OBJECTIVES

In Asia, younger individuals (below age 45) are diagnosed to have type 2 diabetes with increased rates of obesity defined by lower BMI yet with greater visceral adiposity (waist circumference and waisthip ratios). The prevalence data on type 1 diabetes is not well established, considered to be low, but is seen to be increasing as well. This changing phenotype therefore, presents a clinical dilemma in terms of correctly classifying diabetes and deciding on the consequent appropriate treatment. Distinguishing type 1 from type 2 diabetes has become more difficult with type 2 diabetes dramatically increasing in young adults and children. This study aims to define the characteristics of diabetes among young adults in the Philippines to provide a basis for appropriate management amidst changes in diabetes phenotypes seen globally.

METHODS

In this cross-sectional analytic study, we characterized the demographic, metabolic, and autoimmune features of diabetes among young adult Filipinos aged 18 to 45 years old consulting at a tertiary referral center in Manila, Philippines. Baseline serum A1c, FBS, 75-g oral glucose tolerance test, insulin, serum C-peptide, insulin autoantibodies, leptin, adiponectin, lipid profile, and thyroid function tests were obtained from the participants and analyzed. The homeostasis model assessment (HOMA) was used to estimate the insulin sensitivity.

RESULTS

A total of 348 patients with diabetes were included, with females comprising two-thirds of the participants. The mean age at diagnosis of diabetes was 35.9±7.22 years. The mean BMI was 28.12 kg/m2, with median waist to hip ratio (WHR) of 0·93. Metabolic syndrome was found in 60% of participants and 67.82% were obese by body mass index. The mean A1c was 9.07±2.52%. Good glucose control (A1c less than 7.0%) was seen in 23% of participants  while nearly half (48%) had HbA1c which was >9.0%. The median levels of fasting insulin and C-peptide were 12.62 (range 1.33–90.42) mIU/L and 0.78 ng/mL (range 0–16.2), respectively. 

Included participants were diagnosed with diabetes within a year and as such, majority did not have any micro- or macrovascular complications. The most common diabetes complication was sensory neuropathy detected by monofilament testing, which was found in 28% of participants, followed by non-proliferative diabetic retinopathy in 13%. A history of previous diabetic ketoacidosis was found in 10 patients (2.87%). Glutamic acid decarboxylase (GAD) and insulin auto-antibodies were found in 3.2% and 19.3% of participants, respectively. Approximately half (51.73%) of the participants were insulin resistant by HOMA-IR.

CONCLUSION

In contrast with Caucasians and other Asians, diabetes among young Filipino adults is associated with lower BMI but with a similarly high visceral adiposity as shown by an elevated WHR. Metabolic syndrome with insulin resistance as defined by a variety of indices is predominant. Type 1 diabetes with autoantibodies occur in only a small fraction of this population. Data derived from this work can provide a framework for cluster analysis towards personalized management specific to this population.

Human ; Acids ; Adiponectin ; Adiposity ; Adult ; Aged ; Antibodies ; Asia ; Asian ; Asian Continental Ancestry Group ; Autoantibodies ; Body Mass Index ; C-peptide ; Carboxy-lyases ; Child ; Cluster Analysis ; Demography ; Diabetes Complications ; Diabetes Mellitus ; Diabetes Mellitus, Type 1 ; Diabetes Mellitus, Type 2 ; Diabetic Ketoacidosis ; Diabetic Retinopathy ; Diagnosis ; Fasting ; Female ; Glucose ; Glucose Tolerance Test ; Glutamate Decarboxylase ; Glutamic Acid ; Insulin ; Insulin Resistance ; Ketosis ; Leptin ; Lipids ; Metabolic Syndrome ; Obesity ; Patients ; Peptides ; Phenotype ; Philippines ; Population ; Prevalence ; Serum ; Therapeutics ; Thyroid Gland ; Thyroid Function Tests ; Young Adult

Introduction: A common diagnostic error is the tendency to attribute new symptoms directly to the most obvious laboratory abnormality. In pregnancy, a suppressed thyroidstimulating hormone (TSH) with elevated free T4 is frequently presumed to indicate primary hyperthyroidism, overlooking the possibility of benign gestational transient thyrotoxicosis (GTT). We report a case where this pattern led to the misattribution of acute flaccid paralysis to thyrotoxic periodic paralysis, critically delaying the diagnosis of Guillain-Barré syndrome (GBS). Case: A 21-year-old female Malay primigravida at 19 weeks and 5 days presented with a 2-week history of progressive, descending bilateral lower limb weakness culminating in paralysis, associated with vomiting and 5 kg weight loss. On admission, she was febrile (38.0°C) and tachycardic (150 bpm). Neurological examination revealed proximalpredominant flaccid paralysis and hyporeflexia with intact sensation, without thyroid eye signs or goiter. Thyroid function tests showed profound thyrotoxicosis (TSH <0.005 mIU/L, free thyroxine 4 20.16 pmol/L) with hypokalemia (2.9 mmol/L). A neck ultrasound was normal. A provisional diagnosis of thyrotoxic periodic paralysis with impending storm was made, leading to treatment with potassium replacement, propylthiouracil, and hydrocortisone. Despite biochemical improvement, her paralysis persisted. On day 5, she developed acute bulbar palsy and respiratory failure requiring intubation. A subsequent comprehensive workup for infectious, autoimmune (including thyroid antibodies), and nutritional causes was unremarkable. Nerve conduction studies confirmed the acute motor axonal neuropathy (AMAN) variant of GBS. Treatment with a 5-day course of intravenous immunoglobulin resulted in neurological improvement and successful extubation. Conclusion This case highlights the critical pitfall of prematurely attributing acute neurological deficits to abnormal thyroid function tests in pregnancy. Biochemical thyrotoxicosis, including GTT, should not preclude urgent evaluation for life-threatening neurological conditions such as GBS, particularly when weakness is progressive or refractory to metabolic correction.
Female ; Pregnancy ; Thyroid Function Tests

OBJECTIVES: To compare perioperative and mid-term results of multiple versus single arterial off-pump coronary artery bypass grafting (OPCABG) in patients with impaired left ventricular function. METHODS: This study was conducted among 86 patients with a left ventricular ejection fraction (LVEF) <50%, who underwent OPCABG at our hospital between January, 2018 and December, 2021. Of these patients, 22 underwent OPCABG with multiple arterial grafts (multiple graft group) and 64 received a single arterial graft in OPCABG (single graft group). The preoperative, intraoperative, and perioperative data were collected, and the patients were followed up for a mean of 29.28±14.84 months. The perioperative outcomes and follow-up results of the patients were compared, and the factors influencing major adverse cardiovascular events (MACE) were identified using logistic regression. Kaplan-Meier analysis was used to compare the postoperative survival rate without MACE. RESULTS: The patients in multiple graft group had a significantly younger age than those in single graft group (P<0.05), but the other baseline data were similar between the two groups (P>0.05). Perioperative mortality, 24-h postoperative drainage volume, length of ICU stay, intubation time, and the incidence of new-onset atrial fibrillation were all similar between the two groups (P>0.05), but the rate of postoperative hypotension was significantly higher in multiple graft group (34.78% vs 11.54%, P=0.009). No significant differences were found in the incidence of MACE or echocardiographic data during the follow-up. Logistic regression identified the female sex (OR: 0.191, 95% CI: 0.049-0.075) and creatinine level (OR: 1.016, 95% CI: 1.000-1.033) as factors affecting postoperative MACE occurrence. Kaplan-Meier analysis showed no significant difference in MACE-free survival rate between the two groups. CONCLUSIONS OPCABG with multiple arterial grafts does not increase severe perioperative complications or the risk of mid-term MACE in patients with impaired left ventricular function.
Humans ; Follow-Up Studies ; Postoperative Complications/epidemiology* ; Ventricular Dysfunction, Left/physiopathology* ; Coronary Artery Bypass, Off-Pump/adverse effects* ; Male ; Female ; Ventricular Function, Left ; Middle Aged ; Risk Factors ; Aged ; Perioperative Period ; Stroke Volume

OBJECTIVES: To investigate the effect of monotropein on motor function recovery of mice with spinal cord injury (SCI) and explore the underlying mechanism. METHODS: Forty-five adult female C57BL/6 mice were randomized equally into sham operation group, SCI group, and SCI group with daily intraperitoneal monotropein injection. The mice in the former two groups received daily saline injections. Motor function of the mice was evaluated using BMS scores, slant plate test, and footprint analyses. Pathological changes and neuronal counts in the spinal cord were observed using HE, LFB, and Nissl staining. The biological functions of monotropein were explored using GO and KEGG enrichment analyses. NeuN/cleaved caspase-3 immunofluorescence assay and Western blotting were used to detect neuronal apoptosis in the spinal cord of the mice. In cultured HT22 cells, the effect of monotropein on TNF-α-induced cell apoptosis was evaluated using TUNEL staining and Western blotting. In monotropein-treated HT22 cells and SCI mice, the changes in the PI3K/AKT pathway were examined, and the effect of a PI3K/AKT pathway activator (IGF-1) on HT22 cell apoptosis and motor function recovery of SCI mice were observed. RESULTS: SCI mice with monotropein treatment showed significantly improved motor functions with reduced SCI areas and increased myelin retention and neuron counts in the spinal cord. Bioinformatics analysis suggested a role of PI3K/AKT signaling pathway in mediating the anti-apoptotic effects of monotropein. In SCI mice, monotropein obviously reduced apoptotic neurons, decreased expressions of cleaved caspase-3 and Bax and increased Bcl-2 expression in the spinal cord. In HT22 cells, monotropein significantly inhibited TNF-α-induced apoptosis and PI3K/AKT pathway activation. Treatment with IGF-1 obviously increased apoptosis of HT22 cells and exacerbated locomotor dysfunction in SCI mice. CONCLUSIONS Monotropein promotes motor function recovery in SCI mice by reducing neuronal apoptosis possibly by inhibiting the PI3K/AKT signaling pathway.
Animals ; Spinal Cord Injuries/metabolism* ; Apoptosis/drug effects* ; Signal Transduction/drug effects* ; Mice, Inbred C57BL ; Mice ; Proto-Oncogene Proteins c-akt/metabolism* ; Female ; Phosphatidylinositol 3-Kinases/metabolism* ; Neurons/pathology* ; Recovery of Function

OBJECTIVES: To investigate the effect of orexin-A-mediated regulation of ionotropic glutamate receptors for promoting motor function recovery in rats with spinal cord injury (SCI). METHODS: Thirty-six newborn SD rats (aged 7-14 days) were randomized into 6 groups (n=6), including a normal control group, a sham-operated group, and 4 SCI groups with daily intrathecal injection of saline, DNQX, orexin-A, or orexin-A+DNQX for 3 consecutive days after PCI. Motor function of the rats were evaluated using blood-brain barrier (BBB) score and inclined plane test 1 day before and at 1, 3, and 7 days after SCI. For patch-clamp experiment, spinal cord slices from newborn rats in the control, sham-operated, SCI, and SCI+orexin groups were prepared, and ventral horn neurons were acutely isolated to determine the reversal potential and dynamic indicators of glutamate receptor-mediated currents under glutamate perfusion. RESULTS: At 3 and 7 days after SCI, the orexin-A-treated rats showed significantly higher BBB scores and grip tilt angles than those with other interventions. Compared with those treated with DNQX alone, the rats receiving the combined treatment with orexin and DNQX had significantly higher BBB scores and grip tilt angles on day 7 after PCI. In the patch-clamp experiment, the ventral horn neurons from SCI rat models exhibited obviously higher reversal potential and greater rise slope of glutamate current with shorter decay time than those from sham-operated and orexin-treated rats. CONCLUSIONS Orexin-A promotes motor function recovery in rats after SCI possibly by improving the function of the ionotropic glutamate receptors.
Animals ; Spinal Cord Injuries/drug therapy* ; Rats ; Rats, Sprague-Dawley ; Receptors, Ionotropic Glutamate/metabolism* ; Recovery of Function/drug effects* ; Orexins/pharmacology* ; Male ; Female ; Animals, Newborn ; Neuropeptides/pharmacology* ; Intracellular Signaling Peptides and Proteins/pharmacology*

OBJECTIVES: To investigate the effect of hypaphorine (HYP) on Crohn's disease (CD)‑like colitis in mice and its molecular mechanism. METHODS: Thirty male C57BL/6J mice were equally randomized into WT, TNBS, and HYP groups, and in the latter two groups, mouse models of CD-like colitis were established using TNBS with daily gavage of 15 mg/kg HYP or an equivalent volume of saline. The treatment efficacy was evaluated by assessing the disease activity index (DAI), body weight changes, colon length and histopathology. The effect of HYP was also tested in a LPS-stimulated Caco-2 cell model mimicking intestinal inflammation by evaluating inflammatory responses and barrier function of the cells using qRT-PCR and immunofluorescence staining. GO and KEGG analyses were conducted to explore the therapeutic mechanism of HYP, which was validated in both the cell and mouse models using Western blotting. RESULTS: In the mouse models of CD-like colitis, HYP intervention obviously alleviated colitis as shown by significantly reduced body weight loss, colon shortening, DAI and inflammation scores, and expressions of pro-inflammatory factors in the colon tissues. HYP treatment also significantly increased the TEER values, reduced bacterial translocation to the mesenteric lymph nodes, liver, and spleen, lowered serum levels of I-FABP and FITC-dextran, increased the number of colonic tissue cup cells, and upregulated colonic expressions of MUC2 and tight junction proteins (claudin-1 and ZO-1) in the mouse models. In LPS-stimulated Caco-2 cells, HYP treatment significantly inhibited the expressions of pro-inflammatory factors and increased the expressions of tight junction proteins. Western blotting showed that HYP downregulated the expressions of the key proteins in the TLR4/MyD88 signaling pathway in both the in vitro and in vivo models. CONCLUSIONS HYP alleviates CD-like colitis in mice possibly by suppressing intestinal epithelial inflammation and improving gut barrier function.
Animals ; Male ; Mice, Inbred C57BL ; Crohn Disease/drug therapy* ; Mice ; Humans ; Caco-2 Cells ; Intestinal Mucosa/metabolism* ; Colitis/drug therapy* ; Disease Models, Animal ; Inflammation ; Toll-Like Receptor 4/metabolism* ; Myeloid Differentiation Factor 88/metabolism* ; Intestinal Barrier Function

Hypoxic-ischemic (HI) brain damage poses a high risk of death or lifelong disability, yet effective treatments remain elusive. Here, we demonstrated that miR-100-5p levels in the lesioned cortex increased after HI insult in neonatal mice. Knockdown of miR-100-5p expression in the brain attenuated brain injury and promoted functional recovery, through inhibiting the cleaved-caspase-3 level, microglia activation, and the release of proinflammation cytokines following HI injury. Engineered extracellular vesicles (EVs) containing neuron-targeting rabies virus glycoprotein (RVG) and miR-100-5p antagonists (RVG-EVs-Antagomir) selectively targeted brain lesions and reduced miR-100-5p levels after intranasal delivery. Both pre- and post-HI administration showed therapeutic benefits. Mechanistically, we identified protein phosphatase 3 catalytic subunit alpha (Ppp3ca) as a novel candidate target gene of miR-100-5p, inhibiting c-Fos expression and neuronal apoptosis following HI insult. In conclusion, our non-invasive method using engineered EVs to deliver miR-100-5p antagomirs to the brain significantly improves functional recovery after HI injury by targeting Ppp3ca to suppress neuronal apoptosis.
Animals ; MicroRNAs/metabolism* ; Extracellular Vesicles/metabolism* ; Mice ; Recovery of Function/physiology* ; Hypoxia-Ischemia, Brain/therapy* ; Mice, Inbred C57BL ; Antagomirs/administration & dosage* ; Male ; Animals, Newborn ; Apoptosis/drug effects* ; Brain Injuries/metabolism* ; Glycoproteins ; Peptide Fragments ; Viral Proteins

OBJECTIVE: To explore the early changes in various liver function indicators in critically injured trauma patients assessed by intelligent calculation method, aiming to develop more advantageous diagnostic and treatment strategies for traumatic liver injury. METHODS: A retrospective study was conducted. Critically injured trauma patients [injury severity score (ISS) ≥ 16, age > 18 years old] admitted to the Emergency Medical Center of Tianjin Fifth Central Hospital from January 1, 2022, to December 1, 2023 were enrolled. ISS score and acute physiology and chronic health evaluation II (APACHE II) assessed by intelligent calculation method were collected upon patient admission to the emergency medical center. Trends in liver function indicators in fasting venous serum were analyzed at 6, 24 and 72 hours after admission, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), γ-glutamyl transferase (GGT), lactate dehydrogenase (LDH), albumin (ALB), total bilirubin (TBil), prothrombin time (PT). Patients were grouped based on APACHE II scores into those with APACHE II < 15 and APACHE II ≤ 15, and liver function indicators within 6 hours of admission were compared between the two groups. RESULTS: A total of 112 critically injured trauma patients were included, with 83 males and 29 females, an average age of (47.78±14.84) years old. The median ISS score was 21.0 (18.0, 26.0). The most common cause of injury for critically injured trauma patients was road traffic accidents (68 cases, accounting for 60.71%), followed by falls from heights, compression injuries, heavy object injuries, knife stabs, and explosion injuries. The most common injured areas was the limbs and pelvis (97 cases, accounting for 86.61%), followed by chest injuries, surface skin and soft tissue injuries, abdominal and pelvic organ injuries, head injuries, and facial injuries. The proportion of elevated LDH, AST, and ALT within 6 hours of admission was 77.68%, 79.46%, and 52.68%, respectively, while the proportion of decreased ALB was 75.89%, the abnormal rates of ALP, GGT, TBil, and PT were all below 50%. The ALT and AST levels of patients at 24 hours and 72 hours after admission were significantly lower than those at 6 hours after admission [ALT (U/L): 37.0 (22.0, 66.0), 31.0 (21.2, 52.0) vs. 41.0 (25.0, 71.0), AST (U/L): 55.5 (30.0, 93.5), 40.0 (27.0, 63.2) vs. 69.5 (39.0, 130.8), all P < 0.05]. There was no statistically significant difference in ISS score between APACHE II > 15 group (45 cases) and APACHE II ≤ 15 group [67 cases; 21.0 (18.5, 26.5) vs. 20.0 (17.0, 22.0), P > 0.05]. Nevertheless, compared with patients with APACHE II ≤ 15, patients with APACHE II > 15 have a higher abnormality rate of ALT and AST within 6 hours of admission [ALT abnormal rate: 66.44% (29/45) vs. 44.78% (30/67), AST abnormal rate: 93.33% (42/45) vs. 70.15% (47/67), both P < 0.05], and the levels of ALT and AST were higher [ALT (U/L): 56.0 (30.0, 121.0) vs. 35.0 (21.0, 69.0), AST (U/L): 87.0 (48.0, 233.0) vs. 52.0 (31.0, 117.0), both P < 0.05]. CONCLUSIONS Severe trauma patients frequently exhibit a high incidence of reversible early liver function impairment. Based on intelligent calculation method, the utilization of both the ISS and APACHE II scores demonstrates a distinct advantage in the assessment of their early liver injury.
Humans ; Retrospective Studies ; Liver/physiopathology* ; Risk Assessment ; APACHE ; Wounds and Injuries ; Adult ; Injury Severity Score ; Male ; Middle Aged ; Female ; Liver Function Tests ; Alanine Transaminase/blood* ; Young Adult ; Aspartate Aminotransferases/blood*

S-methyl-L-cysteine sulfoxide (SMCO) is a non-protein sulfur-containing amino acid with a variety of functions. There are few reports on the enzymes catalyzing the biosynthesis of SMCO from S-methyl-L-cysteine (SMC). In this study, the flavin-containing monooxygenase gene derived from Schizosaccharomyces pombe (spfmo) was heterologously expressed in Escherichia coli BL21(DE3) and the enzymatic properties of the expressed protein were analyzed. The optimum catalytic conditions of the recombinant SpFMO were 30 ℃ and pH 8.0, under which the enzyme activity reached 72.77 U/g. An appropriate amount of Mg²⁺ improved the enzyme activity. The enzyme kinetic analysis showed that the K_m and k_cat/K_m of SpFMO on the substrate SMC were 23.89 μmol/L and 61.71 L/(min·mmol), respectively. Under the optimal reaction conditions, the yield of SMCO synthesized from SMC catalyzed by SpFMO was 12.31% within 9 h. This study provides reference for the enzymatic synthesis of SMCO.
Schizosaccharomyces/genetics* ; Escherichia coli/metabolism* ; Recombinant Proteins/metabolism* ; Cysteine/biosynthesis* ; Mixed Function Oxygenases/metabolism* ; Schizosaccharomyces pombe Proteins/metabolism* ; Oxygenases/metabolism* ; Kinetics

Flavoprotein monooxygenases(FPMOs) and cytochrome P450(CYP450) oxygenases are pivotal monooxygenases in nature, catalyzing crucial redox reactions in diverse biological processes and contributing to the synthesis of highly complex natural products. While CYP450 enzymes have been extensively reported and studied, numerous FPMOs have also been discovered in past research endeavors, yet their classification, catalytic reactions, and catalytic mechanisms remain to be systematically analyzed. This paper comprehensively reviews the latest advancements in FPMOs research, initiating with a classification based on sequence similarities and distinct structural features. It delves into the catalytic characteristics of three subfamilies(FMO, BVMO, and NMO) within Class B FPMOs of plants, which are integral to biosynthetic pathways of natural products. Class B FPMOs encompass two canonical Rossmann fold motifs(FAD-binding GxGxxG and NADPH-binding GxGxxA), along with a central FMO recognition motif FxGxxxHxxxF/Y/W. These enzymes play a key role in regulating various metabolic routes and precisely modulate plant growth and development. Furthermore, the review summarizes the applications of Class B FPMOs of plants, showcasing through concrete examples their potential in synthesizing natural products such as auxins, indigo, and cyanogenic glycosides. These insights will broaden and deepen our understanding of FPMOs, fostering their transition from fundamental research to practical applications. More optimized biosynthetic pathways can be devised by leveraging FPMOs, conducive to the development of novel strategies and tools for agriculture, plant protection, natural product biosynthesis, and synthetic biology.
Biological Products/metabolism* ; Mixed Function Oxygenases/chemistry* ; Flavoproteins/chemistry* ; Plants/metabolism* ; Plant Proteins/chemistry* ; Cytochrome P-450 Enzyme System/genetics*