A High Creatine Kinase Concentration Might Be a Sign of McArdle Disease in Patient With Type 1 Diabetes

Type 1 diabetes (the pancreas producing little or no insulin) is usually diagnosed in children and young adults and was previously known as juvenile diabetes. McArdle disease is a common metabolic defect caused by an inherited deficit of myophosphorylase. These 2 diseases might have some clinical heterogeneity. Here, we discuss a McArdle disease case where insulin-dependent diabetes overshadows its early diagnosis. In this case, an insulin-dependent 22-year-old female patient with diabetes mellitus had been on diabetes treatment for 15 years. Although her blood glucose was regulated, her anamnesis showed that muscle weakness, fatigue, cramps or myalgia never healed. Based on her anamnesis, the patient was asked to take a nonischemic forearm exercise test, which revealed significant elevation in levels of creatine kinase (5968-7906 U/L), but no increase was found in lactate concentration, but a slight increase in ammonia concentration (not statistically significant) at the end of the test made us consider McArdle disease. A genetic test was done to confirm this possibility. A homozygous c.2128_2130delTTC/p.Phe710del mutation was detected in the examination of exons of the PYGM gene, which confirmed the diagnosis of McArdle disease in our patient. According to the data, this is a rare case of McArdle disease with type 1 diabetes. During treatment for diabetes, if the above-mentioned symptoms are present in a patient, and especially if the patient’s creatine kinase concentration is high, muscle diseases should be suspected. Therefore, we suggest that this case report will provide new insight to clinicians on metabolic defects in this disease and increase the patient comfort. In such cases, an early diagnosis should reduce health costs.

Aerococcus urinae and Globicatella sanguinis Persist in Polymicrobial Urethral Catheter Biofilms Examined in Longitudinal Profiles at the Proteomic Level

Aerococcus urinae ( Au) and Globicatella sanguinis ( Gs) are gram-positive bacteria belonging to the family Aerococcaceae and colonize the human immunocompromised and catheterized urinary tract. We identified both pathogens in polymicrobial urethral catheter biofilms (CBs) with a combination of 16S rDNA sequencing, proteomic analyses, and microbial cultures. Longitudinal sampling of biofilms from serially replaced catheters revealed that each species persisted in the urinary tract of a patient in cohabitation with 1 or more gram-negative uropathogens. The Gs and Au proteomes revealed active glycolytic, heterolactic fermentation, and peptide catabolic energy metabolism pathways in an anaerobic milieu. A few phosphotransferase system (PTS)–based sugar uptake and oligopeptide ABC transport systems were highly expressed, indicating adaptations to the supply of nutrients in urine and from exfoliating squamous epithelial and urothelial cells. Differences in the Au vs Gs metabolisms pertained to citrate lyase and utilization and storage of glycogen (evident only in Gs proteomes) and to the enzyme Xfp that degrades d-xylulose-5′-phosphate and the biosynthetic pathways for 2 protein cofactors, pyridoxal 6′-phosphate and 4′-phosphopantothenate (expressed only in Au proteomes). A predicted ZnuA-like transition metal ion uptake system was identified for Gs while Au expressed 2 LPXTG-anchored surface proteins, one of which had a predicted pilin D adhesion motif. While these proteins may contribute to fitness and virulence in the human host, it cannot be ruled out that Au and Gs fill a niche in polymicrobial biofilms without being the direct cause of injury in urothelial tissues.

The Role of Insulin-Like Growth Factors and Insulin-Like Growth Factor–Binding Proteins in the Nervous System

The insulin-like growth factors (IGF-I and IGF-II) and their receptors are widely expressed in nervous tissue from early embryonic life. They also cross the blood brain barriers by active transport, and their regulation as endocrine factors therefore differs from other tissues. In brain, IGFs have paracrine and autocrine actions that are modulated by IGF-binding proteins and interact with other growth factor signalling pathways. The IGF system has roles in nervous system development and maintenance. There is substantial evidence for a specific role for this system in some neurodegenerative diseases, and neuroprotective actions make this system an attractive target for new therapeutic approaches. In developing new therapies, interaction with IGF-binding proteins and other growth factor signalling pathways should be considered. This evidence is reviewed, gaps in knowledge are highlighted, and recommendations are made for future research.

The Roles of N6-Methyladenosine in Human Diseases

N 6-Methyladenosine methylations and demethylations are associated with a number of human diseases. A chemical and biochemical perspective can complement the biological view of the epigenetic mechanism. The orbital of imino nitrogen and nitrogen-hydrogen orbital displays p-π conjugation and σ-σ hyperconjugation. The electron delocalization attenuates secondary chemical bonding, resulting in low affinities on the imino nitrogen atom to cations. Reduced proton accumulation via N 6-methyladenosine correlates to lower cellular proton levels which may reflect cell physiology and pathogenesis. The lower affinity of the imino nitrogen to divalent cations in the methylated form versus the nonmethylated form may lead to reduced formation of insoluble and rigid calcium oxalate, which was proposed to be the cause of many diseases. The chemical and biochemical attributes of N 6-methyladenosine crosstalk with biological pathways upregulating and/or downregulating gene expressions to give rise to various physiological and biochemical outcomes at the cellular levels and the organismal levels.

Protective Effects of Acridocarpus smeathmannii (DC.) Guill. & Perr. Root Extract against Phenylhydrazine-Induced Haematotoxicity, Biochemical Changes, and Oxidative Stress in Rats

Several strategies for discovering drugs from unexplored natural products continue to strengthen research and development with current commercial evidence supporting their applications. We assessed the effects of the hydroethanolic extract of Acridocarpus smeathmannii root (HEASR) against phenylhydrazine (PHZ)-induced haematotoxicity, biochemical changes, and oxidative stress in male Wistar rats. Groups 1 and 2 controls received normal saline (10 mL/kg/day) and PHZ (60 mg/kg, day 4 and 5), respectively, via oral gavage. Groups 3, 4, and 5 were administered dexamethasone (DXM, 0.014 mg/kg/day, p.o.), HEASR1 (50 mg/kg/day, p.o.) and HEASR2 (200 mg/kg/day, p.o.), respectively. Groups 6, 7, and 8 received HEASR2 (200 mg/kg/day), DXM (0.014 mg/kg/day), or their combination, respectively, and further received PHZ (60 mg/kg/day) intervention on day 4 and 5 only. Treatments lasted for 7 days. Phenylhydrazine toxicity manifested as lowered haemoglobin, white blood cells, lymphocytes, red blood cells, and platelet levels by 45.86%, 53.47%, 75.69%, 46.89%, and 30.29%, respectively, in rats. This was accompanied by an increase in serum alanine (ALT; 108.25%) and aspartate (AST; 78.79%) aminotransferases, urea (84.36%), total cholesterol (81.55%), and triglycerides (123.42%) levels. Similarly, malondialdehyde levels and serum cyclooxygenase-2 activity were elevated ( P < 0.05) in the rats liver and spleen, respectively. Just HEASR alone, or in combination with DXM, preserved haematological and biochemical parameters, cyclooxygenase-2 activity, and corticosterone levels during PHZ intoxication and restored renal histopathological alterations in rats. The HEASR was found to contain high flavonoid and phenolic phytochemicals and demonstrated better in vitro antioxidants inhibitory action.

Cellular States and Secondary Chemical Bonding: A Biochemical View of Major Human Diseases

Nasopharyngeal carcinoma is prevalent in hot and humid areas such as south coastal China and Southeast Asia, but not in the non-coastal southern Chinese Yunnan Province. Secondary chemical bonding may underlie such phenomena. Cancer may be caused by strong acids such as HCl, whereas insoluble and rigid salts such as calcium oxalate are the potential causative factors of heart disease and the Alzheimer disease. The weak organic acids produced by plants counteract strong acids and dissolve insoluble salts, therefore boasting dual roles in disease prevention and treatments. The aforementioned perspective sheds light on the underlying mechanism of human disorders and opens new avenues in the interventions of numerous diseases.

Connexin-43 Enhances the Redesigned Cytosine Deaminase Activity for Suicide Gene Therapy in Human Breast Cancer Cells

Background: Escherichia coli cytosine deaminase (CD) converts 5-fluorocytosine (5-FC), a prodrug, into 5-fluorouracil (5-FU), a chemotherapeutic drug. However, the poor binding affinity of CD towards 5-FC as compared to the natural substrate cytosine, limits its application towards a successful suicide gene therapy. Although F186W mutant was developed to enhance the effect of wild-type CD, still scope for its improvement remains to further minimize the dose-dependent cytotoxicity of the drugs. Hence, in this study, we employ the anti-tumour attribute of the gap junction forming protein connexin-43 (Cx43) in conjunction with CD or F186W mutant. Methods: Lipofectamine was used to co-transfect CD/F186W-pVITRO2 and Cx43-pEGFP-N1 plasmids construct into MCF-7 cells. Comparative analysis of cell viability was observed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium-bromide (MTT) and trypan blue–based assays. To further confirm the mode of cell death was apoptosis, propidium iodide and annexin V/7-aminoactinomycin D (7-AAD)-based apoptosis assays were performed. Results: Semi-quantitative polymerase chain reaction (PCR) confirmed the expression of both Cx43 and CD/F186W genes after transfection. Furthermore, cell viability assays revealed the enhanced activity of F186W-Cx43 compared with CD-Cx43 and F186W alone. The trend of the reduction in cell viability was also reflected in the flow cytometry–based apoptosis analyses. Overall, F186W-Cx43 combination demonstrated its superiority over the CD-Cx43 and F186W mutant alone. Conclusions: The enhanced cytotoxic activity of F186W mutant was further amplified by gap junction protein Cx43.

A Solo Dance or a Tango?

Previous studies have identified genetic factors and Epstein-Barr virus underlying nasopharyngeal carcinoma. A hypothesis postulated that the local buildup of HCl, mediated by hydrogen bond donors and acceptors and basic amino acids, causes cancer. Nasopharyngeal carcinoma incidences are high in the humid southern coastal China, Southeast Asia, and Mediterranean regions, but not in the noncoastal and nonhumid southern Yunnan Province, China, and nonhumid Central China. The nearly saturated humidity in the Huinan period in Guangdong can trigger the expression of proteins with extensive hydrogen bonding to protons, augmenting the formation of HCl that is mutagenic. Given that the Epstein-Barr virus carries high content of hydrogen bond donors and acceptors, the moist environment in the nasal cavity may enable the virus to colonize the site, compounding pertinent investigations as both virus and high humidity are likely to trigger carcinogenesis. Therefore, the phenomena of exceptionally high humidity in regions with high nasopharyngeal cancer rates warrant further investigations.

Aerobic Respiration: Criticism of the Proton-centric Explanation Involving Rotary Adenosine Triphosphate Synthesis, Chemiosmosis Principle, Proton Pumps and Electron Transport Chain

The acclaimed explanation for mitochondrial oxidative phosphorylation (mOxPhos, or cellular respiration) is a deterministic proton-centric scheme involving four components: Rotary adenosine triphosphate (ATP)-synthesis, Chemiosmosis principle, Proton pumps, and Electron transport chain (abbreviated as RCPE hypothesis). Within this write-up, the RCPE scheme is critically analyzed with respect to mitochondrial architecture, proteins’ distribution, structure-function correlations and their interactive dynamics, overall reaction chemistry, kinetics, thermodynamics, evolutionary logic, and so on. It is found that the RCPE proposal fails to explain key physiological aspects of mOxPhos in several specific issues and also in holistic perspectives. Therefore, it is imperative to look for new explanations for mOxPhos.

The Role of the Growth Hormone/Insulin-Like Growth Factor System in Visceral Adiposity

There is substantial evidence that the growth hormone (GH)/insulin-like growth factor (IGF) system is involved in the pathophysiology of obesity. Both GH and IGF-I have direct effects on adipocyte proliferation and differentiation, and this system is involved in the cross-talk between adipose tissue, liver, and pituitary. Transgenic animal models have been of importance in identifying mechanisms underlying these interactions. It emerges that this system has key roles in visceral adiposity, and there is a rationale for targeting this system in the treatment of visceral obesity associated with GH deficiency, metabolic syndrome, and lipodystrophies. This evidence is reviewed, gaps in knowledge are highlighted, and recommendations are made for future research.