Unveiling the role of hypoxia-inducible factor 2alpha in osteoporosis: Implications for bone health.

BACKGROUND: Osteoporosis (OP) has become a major public health problem worldwide. Most OP treatments are based on the inhibition of bone resorption, and it is necessary to identify additional treatments aimed at enhancing osteogenesis. In the bone marrow (BM) niche, bone mesenchymal stem cells (BMSCs) are exposed to a hypoxic environment. Recently, a few studies have demonstrated that hypoxia-inducible factor 2alpha (HIF-2α) is involved in BMSC osteogenic differentiation, but the molecular mechanism involved has not been determined. AIM: To investigate the effect of HIF-2α on the osteogenic and adipogenic differentiation of BMSCs and the hematopoietic function of hematopoietic stem cells (HSCs) in the BM niche on the progression of OP. METHODS: Mice with BMSC-specific HIF-2α knockout (Prx1-Cre;Hif-2αfl/fl mice) were used for in vivo experiments. Bone quantification was performed on mice of two genotypes with three interventions: Bilateral ovariectomy, semilethal irradiation, and dexamethasone treatment. Moreover, the hematopoietic function of HSCs in the BM niche was compared between the two mouse genotypes. In vitro, the HIF-2α agonist roxadustat and the HIF-2α inhibitor PT2399 were used to investigate the function of HIF-2α in BMSC osteogenic and adipogenic differentiation. Finally, we investigated the effect of HIF-2α on BMSCs via treatment with the mechanistic target of rapamycin (mTOR) agonist MHY1485 and the mTOR inhibitor rapamycin. RESULTS: The quantitative index determined by microcomputed tomography indicated that the femoral bone density of Prx1-Cre;Hif-2αfl/fl mice was lower than that of Hif-2αfl/fl mice under the three intervention conditions. In vitro, Hif-2αfl/fl mouse BMSCs were cultured and treated with the HIF-2α agonist roxadustat, and after 7 d of BMSC adipogenic differentiation, the oil red O staining intensity and mRNA expression levels of adipogenesis-related genes in BMSCs treated with roxadustat were decreased; in addition, after 14 d of osteogenic differentiation, BMSCs treated with roxadustat exhibited increased expression of osteogenesis-related genes. The opposite effects were shown for mouse BMSCs treated with the HIF-2α inhibitor PT2399. The mTOR inhibitor rapamycin was used to confirm that HIF-2α regulated BMSC osteogenic and adipogenic differentiation by inhibiting the mTOR pathway. Consequently, there was no significant difference in the hematopoietic function of HSCs between Prx1-Cre;Hif-2αfl/fl and Hif-2αfl/fl mice. CONCLUSION: Our study showed that inhibition of HIF-2α decreases bone mass by inhibiting the osteogenic differentiation and increasing the adipogenic differentiation of BMSCs through inhibition of mTOR signaling in the BM niche.

Improvement of thermostability and catalytic efficiency of xylanase from Myceliophthora thermophilar by N-terminal and C-terminal truncation.

Introduction: Extracting xylanase from thermophilic filamentous fungi is a feasible way to obtain xylanase with good thermal stability. Methods: The transcriptomic data of Myceliophthora thermophilic destructive ATCC42464 were differentially expressed and enriched. By comparing the sequences of Mtxylan2 and more than 10 xylanases, the N-terminal and C-terminal of Mtxylan2 were truncated, and three mutants 28N, 28C and 28NC were constructed. Results and discussion: GH11 xylan Mtxylan2 was identified by transcriptomic analysis, the specific enzyme activity of Mtxylan2 was 104.67 U/mg, and the optimal temperature was 65°C. Molecular modification of Mtxylan2 showed that the catalytic activity of the mutants was enhanced. Among them, the catalytic activity of 28C was increased by 9.3 times, the optimal temperature was increased by 5°C, and the residual enzyme activity remained above 80% after 30 min at 50-65°C, indicating that redundant C-terminal truncation can improve the thermal stability and catalytic performance of GH11 xylanase.

Insight investigation into the response pattern of microbial assembly succession and volatile profiles during the brewing of sauce-flavor baijiu based on bioaugmentation.

To improve the flavor profile and sensory quality of baijiu, the utilization of bioaugmented fermentation inoculated with functional microbiota normally serves as an effective method for directional regulation during the baijiu fermentation process. In this study, a systematic analysis of the succession patterns and volatile flavor compound profiles of microbial communities was carried out by high-throughput sequencing and solid-phase microextraction gas chromatography-mass spectrometry, respectively. The results demonstrated that the Saccharomyces cerevisiae YS222-related bioaugmentation clearly altered the microbial composition, particularly the assembly of bacteria, and promoted the quantity of the most volatile flavoring compounds, including alcohols, esters, and pyrazines. In addition, the correlation analysis showed that Saccharomyces and Lactobacillus in the augmented group were the main biomarkers associated with the dynamics of microbial community and greatly contributed to the brewing of sauce-flavor baijiu, which congruent with the outcomes of the enrichment analysis of integrated metabolic pathway. Thus, this work is beneficial for promoting the quality of baijiu and will serve as a useful reference for clarifying the possible mechanism of augmented fermentation on flavor development.

Nanoemulsion-integrated gelatin/bacterial cellulose nanofibril-based multifunctional film: Fabrication, characterization, and application.

The current requirements of food safety regulations and the environmental impact stemming from plastic packaging can only be addressed by developing suitable bio-nanocomposite films. Therefore, this study is dedicated to the fabrication of multifunctional film composed of gelatin, bacterial cellulose nanofibrils (BCNF), and black pepper essential oil nanoemulsion (BPEONE) and application for duck meat preservation. BCNF was prepared through ultrasonication of cellulose derived from Komagataeibacter xylinus. BPEONE observed spherical morphology with a diameter ranging from 83.7 to 118 nm. A film matrix containing a higher gelatin proportion than BCNF was more effective in trapping BPEONE. However, increasing the BPEONE fraction showed more surface abrasion and voids in the film morphology. A flexible film with good interaction, crystallinity, and greater thermal stability (421 °C) was developed. Nevertheless, film hydrophobicity (118.89°) declined, resulting in a notable effect on water solubility, swelling, and water vapor permeability. Moreover, the film had improved antibacterial and antioxidant activities, coupled with controlled release characteristics. Consequently, the developed film effectively retarded the lipid oxidation, inhibited microbial growth, and extended the shelf life of duck meat at refrigeration (4 °C) by 3 days, and made the film a promising alternative in the realm of bio-active packaging technology.

Improvement of kefir fermentation on rheological and microstructural properties of soy protein isolate gels.

Soy protein isolate (SPI) has become a promising plant-based material as an animal protein products alternative. However, its application was limited due to the weak gelling properties. To investigate the effect of kefir fermentation on SPI gels properties, SPI-polysaccharide gels was produced by unfermented and kefir-fermented SPI using different concentration of KGM, chitosan, and calcium chloride in this study. Characterization of fermented SPI gels showed that fermentation by kefir grains can be applied to improve the textural strength, mechanical structure, and thermal characteristics of SPI gels. Compared to unfermented SPI gels, the water-holding capacity was remarkably enhanced to 63.11% and 65.71% in fermented SPI-chitosan gels. Moreover, the hardness of fermented SPI-KGM gels were significantly increased to 13.43 g and 27.11 g. And the cohesiveness and resilience of fermented-KGM gels were also improved than unfermented samples. Results of rheological characterization and thermogravimetric analysis revealed the strengthened mechanical features and higher thermal stability of fermented SPI gels. Additionally, the main role of hydrophobic interactions and secondary structure variations of SPI gels were demonstrated by intermolecular force measurements, Fourier-transform infrared spectroscopy, and X-ray diffraction. Moreover, the network structure was observed more compact and homogeneous performed by microstructural images in fermented SPI gels. Therefore, this research provided a novel approach combining multi-species fermentation with protein gelation to prepare SPI gel materials with improved nutrition and structural properties.

Simultaneously Enhanced Thermostability and Catalytic Activity of Xylanase from Streptomyces rameus L2001 by Rigidifying Flexible Regions in Loop Regions of the N-Terminus.

The GH11 xylanase XynA from Streptomyces rameus L2001 has favorable hydrolytic properties. However, its poor thermal stability hinders its widespread application in industry. In this study, mutants Mut1 and Mut2 were constructed by rationally combining the mutations 11YHDGYF16, 23AP24/23SP24, and 32GP33. The residual enzyme activity of these combinational mutants was more than 85% when incubated at 80 and 90 °C for 12 h, and thus are the most thermotolerant xylanases known to date. The reduced flexibility of the N-terminus, increased overall rigidity, as well as the surface net charge of Mut1 and Mut2 may be partially responsible for the improved thermal stability. In addition, the specific activity and catalytic efficiency of Mut1 and Mut2 were improved compared with those of wild-type XynA. The broader catalytic cleft and enhanced flexibility of the "thumb" of Mut1 and Mut2 may be partially responsible for the improved specific activity and catalytic efficiency.

Effects of SGLT-2 inhibitors on adipose tissue distribution in patients with type 2 diabetes mellitus: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: Sodium-glucose cotransporter-2 (SGLT-2) inhibitors therapies were reported to affect adipose tissue distribution. However, the available evidence about the effect of SGLT-2 inhibitor on adipose tissue is contradictory. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the effect of SGLT-2 inhibitors on adipose tissue distribution in patients with type 2 diabetes mellitus (T2DM). METHODS: RCTs on SGLT-2 inhibitors on adipose distribution affect in patients with T2DM published in full-text journal databases such as PubMed, Embase, Cochrane Library, and ClinicalTrials.gov databases were searched. The fixed or random effect model was used for meta-analysis, the I2 test was used to evaluate the heterogeneity between studies, and the sensitivity analysis and subgroup analysis were used to explore the source of heterogeneity. Funnel chart and Begg's test were used to estimate publication bias. RESULTS: Overall, 18 RCTs involving 1063 subjects were evaluated. Compared with placebo or other hypoglycemic drugs, SGLT-2 inhibitors significantly reduced visceral adipose tissue (standard mean deviation [SMD] = - 1.42, 95% confidence interval [CI] [- 2.02, - 0.82], I2 = 94%, p < 0.0001), subcutaneous adipose tissue (SMD = - 1.21, 95% CI [- 1.99, - 0.42], I2 = 93%, p = 0.003), ectopic liver adipose tissue (SMD = - 0.70, 95% CI [- 1.20, - 0.20], I2 = 73%, p = 0.006). In addition, body weight (mean deviation [MD] = - 2.60, 95% CI [- 3.30, - 1.89], I2 = 95%, p < 0.0001), waist circumference (MD = - 3.65, 95% CI [- 4.10, - 3.21], I2 = 0%, p < 0.0001), and body mass index (BMI) (MD = - 0.81, 95% CI [- 0.91, - 0.71], I2 = 23%, p < 0.0001) were significantly decreased. However, epicardial fat tissue showed an insignificant reduction (SMD = 0.03, 95% CI [- 0.52, 0.58], I2 = 69%, p = 0.71). Subgroup analysis revealed that appropriate treatment duration (16 - 40 weeks) or young patients with nonalcoholic fatty liver disease (NAFLD) and obesity were the decisive factors for SGLT-2 inhibitors to effectively reduce visceral and subcutaneous adipose tissues. CONCLUSIONS: Our meta-analysis provides evidence that in patients with T2DM, SGLT-2 inhibitors significantly reduce visceral adipose tissue, subcutaneous adipose tissue, and ectopic liver fat, especially in young T2DM patients with NAFLD and high BMI. Appropriate dosing time (16-40 weeks) may have a more significant and stable beneficial effect on VAT and SAT reduction.

Hepatocyte-specific knockout of HIF-2α cannot alleviate carbon tetrachloride-induced liver fibrosis in mice.

Background: The effects of hypoxia inducible factor-2α (HIF-2α) deficiency on liver fibrosis have not been demonstrated in a fibrosis model induced by carbon tetrachloride (CCl4). We aimed to examine whether hepatocyte-specific HIF-2α deletion could ameliorate CCl4-induced liver fibrosis in mice. Methods: Hepatocyte-specific HIF-2α knockout mice were created using an albumin promoter-driven Cre recombinase. HIF-2α knockout (KO) mice and floxed control wild-type (WT) mice were fed a normal diet (ND) and received either twice weekly intraperitoneal injections of CCl4 solution (CCl4 dissolved in olive oil) or the corresponding amount of olive oil for 8 weeks. The indicators of liver function, glucose and lipid metabolism, and liver histology were compared among the different groups. Results: Hepatocyte-specific HIF-2α knockout had no effect on the growth, liver function, glucose or lipid metabolism in mice. CCl4-treated KO and WT mice had a similar pattern of injury and inflammatory cell infiltration in the liver. Quantification of Masson staining, α-smooth muscle actin (α-SMA) immunohistochemistry, and the hydroxyproline (HYP) content revealed similar liver fibrosis levels between KO and WT mice injected intraperitoneally with CCl4. Immunohistochemistry analysis suggested that HIF-2α was mainly expressed in the portal area and hepatic sinusoids but not in hepatocytes. Bioinformatics analyses further indicated that HIF-2α expression was neither liver specific nor hepatocyte specific, and the effect of HIF-2α in hepatocytes on liver fibrosis may not be as important as that in liver sinuses. Conclusions: Hepatocyte HIF-2α expression may not be a key factor in the initiation of liver fibrogenesis, and hepatocyte-specific deletion of HIF-2α may not be the ideal therapeutic strategy for liver fibrosis.

Microbial Community Variations and Bioconversion Improvements during Soybean-Based Fermentation by Kefir Grains.

Soybeans possess unexpected flavors and are difficult to be absorbed by the gastrointestinal tract. Kefir grain fermentation provides diverse strains and bioactive compounds, which may enhance flavor and bioaccessibility. Third-generation sequencing was applied to analyze the microbial diversity in milk and soybean kefir grains in this study. In both types of kefir grains, the most common bacterial genus was Lactobacillus, and their fungal communities were dominated by Kazachstania. Lactobacillus kefiranofaciens was the most abundant species in kefir grains, while Lactobacillus kefiri showed a higher proportion in soybean kefir grains. In addition, the quantification of free amino acids and volatile flavor compounds in soybean solution and soybean kefir have shown the increased content of glutamic acid and a decreased amount of unpleasant beany flavor compounds, demonstrating that the nutritive value and sensory properties of soybean can be improved by kefir grain fermentation. Finally, the bioconversion of isoflavones during fermentation and in vitro digestion was evaluated, suggesting that fermentation is beneficial for aglycone formation and absorption. To conclude, kefir fermentation is proposed to change the microbial structure of kefir grains, promote the nutritional value of soybean-based fermented products, and provide possible solutions for the development of soybean products.

Three Molecular Modification Strategies to Improve the Thermostability of Xylanase XynA from Streptomyces rameus L2001.

Glycoside hydrolase family 11 (GH11) xylanases are the preferred candidates for the production of functional oligosaccharides. However, the low thermostability of natural GH11 xylanases limits their industrial applications. In this study, we investigated the following three strategies to modify the thermostability of xylanase XynA from Streptomyces rameus L2001 mutation to reduce surface entropy, intramolecular disulfide bond construction, and molecular cyclization. Changes in the thermostability of XynA mutants were analyzed using molecular simulations. All mutants showed improved thermostability and catalytic efficiency compared with XynA, except for molecular cyclization. The residual activities of high-entropy amino acid-replacement mutants Q24A and K104A increased from 18.70% to more than 41.23% when kept at 65 °C for 30 min. The catalytic efficiencies of Q24A and K143A increased to 129.99 and 92.26 mL/s/mg, respectively, compared with XynA (62.97 mL/s/mg) when using beechwood xylan as the substrate. The mutant enzyme with disulfide bonds formed between Val3 and Thr30 increased the t1/260 °C by 13.33-fold and the catalytic efficiency by 1.80-fold compared with the wild-type XynA. The high thermostabilities and hydrolytic activities of XynA mutants will be useful for enzymatic production of functional xylo-oligosaccharides.

Improved thermostability, acid tolerance as well as catalytic efficiency of Streptomyces rameus L2001 GH11 xylanase by N-terminal replacement.

The N-terminal of xylanase from 11 family of glycoside hydrolases (GH11 xylanase) has an important effect on its thermostability and catalytic properties. Previous studies have unearthed five important residues located in the N-terminal and successfully improved the thermostability of several GH11 xylanases using amino acid substitutions. In the present study, we applied this tactic to construct a mutant of XynA from Streptomyces rameus L2001, XynAR, and studied its biochemical, catalytic and hydrolytic properties. The results showed that thermostability, acid tolerance as well as catalytic efficiency of XynAR significantly improved compared to those of XynA, while the hydrolytic characteristics changed. Computer simulation analysis showed that this tactic created new hydrogen bonds and electrostatic interactions in the N-terminal, resulting in decrease in the flexibility of N-terminal and surface electrostatic potential as well as a change in the profile of hydrogen bonds between the subsites and substrate in the cleft region of xylanase. This study showed that amino acid substitutions at the key sites of the N-terminal of GH11 xylanase can improve its thermostability and catalytic properties.

Bioprocessing by Decellularized Scaffold Biomaterials in Cultured Meat: A Review.

As novel carrier biomaterials, decellularized scaffolds have promising potential in the development of cellular agriculture and edible cell-cultured meat applications. Decellularized scaffold biomaterials have characteristics of high biocompatibility, bio-degradation, biological safety and various bioactivities, which could potentially compensate for the shortcomings of synthetic bio-scaffold materials. They can provide suitable microstructure and mechanical support for cell adhesion, differentiation and proliferation. To our best knowledge, the preparation and application of plant and animal decellularized scaffolds have not been summarized. Herein, a comprehensive presentation of the principles, preparation methods and application progress of animal-derived and plant-derived decellularized scaffolds has been reported in detail. Additionally, their application in the culture of skeletal muscle, fat and connective tissue, which constitute the main components of edible cultured meat, have also been generally discussed. We also illustrate the potential applications and prospects of decellularized scaffold materials in future foods. This review of cultured meat and decellularized scaffold biomaterials provides new insight and great potential research prospects in food application and cellular agriculture.

Interactions between Mannosylerythritol Lipid-A and Heat-Induced Soy Glycinin Aggregates: Physical and Chemical Characteristics, Functional Properties, and Structural Effects.

Protein-surfactant interactions have a significant influence on food functionality, which has attracted increasing attention. Herein, the effect of glycolipid mannosylerythritol lipid-A (MEL-A) on the heat-induced soy glycinin (11S) aggregates was investigated by measuring the structure, binding properties, interfacial behaviors, and emulsification characteristics of the aggregates. The results showed that MEL-A led to a decrease in the surface tension, viscoelasticity, and foaming ability of the 11S aggregates. In addition, MEL-A with a concentration above critical micelle concentration (CMC) reduced the random aggregation of 11S protein after heat treatment, thus facilitating the formation of self-assembling core-shell particles composed of a core of 11S aggregates covered by MEL-A shells. Infrared spectroscopy, circular dichroism spectroscopy, fluorescence spectroscopy, and isothermal titration calorimetry also confirmed that the interaction forces between MEL-A and 11S were driven by hydrophobic interactions between the exposed hydrophobic groups of the protein and the fatty acid chains or acetyl groups of MEL-A, as well as the hydrogen bonding between mannosyl-D-erythritol groups of MEL-A and amino acids of 11S. The findings of this study indicated that such molecular interactions are responsible for the change in surface behavior and the enhancement of foaming stability and emulsifying property of 11S aggregates upon heat treatment.

A comprehensive review of microorganism-derived cyclic peptides: Bioactive functions and food safety applications.

Cyclic peptides possess advanced structural characteristics of stability and play a vital role in medical treatment and agriculture. However, the biological functions of microorganism-derived cyclic peptides (MDCPs) and their applications in food industry were relatively absent. MDCPs are derived from extensive fermented food or soil. In this review, the synthesis approaches and structural characteristics are overviewed, while the interrelationship between bioactivities and functions is emphasized. This review summarizes the bioactivities of MDCPs from in vitro to in vivo, including antimicrobial activities, immune regulation, and antiviral cell activation. Their multiple functions as well as applications during food product processing, packaging, and storage are also comprehensively reviewed. Remarkably, some potential risks and cytotoxicity of MDCPs are also critically discussed. Moreover, future applications of MDCPs in the development of novel food additives and bioengineering materials are organized. Based on this review of native MDCPs, it is noteworthy that expected improvements of synthetic cyclic peptides in bioactive properties present potential valuable applications in future food, including artificial meat.

The Influence of Different Pretreatment Methods of Highland Barley by Solid-State Fermentation with Agaricus sinodeliciosus var. Chaidam ZJU-TP-08 on Its Nutrient Content, Functional Properties and Physicochemical Characteristics.

To enhance the nutritional value of highland barley (HB), this work investigated the effects of solid-state fermentation (SSF) by Agaricus sinodeliciosus var. Chaidam ZJU-TP-08 on nutrient content, phenolic components, antioxidant activities, and physicochemical characteristics of HB upon different pretreatments (germination, ultrasound and soaking). The results showed that germinated highland barley (GHB) exhibited higher levels of ergosterol (0.19 ± 0.01 mg/g) in all fermentation groups. The content of ß-glucan was higher in the SSF-GHB, with an increase of 24.21% compared to the control. The content of total amino acids, dietary fiber, total phenols and flavonoids were higher in the fermentation HB pretreated by ultrasound, increasing respectively by 5.60%, 61.50%, 25.10% and 65.32% compared to the control group. In addition, the colonized HB exhibited excellent physicochemical characteristics, including increased water solubility index and decreased pasting characteristics. Herein, the nutritional value and the biological activities were enriched in the pretreated HB through SSF, indicating its potential application for nutrition-enriched functional foods.

Clostridium btbubcensis BJN0001, a potentially new species isolated from the cellar mud of Chinese strong-flavor baijiu, produces ethanol, acetic acid and butyric acid from glucose.

A novel strain, designated BJN0001, was isolated from the cellar mud of Chinese strong-flavor baijiu. The complete genome of strain BJN0001 was 2,688,791 bp and annotated with 2610 genes. Whole-genome similarity metrics such as average nucleotide identity (ANI) of BJN0001 with reference genomes reveals clear species boundaries of < 95% ANI value for species. The DNA-DNA hybridization (DDH) values of BJN0001 with the type species were all lower than 70% DDH value for species. Based on these results, the strain BJN0001 was considered a potentially new species of the genus Clostridium. Meanwhile, the fermentation characteristics indicated that the strain had the capability to convert glucose to ethanol, acetic acid and butyric acid, which could provide basic data for revealing its function in baijiu fermentation. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-022-03271-7.

Neutrophils as regulators of macrophage-induced inflammation in a setting of allogeneic bone marrow transplantation.

Clinical data reveal that patients with allogeneic hematopoietic stem cell transplantation (HSCT) are vulnerable to infection and prone to developing severe sepsis, which greatly compromises the success of transplantation, indicating a dysregulation of inflammatory immune response in this clinical setting. Here, by using a mouse model of haploidentical bone marrow transplantation (haplo-BMT), we found that uncontrolled macrophage inflammation underlies the pathogenesis of both LPS- and E.coli-induced sepsis in recipient animals with graft-versus-host disease (GVHD). Deficient neutrophil maturation in GVHD mice post-haplo-BMT diminished modulation of macrophage-induced inflammation, which was mechanistically dependent on MMP9-mediated activation of TGF-ß1. Accordingly, adoptive transfer of mature neutrophils purified from wild-type donor mice inhibited both sterile and infectious sepsis in GVHD mice post-haplo-BMT. Together, our findings identify a novel mature neutrophil-dependent regulation of macrophage inflammatory response in a haplo-BMT setting and provide useful clues for developing clinical strategies for patients suffering from post-HSCT sepsis.

SGLT2 inhibitor dapagliflozin attenuates cardiac fibrosis and inflammation by reverting the HIF-2α signaling pathway in arrhythmogenic cardiomyopathy.

Excessive cardiac fibrosis and inflammation aberrantly contribute to the progressive pathogenesis of arrhythmogenic cardiomyopathy (ACM). Whether sodium-glucose cotransporter-2 inhibitor (SGLT2i), as a new hypoglycemic drug, benefits ACM remains unclear. Cardiomyocyte-specific Dsg2 exon-11 knockout and wild-type (WT) littermate mice were used as the animal model of ACM and controls, respectively. Mice were administered by gavage with either SGLT2i dapagliflozin (DAPA, 1 mg/kg/day) or vehicle alone for 8 weeks. HL-1 cells were treated with DAPA to identify the molecular mechanism in vitro. All mice presented normal glucose homeostasis. DAPA not only significantly ameliorated cardiac dysfunction, adverse remodeling, and ventricular dilation in ACM but also attenuated ACM-associated cardiac fibrofatty replacement, as demonstrated by the echocardiography and histopathological examination. The protein expressions of HIF-2α and HIF-1α were decreased and increased respectively in cardiac tissue of ACM, which were compromised after DAPA treatment. Additionally, NF-κB P65 and IκB phosphorylation, as well as fibrosis indicators (including TGF-ß, α-SMA, Collagen I, and Collagen III) were increased in ACM. However, these trends were markedly suppressed by DAPA treatment. Consistent with these results in vitro, DAPA alleviated the IκB phosphorylation and NF-κB p65 transcriptional activity in DSG2-knockdown HL-1 cells. Interestingly, the elective HIF-2α inhibitor PT2399 almost completely blunted the DAPA-mediated downregulation of indicators concerning cardiac fibrosis and inflammation. SGLT2i attenuated the ACM-associated cardiac dysfunction and adverse remodeling in a glucose-independent manner by suppressing cardiac fibrosis and inflammation via reverting the HIF-2α signaling pathway, suggesting that SGLT2i is a novel and available therapy for ACM.

The clinical efficacy and safety of dapagliflozin in patients with diabetic nephropathy.

OBJECTIVE: To investigate the clinical efficacy and safety of dapagliflozin in the treatment of diabetic nephropathy (DN). METHODS: A total of 120 DN patients admitted to our hospital from June 2017 to March 2020 were divided into control and experimental groups, with 60 cases in each group. The control group received valsartan, and the experimental group received dapagliflozin for 3 months. Body mass index (BMI), hemoglobin A1c (HbA1c), serum creatinine (sCr), uric acid (UA), urine microalbumin (uMA), urine creatinine (uCr), and bilateral kidney function were compared before and after treatment, and adverse reactions in both groups were observed. Serum interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels were also evaluated. RESULTS: After treatment, except for BMI in the control group, all indexes in both groups were significantly improved. The BMI, HbA1c, sCr, UA, and uMA/uCr ratios of the experimental group were lower than those of the control group. Serum albumin (sAlb) levels were increased in both groups, and the experimental group showed a significant difference compared with the control group. Estimated glomerular filtration rate (eGFR) levels were increased in both groups, and the experimental group was higher than the control group, with no significant differences. Serum IL-6 and TNF-α levels in both groups were lower, and the experimental group was significantly lower than the control group. No serious adverse reactions were observed in either group. CONCLUSION: The efficacy of dapagliflozin was demonstrated by its ability to improve diabetes, prevent nephropathy exacerbation, and reduce symptomatic reactions. The low rate of adverse reactions makes dapagliflozin a very safe medication.