its underlying mechanism. Upon stimulation with high glucose (HG), we observed the upregulation of GSDMD and cleaved N-terminus, disruption of cell membrane integrity, and an increase in IL-18 inflammatory cytokines. Also, we found that the expression of caspase-11, GSDMD and GSDMD-N were increased in C57BL/6J mice induced by STZ combined with high sugar and fat. In addition, the pathological results of kidney showed a significant thickening of the glomerular basement membrane, abnormal increasement of extracellular matrix and hyperplasia with blurred boundaries of glomerulus. Furthermore, interfering the expression of GSDMD improved the pathological degree of kidney. These findings indicated that the pyroptosis of GECs during DN was facilitated by the non-classical pathway of caspase-11/GSDMD, ultimately leading to GECs injury and further aggravating the progression of DN. This work highlights the potential of GSDMD as a therapeutic target for the treatment of DN.

Mitochondrial protein MPV17 promotes ß-cell apoptosis in diabetogenesis.

MPV17 is a mitochondrial inner membrane protein, and its deficiency can cause mitochondrial DNA (mtDNA) depletion, increase reactive oxygen species (ROS), and promote apoptosis in several cell types, suggesting that MPV17 plays a protective role in cells although the underlying mechanism remains unknown. To test whether MPV17 is also protective in diabetic kidney disease, we treated Mpv17-deficient mice with streptozotocin (STZ) and surprisingly found that they were resistant to diabetes. Mpv17 deficiency was also found to confer resistance to the diabetes induced by an insulin mutation (Ins2Akita), which represents a mouse model of monogenic diabetes characterized by proinsulin misfolding and ß-cell failure. In both STZ and Ins2Akita models, Mpv17 mutants had significantly less severe ß-cell loss and apoptosis compared with the wild-type mice. We next showed that MPV17 is expressed in ß-cells of mice normally, suggesting that MPV17 acts ß-cells autonomously to facilitate apoptosis. Consistently, Mpv17 knockdown improved the viability and ameliorated the apoptosis of cultured MIN6 cells treated with STZ and palmitic acid (PA), respectively, accompanied by prevention of caspase 3 activation. The proapoptotic effect of MPV17 in ß-cells is in contrast with its known anti-apoptotic effect in other cell types. Thus, we have identified a novel regulator of ß-cell death in diabetes development.

Co-delivery of a tumor microenvironment-responsive disulfiram prodrug and CuO2 nanoparticles for efficient cancer treatment.

Disulfiram (DSF) has been used as a hangover drug for more than seven decades and was found to have potential in cancer treatment, especially mediated by copper. However, the uncoordinated delivery of disulfiram with copper and the instability of disulfiram limit its further applications. Herein, we synthesize a DSF prodrug using a simple strategy that could be activated in a specific tumor microenvironment. Poly amino acids are used as a platform to bind the DSF prodrug through the B-N interaction and encapsulate CuO2 nanoparticles (NPs), obtaining a functional nanoplatform Cu@P-B. In the acidic tumor microenvironment, the loaded CuO2 NPs will produce Cu2+ and cause oxidative stress in cells. At the same time, the increased reactive oxygen species (ROS) will accelerate the release and activation of the DSF prodrug and further chelate the released Cu2+ to produce the noxious copper diethyldithiocarbamate complex, which causes cell apoptosis effectively. Cytotoxicity tests show that the DSF prodrug could effectively kill cancer cells with only a small amount of Cu2+ (0.18 µg mL-1), inhibiting the migration and invasion of tumor cells. In vitro and in vivo experiments have demonstrated that this functional nanoplatform could kill tumor cells effectively with limited toxic side effects, showing a new perspective in DSF prodrug design and cancer treatment.

Design and optimization of GI-PCF supporting the orbital angular momentum modes based on negative curvature structure.

Based on the negative curvature structure, we design a graded-index photonic crystal fiber (GI-PCF) supporting the orbital angular momentum (OAM) mode transmission and discuss its optimization strategy. The core of the designed GI-PCF is sandwiched by three-layer inner air-hole arrays with gradually decreasing air-hole radii and a single outer air-hole array, where the inner side of the annular core forms a graded refractive index distribution. All these structures are clad with negative-curvature tubes. By optimizing characteristic structural parameters, including the air-filling fraction of the outer array, the air-hole radii of the inner arrays, and the thickness of the tubes, the GI-PCF can support 42 OAM modes and most of them have a purity greater than 85%. Compared with conventional structures, the present design of GI-PCF has better properties on an overall level, which can stably transmit multiple OAM modes with high mode purity. These results inject new interest in the flexible design of PCF and have potential applications in various fields, including but not limited to the mode division multiplexing system and terabit data transmission.

Yellow pigment from gardenia fruit: structural identification and evaluation of cytotoxic activity in HepG2 cells by induction of apoptosis.

The preparation process of yellow pigment (YP) from gardenia (Gardenia jasminoides) fruit was investigated, and the main components of YP were characterized by liquid chromatography-time of flight-mass spectrometer/mass spectrometer (LC-TOF-MS/MS). Furthermore, cytotoxic activity in HepG2 cells by induction of apoptosis was also evaluated. The preparation results indicated that the color value of YP was 498.34, which was 8.6 times higher than crude YP. Fifteen compounds in YP were identified, and crocins were the predominant compounds. The cell experiment results showed that YP inhibited the proliferation of HepG2 cells in a time- and dose-dependent manner. Moreover, YP also inhibited HepG2 cells in G2/M stage, increased the level of intracellular reactive oxygen species (ROS), and enhanced cell apoptosis. Real-time quantitative polymerase chain reaction (RT-PCR) analysis revealed the up-regulation of caspase-3, 8, 9, and bax and down-regulation of bcl-2 in HepG2 cells. Overall, these findings suggested that YP had potential cytotoxic activity in HepG2 cells by induction of apoptosis, which might be beneficial to human health. Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-022-01133-9.

New Hypoglycemic Drugs: Combination Drugs and Targets Discovery.

New hypoglycemic drugs, including glucagon-like peptide 1 receptor agonists (GLP-1RA), dipeptidyl peptidase-4 inhibitors (DPP-4i) and sodium-glucose cotransporter 2 inhibitors (SGLT-2i), which brings more options for the treatment of type 2 diabetes (T2DM). They are generally well tolerated, although caution is required in rare cases. Clinical trials have show good glycemic control with combination therapy with new hypoglycemic drugs in prediabetes and T2DM (mostly traditional stepwise therapy), but early combination therapy appears to have faster, more, and longer-lasting benefits. With the widespread clinical application of oral semaglutide, it is time to develop combinations drugs containing new hypoglycemic drugs, especially SGLT-2i and/or GLP-1RA, to control the risk of prediabetes and newly diagnosed T2DM and its cardiovascular complications, while improving patient compliance. Clinical and preclinical studies support that SGLT-2i exerts its protective effect on heart failure through indirect and direct effects. How this comprehensive protective effect regulates the dynamic changes of heart genes needs further study. We provide ideas for the development of heart failure drugs from the perspective of "clinical drug-mechanism-intensive disease treatment." This will help to accelerate the development of heart failure drugs, and to some extent guide the use of heart failure drugs.

Construction of Nursing Practice Model in Case Management of Concurrent Chemotherapy and Radiochemotherapy Treatment in Cervical Cancer.

Objective: To construct a case management model of synchronous radiotherapy and concurrent chemotherapy and radiochemotherapy (CRR) for cervical cancer led by nurses and carry out preliminary implementation and evaluation, so as to explore a new model of nursing practice. Methods: Totally 80 cervical cancer patients were included in this study, 43 patients were in the experimental group, and 37 patients were in the control group. The clinical data, side effects, psychological reactions, and nutritional indexes were collected before and after the intervention. Results: The results of Hospital Anxiety and Depression Scale (HADs) showed that anxiety and depression scores decreased after intervention in the experimental group, and the difference between two groups had significant after intervention (P < 0.05). Serum fatty acids, albumin, and cholesterol in the experimental group were decreased after the intervention. Moreover, the incidence of radiation vaginitis and radiation dermatitis had significant differences between the two groups (P < 0.05). Conclusion: The case management nursing practice mode of concurrent radiotherapy and chemotherapy for cervical cancer can effectively promote the self-management of risk factors, reduce the occurrence of complications, and improve the ability of self-care.

Analysis of the Effect of Phacoemulsification and Intraocular Lens Implantation Combined With Trabeculectomy on Cataract and Its Influence on Corneal Endothelium.

OBJECTIVE: This study aimed to discuss the effect of phacoemulsification and intraocular lens implantation (PHACO + IOL) combined with trabeculectomy (TRAB) on cataracts and its influence on the corneal endothelium. METHODS: We selected 120 cataract patients admitted to our hospital from January 2018 to January 2021. According to different surgical methods, they were divided into the control group and the observation group. The observation group was treated with PHACO + IOL combined with TRAB, the control group only received PHACO. The clinical effect, ophthalmic-related parameters, corneal endothelium, complications, the satisfaction of the two groups were observed. RESULTS: The total effective rate and total satisfaction rate of the observation group were significantly higher than the control group (P < 0.05). One month after the operation, the vision and central anterior chamber depth of the observation group were higher than those of the control group, and intraocular pressure (IOP) was lower than that of the control group (P < 0.05). One month after the operation, the corneal endothelial cell area and cell density in the observation group were not significantly different from those before operation (P > 0.05). There was no significant difference in the total incidence of complications between the two groups (P > 0.05). CONCLUSION: This study concluded that PHACO + IOL combined with TRAB has a good curative effect in the treatment of cataracts, which can improve the patients' vision and IOP, keep the functional integrity of corneal endothelial cells, and does not increase the occurrence of complications, the patients' satisfaction is high.

Corrigendum: MicroRNAs as Regulators of Immune and Inflammatory Responses: Potential Therapeutic Targets in Diabetic Nephropathy.

[This corrects the article DOI: 10.3389/fcell.2020.618536.].

Berberine regulates mesangial cell proliferation and cell cycle to attenuate diabetic nephropathy through the PI3K/Akt/AS160/GLUT1 signalling pathway.

High glucose (HG) is one of the basic factors of diabetic nephropathy (DN), which leads to high morbidity and disability. During DN, the expression of glomerular glucose transporter 1 (GLUT1) increases, but the relationship between HG and GLUT1 is unclear. Glomerular mesangial cells (GMCs) have multiple roles in HG-induced DN. Here, we report prominent glomerular dysfunction, especially GMC abnormalities, in DN mice, which is closely related to GLUT1 alteration. In vivo studies have shown that BBR can alleviate pathological changes and abnormal renal function indicators of DN mice. In vitro, BBR (30, 60 and 90 µmol/L) not only increased the proportion of G1 phase cells but also reduced the proportion of S phase cells under HG conditions at different times. BBR (60 µmol/L) significantly reduced the expression of PI3K-p85, p-Akt, p-AS160, membrane-bound GLUT1 and cyclin D1, but had almost no effect on total protein. Furthermore, BBR significantly declined the glucose uptake and retarded cyclin D1-mediated GMC cell cycle arrest in the G1 phase. This study demonstrated that BBR can inhibit the development of DN, which may be due to BBR inhibiting the PI3K/Akt/AS160/GLUT1 signalling pathway to regulate HG-induced abnormal GMC proliferation and the cell cycle, supporting BBR as a potential therapeutic drug for DN.

Adjunctive Er:YAG laser in non-surgical periodontal therapy of patients with inadequately controlled type 2 diabetes mellitus: A split-mouth randomized controlled study.

BACKGROUND AND OBJECTIVE: Limited studies are available comparing the outcomes of non-surgical periodontal therapy (NSPT) with or without adjunctive Er:YAG laser (ERL) in patients with type 2 diabetes mellitus (T2DM). This study evaluated the effects of ERL adjunctive NSPT on single-rooted teeth of inadequately controlled T2DM patients with periodontitis. METHODS: Twenty-two inadequately controlled T2DM participants with periodontitis were recruited. Adopting a double-blinded split-mouth design and under block randomization, we investigated the effects of ERL in calculus removal then degranulation mode, or a sham treatment, adjunct NSPT, which included two visits of full-mouth root surface debridement delivered within 4-10 days, to test or control single-rooted teeth (Wuxi Stomatology Hospital, trial 2017-016). We followed periodontal parameters (plaque %, bleeding on probing [BOP] %, probing pocket depth [PPD], probing attachment level [PAL]) and selected systemic parameters (fasting plasma glucose [FPG], glycosylated hemoglobin [HbA1c%], high sensitivity C-reactive protein) at baseline, one, three, and six months after periodontal treatment. RESULTS: The study was completed as planned. Periodontal parameters, FPG and HbA1c% of the 22 participants appeared significantly improved at six months (p < 0.001). The 44 ERL treated, compared to 44 sham treated single-rooted teeth exhibited significant improvement in BOP, mean PPD, and mean PAL at various postoperative follow-up time points (effect size ≥0.44; p < 0.001). No adverse event was reported. CONCLUSION: Periodontal treatment outcomes in the T2DM patients with inadequate glycemic control were better in the single-rooted teeth received ERL adjunct NSPT. Further studies are warranted to confirm the observations reported in this short-term clinical study.