FERREG: ferroptosis-based regulation of disease occurrence, progression and therapeutic response.

Ferroptosis is a non-apoptotic, iron-dependent regulatory form of cell death characterized by the accumulation of intracellular reactive oxygen species. In recent years, a large and growing body of literature has investigated ferroptosis. Since ferroptosis is associated with various physiological activities and regulated by a variety of cellular metabolism and mitochondrial activity, ferroptosis has been closely related to the occurrence and development of many diseases, including cancer, aging, neurodegenerative diseases, ischemia-reperfusion injury and other pathological cell death. The regulation of ferroptosis mainly focuses on three pathways: system Xc-/GPX4 axis, lipid peroxidation and iron metabolism. The genes involved in these processes were divided into driver, suppressor and marker. Importantly, small molecules or drugs that mediate the expression of these genes are often good treatments in the clinic. Herein, a newly developed database, named 'FERREG', is documented to (i) providing the data of ferroptosis-related regulation of diseases occurrence, progression and drug response; (ii) explicitly describing the molecular mechanisms underlying each regulation; and (iii) fully referencing the collected data by cross-linking them to available databases. Collectively, FERREG contains 51 targets, 718 regulators, 445 ferroptosis-related drugs and 158 ferroptosis-related disease responses. FERREG can be accessed at https://idrblab.org/ferreg/.

Impact of Charlson Comorbidity Index on in-hospital mortality of patients with hyperglycemic crises: A propensity score matching analysis.

AIM: This study was designed to investigate the association between Charlson Comorbidity Index (CCI) and in-hospital mortality and other clinical outcomes among patients with hyperglycemic crises. METHOD: This retrospective cohort study was conducted using data from electric medical records. A total of 1668 diabetic patients with hyperglycemic crises from six tertiary hospitals met the inclusion criteria. CCI < 4 was defined as low CCI and CCI ≥ 4 was defined as high CCI. Propensity score matching (PSM) with the 1:1 nearest neighbour matching method and the caliper value of 0.02 was used to match the baseline characteristics of patients with high CCI and low CCI to reduce the confounding bias. In-hospital mortality, ICU admission, hypoglycemia, hypokalemia, acute kidney injury, length of stay (LOS), and hospitalisation expense between low CCI and high CCI were compared and assessed. Univariate and multivariate regression were applied to estimate the impact of CCI on in-hospital and other clinical outcomes. OUTCOME: One hundred twenty-one hyperglycemic crisis (HC) patients died with a mortality rate of 7.3%. After PSM, compared with low CCI, patients with high CCI suffered higher in-hospital mortality, ICU admission, LOS, and hospitalisation expenses. After multivariate regression, age (aOR: 1.12, 95% confidence interval [CI]: 1.06-1.18, p < 0.001), CCI(aOR: 4.42, 95% CI: 1.56-12.53, p = 0.005), uninsured (aOR: 22.32, 95% CI: 4.26-116.94, p < 0.001), shock (aOR: 10.57, 95% CI: 1.41-79.09, p = 0.022), mechanical ventilation (aOR: 75.29, 95% CI: 12.37-458.28, p < 0.001), and hypertension (aOR: 4.34, 95% CI: 1.37-13.82, p = 0.013) were independent risk factors of in-hospital mortality of HC patients. Besides, high CCI was an independent risk factor for higher ICU Admission (aOR: 5.91, 95% CI: 2.31-15.08, p < 0.001), hypoglycemia (aOR: 2.19, 95% CI:1.01-4.08, p = 0.049), longer LOS (aOR: 1.23, 95% CI: 1.19-2.27, p = 0.021), and higher hospitalisation expense (aOR: 2089.97, 95% CI: 193.33-3988.61, p = 0.031) of HC patients. CONCLUSION: CCI is associated with in-hospital mortality, ICU admission, hypoglycemia, LOS, and hospitalisation expense of HC patients. CCI could be an ideal indicator to identify, monitor, and manage chronic comorbidities among HC patients.

Sinomenine attenuates bleomycin-induced pulmonary fibrosis, inflammation, and oxidative stress by inhibiting TLR4/NLRP3/TGFß signaling.

OBJECTIVE: The present work concentrated on validating whether sinomenine alleviates bleomycin (BLM)-induced pulmonary fibrosis, inflammation, and oxidative stress. METHODS: A rat model of pulmonary fibrosis was constructed through intratracheal injection with 5 mg/kg BLM, and the effects of 30 mg/kg sinomenine on pulmonary inflammation, fibrosis, apoptosis, and 4-hydroxynonenal density were evaluated by hematoxylin and eosin staining, Masson's trichrome staining, TUNEL staining, and immunohistochemistry. Hydroxyproline content and concentrations of inflammatory cytokines and oxidative stress markers were detected using corresponding kits. MRC-5 cells were treated with 10 ng/ml PDGF, and the effects of 1 mM sinomenine on cell proliferation were assessed by EdU assays. The mRNA expression of inflammatory cytokines and the protein levels of collagens, fibrosis markers, and key markers involved in the TLR4/NLRP3/TGFß signaling were tested with RT-qPCR and immunoblotting analysis. RESULTS: Sinomenine attenuated pulmonary fibrosis and inflammation while reducing hydroxyproline content and the protein expression of collagens and fibrosis markers in BLM-induced pulmonary fibrosis rats. Sinomenine reduced apoptosis in lung samples of BLM-challenged rats by increasing Bcl-2 and reducing Bax and cleaved caspase-3 protein expression. In addition, sinomenine alleviated inflammatory response and oxidative stress in rats with pulmonary fibrosis induced by BLM. Moreover, sinomenine inhibited the TLR4/NLRP3/TGFß signaling pathway in lung tissues of BLM-stimulated rats. Furthermore, TLR4 inhibitor, TAK-242, attenuated PDGF-induced fibroblast proliferation and collagen synthesis in MRC-5 cells. CONCLUSION: Sinomenine attenuates BLM-caused pulmonary fibrosis, inflammation, and oxidative stress by inhibiting the TLR4/NLRP3/TGFß signaling, indicating that sinomenine might become a therapeutic candidate to treat pulmonary fibrosis.

Circular RNA KIAA0564 Serves as a Competitive Endogenous RNA for MicroRNA-424-5p, Mediating the Expression of Lysine Demethylase 4a, Thereby Facilitating Intervertebral Disc Degeneration.

A growing body of research has confirmed the involvement of circular RNAs (circRNAs) in the regulation of intervertebral disc degeneration (IDD) progression. However, the underlying molecular networks remain largely elusive. This study aimed to explore whether a novel circRNA, named circKIAA0564, affects nucleus pulposus (NP) cell injury and to elucidate its molecular mechanism. Both in vivo and in vitro IDD models were established, and the expression patterns of circKIAA0564/miR-424-5p/lysine demethylase 4a (KDM4A) were evaluated through quantitative reverse transcription PCR and Western blot analysis. Actinomycin D, RNase R, and Northern blotting were utilized to assess the circular structure of circKIAA0564. The Cell Counting Kit-8, flow cytometry, enzyme-linked immunosorbent assay, commercial assay kits, Western blotting, and reactive oxygen species (ROS) probes were employed to assess the inflammatory and oxidative stress status in NP cells and tissues. Hematoxylin and eosin and TUNEL staining were used to evaluate pathological damage in mouse NP tissues. RNA immunoprecipitation and dual-luciferase reporter assays were conducted to assess the direct targeting relationships among circKIAA0564, miR-424-5p, and KDM4A. CircKIAA0564 was found to be abnormally overexpressed in IDD, functioning as a novel circRNA. Knockdown of circKIAA0564 ameliorated interleukin-1 beta (IL-1ß)-induced inflammation and oxidative stress in NP cells. The therapeutic effect of circKIAA0564 knockdown on NP cells was reversed by the silencing of miR-424-5p. Overexpression of circKIAA0564 exacerbated IL-1ß-induced NP cell injury, a process that was reversed by knockdown of KDM4A. CircKIAA0564 activated the toll-like receptor 4 (TLR4)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)/NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) signaling pathway by regulating the miR-424-5p/KDM4A axis. CircKIAA0564 exacerbates IL-1ß-induced inflammation and oxidative stress in NP cells by competitively binding miR-424-5p, thereby mediating KDM4A and activating the TLR4/NF-κB/NLRP3 signaling pathway. These findings provide robust data support for targeted therapy of IDD and the development of future pharmaceuticals.

Uvaol alleviates oxidative stress induced human umbilical vein endothelial cell injury by suppressing mitogen-activated protein kinase signaling pathway.

Deep venous thrombosis (DVT) is a potentially life-threatening disorder with high morbidity. Uvaol is a natural pentacyclic triterpene possessing multiple pharmacological activities. Nevertheless, the role of uvaol in DVT is unclarified. Human umbilical vein endothelial cells (HUVECs) were treated with hydrogen peroxide (H 2 O 2 ) to mimic DVT in vitro . CCK-8 assay and flow cytometry were utilized for measuring cell viability and apoptosis, respectively. Levels of the cell injury marker, thrombosis-associated factors, inflammatory cytokines, and oxidative stress-related markers were examined by commercial assay kits. Western blotting was used for evaluating the expression of mitogen-activated protein kinase (MAPK) signaling-associated proteins. Uvaol treatment attenuated H 2 O 2 -induced HUVEC apoptosis and injury. Uvaol reduced the expression of pro-thrombotic factors and inflammatory cytokines and attenuated oxidative stress in H 2 O 2 -stimulated HUVECs. Uvaol inhibited MAPK signaling pathway in H 2 O 2 -stimulated HUVECs. Activating MAPK signaling reversed uvaol-mediated protective effects on H 2 O 2 -treated HUVECs. Uvaol treatment alleviates H 2 O 2 -induced HUVEC injury, apoptosis, and oxidative stress by inactivating MAPK signaling.

Optimization of 3D printing supply chain in the era of live streaming e-commerce.

This study examines the effects of the rising live streaming e-commerce on the 3DP supply chain, employing system dynamics to develop separate models for pure polymer and polymer-metal mixed printing. The analysis focuses on optimizing the 3DP supply chain configuration. Results indicate that, based solely on printing time, cost, and quality metrics, Corporate-live-3DP services are optimal for live commerce scenarios. However, despite this, Private-live-3DP maintains a substantial consumer base in practice, as evidenced by literature data and case studies. Both models pose significant challenges to conventional supply chains, necessitating adaptation. For Corporate-live-3DP, optimization strategies may include technology advancements, digital transformation, agile manufacturing, global network optimization, innovative management, collaborative R&D, fine-tuned inventory control, quality system upgrades, talent development, and organizational restructuring. Conversely, Private-live-3DP can be optimized through consolidation of private 3D printing resources, demand prediction and order optimization, supply chain collaboration platforms, quality management extensions, inventory strategy adjustments, increased transparency, regulatory compliance, and risk mitigation measures.

Berberine inhibits the malignant cell phenotype by inactivating PI3K/AKT/mTOR signaling in laryngeal squamous cell carcinoma.

BACKGROUND: Berberine is an active compound found in different herbs used in Chinese medicine and is well-known for its potential anticancer properties. The study aimed to figure out the role of berberine in regulating the malignant behavior of laryngeal squamous cell carcinoma (LSCC) cells. METHODS: LSCC cell lines (SNU-899 and AMC-HN-8) were treated with different concentrations of berberine (0-200 µM) to determine its cytotoxicity. The migration, invasion, and apoptosis of LSCC cells were measured by wound healing assays, Transwell assays, and flow cytometry. Western blot was performed for the quantification of proteins involved in PI3K/AKT/mTOR signaling. RESULTS: The viability of LSCC cells was dose-dependently reduced by berberine. Berberine dampened LSCC cell migration and invasion while augmenting cell apoptosis, as evidenced by a reduced wound closure rate, a decrease in invaded cell number, and a surge in cell apoptosis in the context of berberine stimulation. Importantly, the effects of berberine on the cancer cell process were enhanced by LY294002 (an inhibitor for PI3K) treatment. Moreover, the protein levels of phosphorylated PI3K, AKT, and mTOR were markedly reduced in response to berberine treatment. CONCLUSION: Berberine inhibits cell viability, migration, and invasion but augments cell apoptosis by inactivating PI3K/AKT/mTOR signaling in LSCC.

Molecular weight control of poly-γ-glutamic acid reveals novel insights into extracellular polymeric substance synthesis in Bacillus licheniformis.

BACKGROUND: The structural diversity of extracellular polymeric substances produced by microorganisms is attracting particular attention. Poly-gamma-glutamic acid (γ-PGA) is a widely studied extracellular polymeric substance from Bacillus species. The function of γ-PGA varies with its molecular weight (Mw). RESULTS: Herein, different endogenous promoters in Bacillus licheniformis were selected to regulate the expression levels of pgdS, resulting in the formation of γ-PGA with Mw values ranging from 1.61 × 103 to 2.03 × 104 kDa. The yields of γ-PGA and exopolysaccharides (EPS) both increased in the pgdS engineered strain with the lowest Mw and viscosity, in which the EPS content was almost tenfold higher than that of the wild-type strain. Subsequently, the compositions of EPS from the pgdS engineered strain also changed. Metabolomics and RT-qPCR further revealed that improving the transportation efficiency of EPS and the regulation of carbon flow of monosaccharide synthesis could affect the EPS yield. CONCLUSIONS: Here, we present a novel insight that increased pgdS expression led to the degradation of γ-PGA Mw and changes in EPS composition, thereby stimulating EPS and γ-PGA production. The results indicated a close relationship between γ-PGA and EPS in B. licheniformis and provided an effective strategy for the controlled synthesis of extracellular polymeric substances.

MicroRNA-375-3p Alleviates Salicylate-Induced Neuronal Injury by Targeting ELAVL4 in Tinnitus.

Purpose Tinnitus is a phantom perception of sound in the absence of acoustic source. Previous evidence has indicated that miR-375-3p is downregulated in rats with tinnitus in comparison to the controls. Nevertheless, its molecular mechanism underlying tinnitus pathogenesis is unclarified. Methods SH-SY5Y cells were differentiated into neuronlike cells and stimulated with salicylate to mimic tinnitus in vitro. Immunofluorescence staining was utilized for measuring expression of NR2B (glutamate ionotropic receptor NMDA type subunit 2B). Intracellular reactive oxygen species (ROS) level was determined using DCFH-DA assay kit. Real-time quantitative polymerase chain reaction as well as western blotting was utilized for examining RNA and protein levels. Luciferase reporter assay was implemented for verifying the interaction between miR-375-3p and ELAVL4 (ELAV-like RNA-binding protein 4). Results Salicylate treatment enhanced levels of NR2B and the early immediate gene ARC as well as ROS production. miR-375-3p was downregulated in salicylate-treated group. Overexpressing miR-375-3p attenuated the effects induced by salicylate in SH-SY5Y cells. miR-375-3p targeted ELAVL4 and upregulating ELAVL4 reversed miR-375-3p upregulation-triggered effects on SH-SY5Y cells under salicylate treatment. Conclusion miR-375-3p mitigates salicylate-triggered neuronal injury in SH-SY5Y cells by regulating ELAVL4 expression.

Supplementation with NAD+ and its precursors: A rescue of female reproductive diseases.

Nicotinamide adenine dinucleotide (NAD+) is an essential coenzyme involved in many pathophysiological processes. Supplementation with NAD+ and its precursors has been demonstrated as an emerging therapeutic strategy for the diseases. NAD+ also plays an important role in the reproductive system. Here, we summarize the function of NAD+ in various reproductive diseases and review the application of NAD+ and its precursors in the preservation of reproductive capacity and the prevention of embryonic malformations. It is shown that NAD+ shows good promise as a therapeutic approach for saving reproductive capacity.

ß-Carotene production from sugarcane molasses by a newly isolated Rhodotorula toruloides L/24-26-1.

Production of carotenoids by yeast fermentation is an advantaged technology due to its easy scaling and safety. Nevertheless, carotenoid production needs an economic culture medium and other efficient yeast stains. The study aims to isolate and identify a yeast strain capable of producing carotenoids using a cost-effective substrate. A new strain was identified as Rhodotorula toruloides L/24-26-1, which can produce carotenoids at different pretreated and unpretreated sugarcane molasses concentrations (40 and 80 g/L). The highest biomass concentration (18.6 ± 0.6 g/L) was reached in the culture using 80 g/L of hydrolyzed molasses. On the other hand, the carotenoid accumulation reached the maximum value using pretreated molasses at 40 g/L (715.4 ± 15.1 µg/g d.w). In this case, the ß-carotene was 1.5 times higher than that on the control medium. The yeast growth in molasses was not correlated with carotenoid production. The most outstanding production of The DPPH, ABTS, and FRAP tests demonstrated the antioxidant activity of the obtained carotenogenic extracts. This research demonstrated the R. toruloides L/24-26-1 strain biotechnological potential for carotenoid compounds. The yeast produces carotenoids with antioxidant activity in an inexpensive medium, such as sulfuric acid pretreated and unpretreated molasses.

Dual targeting total saponins of Pulsatilla of natural polymer crosslinked gel beads with multiple therapeutic effects for ulcerative colitis treatment.

Oral colon targeted drug delivery system (OCTDDS) is desirable for the treatment of ulcerative colitis (UC). In this study, we designed a partially oxidized sodium alginate-chitosan crosslinked microsphere for UC treatment. Dissipative particle dynamics (DPD) was used to study the formation and enzyme response of gel beads from a molecular perspective. The formed gel beads have a narrow particle size distribution, a compact structure, low cytotoxicity and great colon targeting in vitro and in vivo. Animal experiments demonstrated that gel beads promoted colonic epithelial barrier integrity, decreased the level of pro-inflammatory factors, accelerated the recovery of intestinal microbial homeostasis in UC rats and restored the intestinal metabolic disorders. In conclusion, our gel bead is a promising approach for the treatment of UC and significant for the researches on the pathogenesis and treatment mechanism of UC.

AQP4 regulates ferroptosis and oxidative stress of Muller cells in diabetic retinopathy by regulating TRPV4.

Diabetic retinopathy (DR) is a common microvascular complication that causes visual impairment or loss. Aquaporin 4 (AQP4) is a regulatory protein involved in water transport and metabolism. In previous studies, we found that AQP4 is related to hypoxia injury in Muller cells. Transient receptor potential cation channel subfamily V member 4 (TRPV4) is a non-selective cation channel protein involved in the regulation of a variety of ophthalmic diseases. However, the effects of AQP4 and TRPV4 on ferroptosis and oxidative stress in high glucose (HG)-treated Muller cells are unclear. In this study, we investigated the functions of AQP4 and TRPV4 in DR. HG was used to treat mouse Muller cells. Reverse transcription quantitative polymerase chain reaction was used to measure AQP4 mRNA expression. Western blotting was used to detect the protein levels of AQP4, PTGS2, GPX4, and TRPV4. Cell count kit-8, flow cytometry, 5,5',6,6'-tetrachloro-1,1,3,3'-tetraethylbenzimidazolyl carbocyanine iodide staining, and glutathione (GSH), superoxide dismutase (SOD), and malondialdehyde (MDA) kits were used to evaluate the function of the Muller cells. Streptozotocin was used to induce DR in rats. Haematoxylin and eosin staining was performed to stain the retina of rats. GSH, SOD, and MDA detection kits, immunofluorescence, and flow cytometry assays were performed to study the function of AQP4 and TRPV4 in DR rats. Results found that AQP4 and TRPV4 were overexpressed in HG-induced Muller cells and streptozotocin-induced DR rats. AQP4 inhibition promoted proliferation and cell cycle progression, repressed cell apoptosis, ferroptosis, and oxidative stress, and alleviated retinal injury in DR rats. Mechanistically, AQP4 positively regulated TRPV4 expression. Overexpression of TRPV4 enhanced ferroptosis and oxidative stress in HG-treated Muller cells, and inhibition of TRPV4 had a protective effect on DR-induced retinal injury in rats. In conclusion, inhibition of AQP4 inhibits the ferroptosis and oxidative stress in Muller cells by downregulating TRPV4, which may be a potential target for DR therapy.

The pathological mechanisms and potential therapeutic drugs for myocardial ischemia reperfusion injury.

BACKGROUND: Cardiovascular disease is the main cause of death and disability, with myocardial ischemia being the predominant type that poses a significant threat to humans. Reperfusion, an essential therapeutic approach, promptly reinstates blood circulation to the ischemic myocardium and stands as the most efficacious clinical method for myocardial preservation. Nevertheless, the restoration of blood flow associated with this process can potentially induce myocardial ischemia-reperfusion injury (MIRI), thereby diminishing the effectiveness of reperfusion and impacting patient prognosis. Therefore, it is of great significance to prevent and treat MIRI. PURPOSE: MIRI is an important factor affecting the prognosis of patients, and there is no specific in-clinic treatment plan. In this review, we have endeavored to summarize its pathological mechanisms and therapeutic drugs to provide more powerful evidence for clinical application. METHODS: A comprehensive literature review was conducted using PubMed, Web of Science, Embase, Medline and Google Scholar with a core focus on the pathological mechanisms and potential therapeutic drugs of MIRI. RESULTS: Accumulated evidence revealed that oxidative stress, calcium overload, mitochondrial dysfunction, energy metabolism disorder, ferroptosis, inflammatory reaction, endoplasmic reticulum stress, pyroptosis and autophagy regulation have been shown to participate in the process, and that the occurrence and development of MIRI are related to plenty of signaling pathways. Currently, a range of chemical drugs, natural products, and traditional Chinese medicine (TCM) preparations have demonstrated the ability to mitigate MIRI by targeting various mechanisms. CONCLUSIONS: At present, most of the research focuses on animal and cell experiments, and the regulatory mechanisms of each signaling pathway are still unclear. The translation of experimental findings into clinical practice remains incomplete, necessitating further exploration through large-scale, multi-center randomized controlled trials. Given the absence of a specific drug for MIRI, the identification of therapeutic agents to reduce myocardial ischemia is of utmost significance. For the future, it is imperative to enhance our understanding of the pathological mechanism underlying MIRI, continuously investigate and develop novel pharmaceutical agents, expedite the clinical translation of these drugs, and foster innovative approaches that integrate TCM with Western medicine. These efforts will facilitate the emergence of fresh perspectives for the clinical management of MIRI.

Kinetic Resolution of Helicenols via Palladium-Catalyzed Atroposelective C-C Bond Cleavage/Ring-Opening Reaction.

Helicenes represent a class of inherently chiral structures that lack conventional chiral elements, such as stereogenic centers, chiral axes, or plane. The asymmetric synthesis of these helical compounds can be particularly challenging as a result of their pronounced molecular strain. In this study, we report a palladium-catalyzed atroposelective carbon-carbon bond cleavage reaction of helical tertiary alcohols. Because the helical alcohols are configurationally stable, the reaction proceeded through a kinetic resolution pathway, resulting in achieving optically active helicenols alongside the sterically hindered axially chiral products.

High-Flow Nasal Oxygen versus Conventional Nasal Cannula in Preventing Hypoxemia in Elderly Patients Undergoing Gastroscopy with Sedation: A Randomized Controlled Trial.

Background: We aimed to compare the prevention of hypoxemia using High-flow nasal oxygen (HFNO) or regular nasal tubing (CNC) in elderly patients undergoing gastroscopy with sedation. Methods: This study was a prospective, randomized, controlled trial conducted at a single center. We included elective patients aged 65 and above who were undergoing gastroscopy with sedation. In the intervention group (HFNO), we set the oxygen flow rate to 60 liters per minute with an oxygen fraction (FiO2) of 0.6, while in the control group (CNC), it was 6 liters per minute. The primary outcome was the occurrence of hypoxemia (defined as Spo2 < 90%). Results: A total of 125 participants were enrolled (HFNO group: n = 63; CNC group: n = 62). The occurrence of hypoxemia was found to be significantly lower in the HFNO group compared to the CNC group (3.2% vs. 22.6%, p = 0.001). Additionally, a significantly shorter duration of low oxygen levels was observed in the HFNO group [0.0 seconds (0.0-13.0)] compared to the CNC group [0.0 seconds (0.0-124.0), p<0.001]. Moreover, a higher minimum Spo2 value was achieved in the HFNO group [99.0% (98.0-100.0) vs. 96.5% (91.0-99.0), p < 0.001], and a shorter recovery time was recorded [0.5 minutes (0.0-0.5) vs. 0.5 minutes (0.0-1.0), p = 0.016] in comparison to the CNC group. There were no differences in terms of comfort level [0 (0-4) vs. 0 (0-5), p = 0.268] between the two groups. Conclusions: The HFNO system was determined to be a safe and highly effective method for oxygen delivery, leading to a reduction in the occurrence of hypoxemia in elderly patients undergoing gastroscopy with sedation. It is recommended that HFNO be considered as the standard approach for management in this population.

Teneligliptin mitigates diabetic cardiomyopathy by inhibiting activation of the NLRP3 inflammasome.

BACKGROUND: Diabetic cardiomyopathy (DCM), which is a complication of diabetes, poses a great threat to public health. Recent studies have confirmed the role of NLRP3 (NOD-like receptor protein 3) activation in DCM development through the inflammatory response. Teneligliptin is an oral hypoglycemic dipeptidyl peptidase-IV inhibitor used to treat diabetes. Teneligliptin has recently been reported to have anti-inflammatory and protective effects on myocardial cells. AIM: To examine the therapeutic effects of teneligliptin on DCM in diabetic mice. METHODS: Streptozotocin was administered to induce diabetes in mice, followed by treatment with 30 mg/kg teneligliptin. RESULTS: Marked increases in cardiomyocyte area and cardiac hypertrophy indicator heart weight/tibia length reductions in fractional shortening, ejection fraction, and heart rate; increases in creatine kinase-MB (CK-MB), aspartate transaminase (AST), and lactate dehydrogenase (LDH) levels; and upregulated NADPH oxidase 4 were observed in diabetic mice, all of which were significantly reversed by teneligliptin. Moreover, NLRP3 inflammasome activation and increased release of interleukin-1ß in diabetic mice were inhibited by teneligliptin. Primary mouse cardiomyocytes were treated with high glucose (30 mmol/L) with or without teneligliptin (2.5 or 5 µM) for 24 h. NLRP3 inflammasome activation. Increases in CK-MB, AST, and LDH levels in glucose-stimulated cardiomyocytes were markedly inhibited by teneligliptin, and AMP (p-adenosine 5'-monophosphate)-p-AMPK (activated protein kinase) levels were increased. Furthermore, the beneficial effects of teneligliptin on hyperglycaemia-induced cardiomyocytes were abolished by the AMPK signaling inhibitor compound C. CONCLUSION: Overall, teneligliptin mitigated DCM by mitigating activation of the NLRP3 inflammasome.

Maternal red blood cell alloimmunization prevalence in the United States.

Hemolytic disease of fetus and newborn (HDFN) is a life-threatening disease mediated by maternal alloimmunization to red blood cell (RBC) antigens. Studies of maternal alloimmunization prevalence in the United States (U.S.) lack national data. This study describes prevalence and trends in alloimmunization in pregnancy in the U.S. RBC antibodies (abs) were identified in a large, nationwide, commercial laboratory database from 2010-2021. The cohort comprised pregnancies for which the year of lab collection and patient's state of residence were available. Data were normalized based on U.S. Centers for Disease Control and Prevention estimates of live births and weighted by year and U.S. Census Division. Cochrane-Armitage tests assessed temporal trends of alloimmunization. Of 9,876,196 pregnancies, 1.5% (147,262) screened positive for RBC abs, corresponding to an estimated prevalence of 1,518/100,000 pregnancies. Of identified RBC abs, anti-D comprised 64.1% (586/100,000 pregnancies). Prevalence of other high-risk RBC abs for HDFN included anti-K (68/100,000) and anti-c (29/100,000). Incidence of all three high-risk abs increased from 2010-21 (all p<0.001). Among almost 10 million pregnancies in the US, comprising an estimated 14.4% of all pregnancies, 1.5% screened positive for RBC abs. Almost three-quarters (74.3%; 683/100,000) of RBC abs identified were high-risk for HDFN. Though prevalence of anti-D is difficult to interpret without the ability to distinguish alloimmunization from passive immunity, it remains problematic in HDFN, ranking second only to anti-K in critical titers. Given the sequelae of HDFN, new initiatives are required to reduce the incidence of alloimmunization in patients of reproductive potential.

The Role of Hydrogen Bonds in Thermally Responsive Crystallization-Driven Template Autocatalysis.

Autocatalysis has been well recognized to implicate in the emergence of life and is intrinsic to the biomolecular replication. Recently, an efficient template autocatalysis driven by solvent-free crystallization has been reported. Herein, we unveil the role of intermolecular hydrogen (H) bonds formed by amides in crystallization-driven template autocatalysis (CDTA), which involves the autocatalytic activity, template selectivity, and thermal responsiveness. We found that the thermal-induced cis-trans isomerization of amides possibly affects the H-bonding-mediated template ability of products for autocatalytic transformation. As a result, CDTA can be reversibly inhibited and activated by tuning the reaction temperatures. Our work sheds light on the significance of noncovalent H-bonding interactions in artificial self-replicators.

The tibial capsular reflection and septum in posterior compartment are safe and reliable soft-tissue landmark for tibial tunnel drilling in posterior cruciate ligament reconstruction.

PURPOSE: To investigate the validity of using tibial capsular reflection and septum in the posterior compartment as landmark during posterior cruciate ligament (PCL) reconstruction (PCLR). METHODS: Anatomic measurements were obtained for 12 fresh human cadaveric knee specimens to observe the spatial position of the tibial insertion of the PCL in relation to the posterior septum and the capsular reflection in the posterior compartment. Sixty patients who underwent reconstruction of the PCL between 2020 and 2023 were also retrospectively investigated. The tibial tunnel was replaced in all patients using the same method (with reference to the tibial capsular reflection and the posterior septum). The placement of the tibial tunnel was assessed using X-ray fluoroscopy intraoperatively and computed tomography and three-dimensional reconstruction postoperatively. RESULTS: All fibres in the tibial insertion of the PCL in the 12 cadaveric specimens were located in the posteromedial compartment, adjacent to the posterior septum. The inferior border of the PCL insertion is adjacent to the tibial capsular reflection, which is attached at the champagne glass drop-off of the posterior tibia. In our previous cases, none of the patients experienced postoperative or intraoperative complications such as neurovascular injury, and the angle between the pin and the PCL facet was 93.1 ± 3.9° as measured on intraoperative radiographs. The mean distance from the centre of the tibial tunnel outlet to the inferior border of the PCL insertion was 5.6 ± 1.1 mm, and the distance from the centre of the tibial tunnel outlet to the outer border of the PCL insertion as a percentage of the length of the inferior border of PCL insertion was 42.2 ± 6.3%. CONCLUSION: The tibial capsular reflection and septum in the posterior compartment are safe and reliable soft-tissue landmark for tibial tunnel drilling in PCLR. LEVEL OF EVIDENCE: Level Ⅳ.