BACKGROUND: AMP-activated protein kinase (AMPK) is a serine/threonine protein kinase that plays a pivotal role in the balance of cellular energy metabolism. Recent studies have reported that AMPK has numerous roles in physiological conditions, and dysregulation of AMPK induces pathological processes and diseases. However, the role of AMPK and its activators have not yet been studied in the context of hair growth regulation. OBJECTIVE: To investigate the effects of metformin on dermal papilla (DP) and outer root sheath (ORS) cells, as well as the role of the AMPK pathway in hair growth. METHODS: We evaluated whether metformin, a well-known AMPK activator, had any beneficial effects on hair growth. In addition, to evaluate the molecular and cellular mechanisms that were involved, protein levels of AMPK and β-catenin were analyzed. RESULTS: Metformin increased the cellular proliferation of human DP and ORS cells. Ki-67 expression was also significantly increased after metformin treatment in the ex vivo hair follicle organ culture. Furthermore, DP and ORS cells treated with metformin had a significant increase in AMPK phosphorylation, which in turn suppressed β-catenin degradation and enhanced its nuclear accumulation. CONCLUSION: We demonstrated that metformin promoted hair growth via the AMPK/β-catenin signaling pathway in vitro with DP and ORS cells. The hair-promoting effects of AMPK activators may potentially be used for the treatment of alopecia, and further investigation will be needed in the future.
Alopecia ; AMP-Activated Protein Kinases ; beta Catenin ; Cell Proliferation ; Energy Metabolism ; Hair Follicle ; Hair ; Humans ; In Vitro Techniques ; Metformin ; Organ Culture Techniques ; Pathologic Processes ; Phosphorylation ; Protein Kinases

The pancreatoduodenal groove is a small area where pathologic processes involving the distal bile duct, duodenum, pancreatic head, ampulla of Vater, and retroperitoneum converge. Despite great advances in imaging techniques, a definitive preoperative diagnosis is challenging because of the complex anatomy of this area. Therefore, surgical intervention is frequently required because of the inability to completely exclude malignancy. We report 3 cases of patients with different groove pathologies but similar clinical and imaging presentation, and show the essential role of endoscopic ultrasound (EUS) in making a specific preoperative diagnosis, excluding malignancy in the first case, changing diagnosis in the second case, and confirming malignancy in the third case. EUS was a fundamental tool in this cohort of patients, not only because of its ability to provide superior visualization of a difficult anatomical region, but because of the ability to guide precise, real-time procedures, such as fine-needle aspiration.
Ampulla of Vater ; Bile Ducts ; Biopsy, Fine-Needle ; Cohort Studies ; Diagnosis ; Duodenum ; Head ; Humans ; Pancreatic Neoplasms ; Pathologic Processes ; Pathology ; Ultrasonography

Na⁺/H⁺ exchangers (NHEs) have been shown to be involved in regulating cell volume and maintaining fluid and electrolyte homeostasis. Pooled evidences have suggested that loss of Na⁺/H⁺ exchanger isoform 8 (NHE8) impairs intestinal mucosa. Whether NHE8 participates in the pathology of infectious colitis is still unknown. Our previous study demonstrated that somatostatin (SST) could stimulate the expression of intestinal NHE8 so as to facilitate Na⁺ absorption under normal condition. This study further explored whether NHE8 participates in the pathological processes of infectious colitis and the effects of SST on intestinal NHE8 expression in the setting of infectious colitis. Our data showed that NHE8 expression was reduced in Citrobacter rodentium (CR) infected mice. Up-regulation of NHE8 improved diarrhea symptom and mucosal damage induced by CR. In vitro, a similar observation was also seen in Enteropathogenic E. coli (EPEC) infected Caco-2 cells. Seglitide, a SST receptor (SSTR) 2 agonist, partly reversed the inhibiting action of EPEC on NHE8 expression, but SSTR5 agonist (L-817,818) had no effect on the expression of NHE8. Moreover, SST blocked the phosphorylation of p38 in EPEC-infected Caco-2 cells. Taken together, these results suggest that enhancement of intestinal NHE8 expression by SST could ameliorate the symptoms of mice with infectious colitis.
Absorption ; Animals ; Anti-Inflammatory Agents ; Caco-2 Cells ; Cell Size ; Citrobacter rodentium ; Colitis* ; Diarrhea* ; Enteropathogenic Escherichia coli ; Homeostasis ; Humans ; In Vitro Techniques ; Intestinal Mucosa ; Mice* ; Pathologic Processes ; Pathology ; Phosphorylation ; Somatostatin* ; Up-Regulation*

Exosomes are membranous vesicles of 30-150 nm in diameter that are derived from the exocytosis of the intraluminal vesicles of many cell types including immune cells, stem cells, cardiovascular cells and tumor cells. Exosomes participate in intercellular communication by delivering their contents to recipient cells, with or without direct contact between cells, and thereby influence physiological and pathological processes. They are present in various body fluids and contain proteins, nucleic acids, lipids, and microRNAs that can be transported to surrounding cells. Theragnosis is a concept in next-generation medicine that simultaneously combines accurate diagnostics with therapeutic effects. Molecular components in exosomes have been found to be related to certain diseases and treatment responses, indicating that they may have applications in diagnosis via molecular imaging and biomarker detection. In addition, recent studies have reported that exosomes have immunotherapeutic applications or can act as a drug delivery system for targeted therapies with drugs and biomolecules. In this review, we describe the formation, structure, and physiological roles of exosomes. We also discuss their roles in the pathogenesis and progression of diseases including neurodegenerative diseases, cardiovascular diseases, and cancer. The potential applications of exosomes for theragnostic purposes in various diseases are also discussed. This review summarizes the current knowledge about the physiological and pathological roles of exosomes as well as their diagnostic and therapeutic uses, including emerging exosome-based therapies that could not be applied until now.
Body Fluids ; Cardiovascular Diseases ; Diagnosis ; Drug Delivery Systems ; Exocytosis ; Exosomes* ; MicroRNAs ; Molecular Imaging ; Neurodegenerative Diseases ; Nucleic Acids ; Pathologic Processes ; Stem Cells ; Therapeutic Uses

STUDY DESIGN: A retrospective study. PURPOSE: Our objectives were to determine the association between the pathological changes of disc herniation and the interval between primary and revision surgeries and to investigate the frequency and site of the dural laceration in the primary and revision surgeries. OVERVIEW OF LITERATURE: Among 382 patients who underwent microsurgical lumbar discectomy, we investigated 29 who underwent revision surgery to analyze recurrent herniation pathologies and complications to determine the manner in which lumbar disc herniation can be more efficiently managed. METHODS: Of 29 patients, 22 had recurrent disc herniation at the same level and site. The pathological changes associated with compression factors were classified into the following two types depending on intraoperative findings: (1) true recurrence and (2) minor recurrence with peridural fibrosis (>4 mm thickness). The sites of dural laceration were examined using video footage and operative records. RESULTS: The pathological findings and days between the primary and revision surgeries showed no statistical difference (p=0.14). Analysis of multiple factors, revealed no significant difference between the primary and revision surgery groups with regard to hospital days (p=0.23), blood loss (p=0.99), and operative time (p=0.67). Dural lacerations obviously increased in the revision surgery group (1.3% vs. 16.7%, p < 0.01) and were mainly located near the herniated disc in the primary surgery group and near the root shoulder in the revision surgery group, where severe fibrosis and adhesion were confirmed. To avoid dural laceration during revision surgery, meticulous decompressive manipulation must be performed around the root sleeve. CONCLUSIONS: We recommend that meticulous epidural dissection around the scar formation must be performed during revision surgery to avoid complications.
Cicatrix ; Diskectomy ; Fibrosis ; Humans ; Intervertebral Disc Displacement ; Lacerations ; Operative Time ; Pathologic Processes ; Pathology ; Recurrence ; Reoperation ; Retrospective Studies ; Shoulder

Since neuromuscular blocking agents (NMBAs) were introduced to the surgical field, they have become almost mandatory for the induction and maintenance of anesthesia. However, resistance to NMBAs can develop in certain pathological states, such as central nerve injury, burns, and critical illnesses. During such pathological processes, quantitative and qualitative changes occur in the physiology of acetylcholine and the acetylcholine receptor (AChR) at the neuromuscular junction. Up-regulation of AChR leads to changes in the pharmacokinetics and pharmacodynamics of NMBA. As NMBA resistance may result in problems during anesthesia, it is of utmost importance to understand the mechanisms of NMBA resistance and their associations with pathological status to maintain adequate neuromuscular relaxation. This review presents the current knowledge of pharmacokinetic and pharmacodynamic changes and pathological status associated with NMBA resistance.
Acetylcholine ; Anesthesia ; Burns ; Critical Illness ; Drug Resistance ; Neuromuscular Blockade* ; Neuromuscular Blocking Agents* ; Neuromuscular Junction ; Pathologic Processes ; Pharmacokinetics ; Physiology ; Receptors, Cholinergic ; Relaxation ; Up-Regulation

OBJECTIVE: Bipolar disorder (BD) is a chronic mood disorder characterized by recurrent episodes that has a lifetime prevalence of 0.4–5.5%. The neurochemical mechanism of BD is not fully understood. Oxidative stress in neurons causes lipid peroxidation in proteins associated with neuronal membranes and intracellular enzymes and it may lead to dysfunction in neurotransmitter reuptake and enzyme activities. These pathological processes are thought to occur in brain regions associated with affective functions and emotions in BD. The relationship between the number of manic episodes and total oxidant-antioxidant capacity was investigated in this study. METHODS: Eighty-two BD patients hospitalized due to manic symptoms and with no episodes of depression were enrolled in the study. Thirty of the 82 patients had had their first episode of mania, and the other 52 patients had had two or more manic episodes. The control group included 45 socio-demographically matched healthy individuals. Serum total antioxidant capacity (TAC) and total oxidant capacity (TOC) measurements of the participants were performed. The oxidative stress index (OSI) was calculated by TOC/TAC. RESULTS: There were no significant differences in OSI scores between BD patients with first-episode mania and BD patients with more than one manic episode. However, OSI scores in both groups were significantly higher than in the control group. TOC levels of BD patients with first-episode mania were found to be significantly higher than TOC levels of BD patients with more than one manic episode and healthy controls. There were no significant differences in TAC levels between BD patients with first-episode mania and BD patients with more than one manic episode. TAC levels in both groups were significantly higher than in the control group. CONCLUSION: Significant changes in oxidative stress indicators were observed in this study, confirming previous studies. Increased levels of oxidants were shown with increased disease severity rather than with the number of manic episodes. Systematic studies, including of each period of the disorder, are needed for using the findings indicating deterioration of oxidative parameters.
Bipolar Disorder* ; Brain ; Depression ; Humans ; Lipid Peroxidation ; Membranes ; Mood Disorders ; Neurons ; Neurotransmitter Agents ; Oxidants ; Oxidative Stress* ; Pathologic Processes ; Prevalence

Circular RNAs (circRNAs) are currently classed as non-coding RNAs that, unlike the better known canonical linear RNAs, form a covalently closed continuous loop without 5′ or 3′ polarities. With the development of high throughput sequencing technology, a large number of circRNAs have been discovered in many species. More importantly, growing evidence suggests that circRNAs are abundant, evolutionally conserved, and relatively stable in cells and tissues. Strikingly, recent studies have discovered that circRNAs can serve as microRNA sponges, interact with RNA-binding protein, and regulate gene transcription, as well as protein translation. Osteoarthritis (OA) is the most common chronic degenerative joint disease. CircRNAs are differentially expressed in OA cartilage. Moreover, some circRNAs are involved in multiple pathological processes during OA, mainly extracellular matrix degradation, inflammation, and apoptosis. In this review, we briefly delineate the biogenesis, characteristics, and biofunctions of circRNAs, and then, focus on the role of circRNAs in the occurrence and progression OA.
Apoptosis ; Cartilage ; Cartilage, Articular ; Extracellular Matrix ; Inflammation ; Joint Diseases ; MicroRNAs ; Osteoarthritis* ; Pathologic Processes ; Porifera ; Protein Biosynthesis ; RNA* ; RNA, Untranslated ; RNA-Binding Proteins

Nitric oxide (NO) mediates various physiological and pathological processes, including cell proliferation, differentiation, and inflammation. Protein S-nitrosylation (SNO), a NO-mediated reversible protein modification, leads to changes in the activity and function of target proteins. Recent findings on protein-protein transnitrosylation reactions (transfer of an NO group from one protein to another) have unveiled the mechanism of NO modulation of specific signaling pathways. The intracellular level of S-nitrosoglutathione (GSNO), a major reactive NO species, is controlled by GSNO reductase (GSNOR), a major regulator of NO/SNO signaling. Increasing number of GSNOR-related studies have shown the important role that denitrosylation plays in cellular NO/SNO homeostasis and human pathophysiology. This review introduces recent evidence of GSNO-mediated NO/SNO signaling depending on GSNOR expression or activity. In addition, the applicability of GSNOR as a target for drug therapy will be discussed in this review.
Cell Proliferation ; Drug Therapy ; Homeostasis ; Humans ; Inflammation ; Nitric Oxide ; Oxidoreductases* ; Pathologic Processes ; S-Nitrosoglutathione*

Ankylosing spondylitis (AS) is a type of autoimmune disease that predominantly affects the spine and sacroiliac joints. However, the pathogenesis of AS remains unclear. Some evidence indicates that infection with bacteria, especially Gram-negative bacteria, may have an important role in the onset and progression of AS. Recently, many studies have demonstrated that mesenchymal stem cells (MSCs) dysfunction may contribute to the pathogenesis of many rheumatic diseases. We previously demonstrated that MSCs from AS patients exhibited markedly enhanced osteogenic differentiation capacity in vitro under non-inflammatory conditions. However, the properties of MSCs from AS patients in an inflammatory environment have never been explored. Lipopolysaccharide (LPS), a proinflammatory substance derived from the outer membrane of Gram-negative bacteria, can alter the status and function of MSCs. However, whether MSCs from AS patients exhibit abnormal responses to LPS stimulation has not been reported. Autophagy is a lysosome-mediated catabolic process that participates in many physiological and pathological processes. The link between autophagy and AS remains largely unknown. The level of autophagy in ASMSCs after LPS stimulation remains to be addressed. In this study, we demonstrated that although the basal level of autophagy did not differ between MSCs from healthy donors (HDMSCs) and ASMSCs, LPS-induced autophagy was weaker in ASMSCs than in HDMSCs. Specifically, increased TRAF4 expression in ASMSCs impaired LPS-induced autophagy, potentially by inhibiting the phosphorylation of Beclin-1. These data may provide further insight into ASMSC dysfunction and the precise mechanism underlying the pathogenesis of AS.
Autoimmune Diseases ; Autophagy* ; Bacteria ; Gram-Negative Bacteria ; Humans ; In Vitro Techniques ; Membranes ; Mesenchymal Stromal Cells* ; Pathologic Processes ; Phosphorylation ; Rheumatic Diseases ; Sacroiliac Joint ; Spine ; Spondylitis, Ankylosing* ; Tissue Donors ; TNF Receptor-Associated Factor 4*