The ideal treatment timing for diabetic retinopathy: the molecular pathological mechanisms underlying early-stage diabetic retinopathy are a matter of concern.

Diabetic retinopathy (DR) is a prevalent complication of diabetes, significantly impacting patients' quality of life due to vision loss. No pharmacological therapies are currently approved for DR, excepted the drugs to treat diabetic macular edema such as the anti-VEGF agents or steroids administered by intraocular route. Advancements in research have highlighted the crucial role of early intervention in DR for halting or delaying disease progression. This holds immense significance in enhancing patients' quality of life and alleviating the societal burden associated with medical care costs. The non-proliferative stage represents the early phase of DR. In comparison to the proliferative stage, pathological changes primarily manifest as microangiomas and hemorrhages, while at the cellular level, there is a loss of pericytes, neuronal cell death, and disruption of components and functionality within the retinal neuronal vascular unit encompassing pericytes and neurons. Both neurodegenerative and microvascular abnormalities manifest in the early stages of DR. Therefore, our focus lies on the non-proliferative stage of DR and we have initially summarized the mechanisms involved in its development, including pathways such as polyols, that revolve around the pathological changes occurring during this early stage. We also integrate cutting-edge mechanisms, including leukocyte adhesion, neutrophil extracellular traps, multiple RNA regulation, microorganisms, cell death (ferroptosis and pyroptosis), and other related mechanisms. The current status of drug therapy for early-stage DR is also discussed to provide insights for the development of pharmaceutical interventions targeting the early treatment of DR.

Effects of Three Essential Oil Fumigation Treatments on the Postharvest Control of Botrytis cinerea and Their Efficacy as Preservatives of Cherry Tomatoes.

Cherry tomatoes (Solanum lycopersicum) are becoming increasingly popular due to their nutrition and delicious flavor. However, cherry tomatoes are highly perishable and susceptible to various pathogenic microorganisms after harvest, such as Botrytis cinerea. In the pretest experiment, we screened out three kinds of plant essential oils (EOs) (Torreya grandis oil, Eriobotrya japonica oil, and Citrus medica oil) that have strong fungicidal activity on B. cinerea from cherry tomatoes. To further evaluate the postharvest preservation application prospect of these three oils for cherry tomatoes, the oils were extracted from different parts of three plants by hydrodistillation, and their chemical constituents were analyzed by gas chromatography-mass spectrometry. The main representative components of T. grandis oil, E. japonica oil, and C. medica oil were δ-cadinene (11.76%), transnerolidol (9.70%), and 5,7-dimethoxycoumarin (23.22%), respectively. These three EOs effectively inhibited the mycelial growth of B. cinerea in vitro, with EC50 values of 81.672, 144.046, and 221.500 µl/liter, respectively. Compared with the blank control and other oil treatments, the T. grandis oil (at a concentration of 200 µl/liter) fumigation treatment was more effective at inhibiting the growth rate of the pathogen. In addition, the phenolic content and phenylalanine ammonia lyase, ß-1,3-glucanase, chitinase, and peroxidase activities of tomatoes significantly increased on the seventh day due to the T. grandis oil treatment. The present study shows that these three oils with high extraction rates have preservation potential for cherry tomatoes. Among these three EOs, T. grandis oil can be used to further develop preservative products as a fumigant.

Severe hypothyroidism after orthognathic surgery: a case report.

Hypothyroidism is a common endocrine disease with reduced systemic metabolism, but the initial diagnosis is rare in oral and maxillofacial surgery. Due to the nonspecific symptoms, it is easy to be misdiagnosed and missed diagnosis which results in serious consequences. This paper presents a case of severe hypothyroidism which was characterized by airway obstruction, facial swelling, unexplained anaemia and bipedal edema after orthognathic surgery. With review of relevant literatures, this article discusses the risk factors, symptoms, diagnosis and therapy of hypothyroidism.

New Enantiomers of a Nor-Bisabolane Derivative and Two New Phthalides Produced by the Marine-Derived Fungus Penicillium chrysogenum LD-201810.

Marine-derived fungi are a treasure house for the discovery of structurally novel secondary metabolites with potential pharmaceutical value. In this study, a pair of new nor-bisabolane derivative enantiomers (±)-1 and two new phthalides (4 and 5), as well as four known metabolites, were isolated from the culture filtrate of the marine algal-derived endophytic fungus Penicillium chrysogenum LD-201810. Their structures were established by detailed interpretation of spectroscopic data (1D/2D NMR and ESI-MS). The optical resolution of compound (±)-1 by chiral HPLC successfully afforded individual enantiomers (+)-1 and (-)-1, and their absolute configurations were determined by TDDFT-ECD calculations. Compound (±)-1 represents the first example of bisabolane analogs with a methylsulfinyl substituent group, which is rare in natural products. All of the isolated compounds 1-7 were evaluated for their cytotoxic activity against A549, BT-549, HeLa, HepG2, MCF-7, and THP-1 cell lines, as well as for antifungal activity against four plant pathogenetic fungi (Alternaria solani, Botrytis cinerea, Fusarium oxysporum, and Valsa mali). Compound 2, a bisabolane-type sesquiterpenoid, was shown to possess excellent activity for control of B. cinerea with half-maximal inhibitory concentration (IC50) of 13.6 µg/mL, whereas the remaining investigated compounds showed either weak or no cytotoxic/antifungal activity in this study.

Bioactive Compounds from Plant-Based Functional Foods: A Promising Choice for the Prevention and Management of Hyperuricemia.

Hyperuricemia is a common metabolic disease that is caused by high serum uric acid levels. It is considered to be closely associated with the development of many chronic diseases, such as obesity, hypertension, hyperlipemia, diabetes, and cardiovascular disorders. While pharmaceutical drugs have been shown to exhibit serious side effects, and bioactive compounds from plant-based functional foods have been demonstrated to be active in the treatment of hyperuricemia with only minimal side effects. Indeed, previous reports have revealed the significant impact of bioactive compounds from plant-based functional foods on hyperuricemia. This review focuses on plant-based functional foods that exhibit a hypouricemic function and discusses the different bioactive compounds and their pharmacological effects. More specifically, the bioactive compounds of plant-based functional foods are divided into six categories, namely flavonoids, phenolic acids, alkaloids, saponins, polysaccharides, and others. In addition, the mechanism by which these bioactive compounds exhibit a hypouricemic effect is summarized into three classes, namely the inhibition of uric acid production, improved renal uric acid elimination, and improved intestinal uric acid secretion. Overall, this current and comprehensive review examines the use of bioactive compounds from plant-based functional foods as natural remedies for the management of hyperuricemia.

Cytotoxic Secondary Metabolites Isolated from the Marine Alga-Associated Fungus Penicillium chrysogenum LD-201810.

A new pentaketide derivative, penilactonol A (1), and two new hydroxyphenylacetic acid derivatives, (2'R)-stachyline B (2) and (2'R)-westerdijkin A (3), together with five known metabolites, bisabolane-type sesquiterpenoids 4-6 and meroterpenoids 7 and 8, were isolated from the solid culture of a marine alga-associated fungus Penicillium chrysogenum LD-201810. Their structures were elucidated based on extensive spectroscopic analyses, including 1D/2D NMR and high resolution electrospray ionization mass spectra (HRESIMS). The absolute configurations of the stereogenic carbons in 1 were determined by the (Mo2(OAc)4)-induced circular dichroism (CD) and comparison of the calculated and experimental electronic circular dichroism (ECD) spectra, while the absolute configuration of the stereogenic carbon in 2 was established using single-crystal X-ray diffraction analysis. Compounds 2 and 3 adapt the 2'R-configuration as compared to known hydroxyphenylacetic acid-derived and O-prenylated natural products. The cytotoxicity of 1-8 against human carcinoma cell lines (A549, BT-549, HeLa, HepG2, MCF-7, and THP-1) was evaluated. Compound 3 exhibited cytotoxicity to the HepG2 cell line with an IC50 value of 22.0 µM. Furthermore, 5 showed considerable activities against A549 and THP-1 cell lines with IC50 values of 21.2 and 18.2 µM, respectively.

Placensin is a glucogenic hormone secreted by human placenta.

FBN1 encodes asprosin, a glucogenic hormone, following furin cleavage of the C-terminus of profibrillin 1. Based on evolutionary conservation between FBN1 and FBN2, together with conserved furin cleavage sites, we identified a peptide hormone placensin encoded by FBN2 based on its high expression in trophoblasts of human placenta. In primary and immortalized murine hepatocytes, placensin stimulates cAMP production, protein kinase A (PKA) activity, and glucose secretion, accompanied by increased expression of gluconeogenesis enzymes. In situ perfusion of liver and in vivo injection with placensin also stimulate glucose secretion. Placensin is secreted by immortalized human trophoblastic HTR-8/SVneo cells, whereas placensin treatment stimulates cAMP-PKA signaling in these cells, accompanied by increases in MMP9 transcripts and activities, thereby promoting cell invasion. In pregnant women, levels of serum placensin increase in a stage-dependent manner. During third trimester, serum placensin levels of patients with gestational diabetes mellitus are increased to a bigger extent compared to healthy pregnant women. Thus, placensin represents a placenta-derived hormone, capable of stimulating glucose secretion and trophoblast invasion.

Antineoplastic Constituents from the Chemical Diversified Extract of Radix puerariae.

To enhance the structural diversity of isoflavonoids and provide more derivatives for the biological screening, a semisynthetic mixture was generated by diversification of the crude extract of Radix puerariae (Pueraria montana var. lobata) through the chemical reaction with hydrazine hydrate. Eleven 3,4-diarylpyrazoles (1-11) and two 5-phenyl-6-benzyldihydropyridazinones (12 and 13) were isolated from the semisynthetic mixture, and their structures were identified by spectroscopic methods in combination with X-ray crystallographic analysis. Among them, nine compounds (5-13) were new derivatives. All the compounds were evaluated on the inhibitory activities against the prostate cancer cell lines LNCaP and PC3. Compounds 12 and 13 were found to exhibit much more potent inhibitory activities against the androgen dependent LNCaP cells than the androgen independent PC3 cells. Rapid synthesis of new 3,4-diarylpyrazoles and two 5-phenyl-6-benzyldihydropyridazinones with significant biological activity highlights the great potential of one-pot combinatorial modification for the diversification of natural products.

UHPLC/Q-TOFMS-based plasma metabolomics of polycystic ovary syndrome patients with and without insulin resistance.

Polycystic ovary syndrome (PCOS), characterized with menstrual irregularities, hyperandrogenism and ovulatory abnormalities, is usually companied with insulin resistance (IR) and accounts for one of the most prevalent reproductive dysfunction of premenopausal women. Despite accumulating investigations, diagnostic standards of this pathological condition remain obscure. The aim of present study is to characterize the plasma metabolic characteristics of PCOS patients with and without IR, and subsequently identify the potential biomarkers for the diagnosis of PCOS and its IR complication. A total of 59 plasma samples from eligible healthy controls (CON, n=19), PCOS patients without IR (non-IR PCOS, n=19) and PCOS patients with IR (IR PCOS, n=21) were profiled by an ultra high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC/Q-TOFMS) followed by multivariate statistical analysis. Compared to the healthy controls, significant decrease in the levels of phosphocholines (PCs) and lyso PC (18:2), and increase in trilauric glyceride level were observed in the plasma of IR PCOS. Meanwhile, the significant increase in the levels of saturated fatty acids (palmitic acid and stearic acid) and decanoylcarnitine, and decrease in PC (36:2) and PS (36:0) were found in non-IR PCOS patients. Trilauric glyceride and decanoylcarnitine were identified as the potential biomarkers with the highest sensitivity and specificity for the diagnosis of PCOS patients with and without IR, respectively. Furthermore, based on these alterations of metabolites, MetPA network pathway analysis suggested a profound involvement of the abnormalities of glycerophospholipid, glycerolipid and fatty acid metabolisms in the pathogenesis of PCOS and IR complications. Collectively, LC-MS-based metabolomics provides a promising strategy for complementary diagnosis of PCOS and its IR complication and offers a new insight to understand their pathogenesis mechanisms.

EFFECT OF INTRAPERITONEAL RESUSCITATION WITH DIFFERENT CONCENTRATIONS OF SODIUM PYRUVATE ON INTESTINAL ISCHEMIA REPERFUSION INJURY IN HEMORRHAGIC SHOCK RAT.

OBJECTIVE: To determine the effects of intraperitoneal resuscitation (PR) with different concentrations of sodium pyruvate (PY) on intestinal ischemia reperfusion injury in rats hemorrhagic shock (HS). METHODS: Sixty rats were randomly assigned to six groups. These included: group SHAM, intravenous resuscitation only (VR) group, and four PR groups based on resuscitation fluid: glucose-lactate-based peritoneal dialysis solution (LA), and PY-1.1%, PY-1.6%, and PY-2.2% (concentrations in grams/dL). Mean arterial pressure (MAP) was monitored continuously. Blood pH, base excess (BE), lactate, intestinal myeloperoxidase (MPO), malondialdehyde (MDA), tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), activated caspase-3, and zonula occludens-1 (ZO-1) were measured; intestinal mucosal damage index (IMDI) and subcellular changes were observed; apoptotic index (AI) was calculated. RESULTS: Three hours after resuscitation, in PY groups, MPO, MDA, IMDI, AI, TNF-alpha, and IL-6 were significantly lower than VR and LA groups, while pH and BE were higher. PY groups showed less expression of activated caspase-3 but elevated ZO-1. Among PY groups, group PY-1.1% had the lowest MPO, MDA and TNF-alpha, and had less pathological damage and subcellular changes than other experimental groups. CONCLUSIONS: PR using PY solution combined with VR provided protection against intestinal ischemia-reperfusion injury following HS and resuscitation. Under the same hypertonic condition, 1.1% PY solution showed significant advantages compared with 2.2% and 1.6% solutions. The underlying mechanisms may include the maintenance of hemodynamic stability, regulation of homeostasis, inhibition of oxidative stress and inflammation, and protection of intestinal epithelial tight junction barrier function.

An Intracellular Laccase Is Responsible for Epicatechin-Mediated Anthocyanin Degradation in Litchi Fruit Pericarp.

In contrast to the detailed molecular knowledge available on anthocyanin synthesis, little is known about its catabolism in plants. Litchi (Litchi chinensis) fruit lose their attractive red color soon after harvest. The mechanism leading to quick degradation of anthocyanins in the pericarp is not well understood. An anthocyanin degradation enzyme (ADE) was purified to homogeneity by sequential column chromatography, using partially purified anthocyanins from litchi pericarp as a substrate. The purified ADE, of 116 kD by urea SDS-PAGE, was identified as a laccase (ADE/LAC). The full-length complementary DNA encoding ADE/LAC was obtained, and a polyclonal antibody raised against a deduced peptide of the gene recognized the ADE protein. The anthocyanin degradation function of the gene was confirmed by its transient expression in tobacco (Nicotiana benthamiana) leaves. The highest ADE/LAC transcript abundance was in the pericarp in comparison with other tissues, and was about 1,000-fold higher than the polyphenol oxidase gene in the pericarp. Epicatechin was found to be the favorable substrate for the ADE/LAC. The dependence of anthocyanin degradation by the enzyme on the presence of epicatechin suggests an ADE/LAC epicatechin-coupled oxidation model. This model was supported by a dramatic decrease in epicatechin content in the pericarp parallel to anthocyanin degradation. Immunogold labeling transmission electron microscopy suggested that ADE/LAC is located mainly in the vacuole, with essential phenolic substances. ADE/LAC vacuolar localization, high expression levels in the pericarp, and high epicatechin-dependent anthocyanin degradation support its central role in pigment breakdown during pericarp browning.

Serum inter-cellular adhesion molecule 1 is an early marker of diagnosis and prediction of severe acute pancreatitis.

AIM: To determine if serum inter-cellular adhesion molecule 1 (ICAM-1) is an early marker of the diagnosis and prediction of severe acute pancreatitis (SAP) within 24 h of onset of pain, and to compare the sensitivity, specificity and prognostic value of this test with those of acute physiology and chronic health evaluation (APACHE) II score and interleukin-6 (IL-6). METHODS: Patients with acute pancreatitis (AP) were divided into two groups according to the Ranson's criteria: mild acute pancreatitis (MAP) group and SAP group. Serum ICAM-1, APACHE II and IL-6 levels were detected in all the patients. The sensitivity, specificity and prognostic value of the ICAM-1, APACHE II score and IL-6 were evaluated. RESULTS: The ICAM-1 level in 36 patients with SAP within 24 h of onset of pain was increased and was significantly higher than that in the 50 patients with MAP and the 15 healthy volunteers (P < 0.01). The ICAM-1 level (25 ng/mL) was chosen as the optimum cutoff to distinguish SAP from MAP, and the sensitivity, specificity, positive predictive value, negative predictive value (NPV), positive likelihood ratio and negative likelihood ratio were 61.11%, 71.42%, 0.6111, 0.7142, 2.1382 and 0.5445, respectively. The area under the curve demonstrated that the prognostic accuracy of ICAM-1 (0.712) was similar to the APACHE-II scoring system (0.770) and superior to IL-6 (0.508) in distinguishing SAP from MAP. CONCLUSION: ICAM-1 test is a simple, rapid and reliable method in clinical practice. It is an early marker of diagnosis and prediction of SAP within the first 24 h after onset of pain or on admission. As it has a relatively low NPV and does not allow it to be a stand-alone test for the diagnosis of AP, other conventional diagnostic tests are required.