Role of Piezo2 in Schwann Cell Volume Regulation and Its Impact on Neurotrophic Release Regulation.

BACKGROUND/AIMS: Tactile perception relies on mechanoreceptors and nerve fibers, including c-fibers, Aß-fibers and Aδ-fibers. Schwann cells (SCs) play a crucial role in supporting nerve fibers, with non-myelinating SCs enwrapping c-fibers and myelinating SCs ensheathing Aß and Aδ fibers. Recent research has unveiled new functions for cutaneous sensory SCs, highlighting the involvement of nociceptive SCs in pain perception and Meissner corpuscle SCs in tactile sensation. Furthermore, Piezo2, previously associated with Merkel cell tactile sensitivity, has been identified in SCs. The goal of this study was to investigate the channels implicated in SC mechanosensitivity and the release process of neurotrophic factor secretion. METHODS: Immortalized IFRS1 SCs and human primary SCs generated two distinct subtypes of SCs: undifferentiated and differentiated SCs. Quantitative PCR was employed to evaluate the expression of differentiation markers and mechanosensitive channels, including TRP channels (TRPV4, TRPM7 and TRPA1) and Piezo channels (Piezo1 and Piezo2). To validate the functionality of specific mechanosensitive channels, Ca2+ imaging and electronic cell sizing experiments were conducted under hypotonic conditions, and inhibitors and siRNAs were used. Protein expression was assessed by Western blotting and immunostaining. Additionally, secretome analysis was performed to evaluate the release of neurotrophic factors in response to hypotonic stimulation, with BDNF, a representative trophic factor, quantified using ELISA. RESULTS: Induction of differentiation increased Piezo2 mRNA expression levels both in IFRS1 and in human primary SCs. Both cell types were responsive to hypotonic solutions, with differentiated SCs displaying a more pronounced response. Gd3+ and FM1-43 effectively inhibited hypotonicity-induced Ca2+ transients in differentiated SCs, implicating Piezo2 channels. Conversely, inhibitors of Piezo1 and TRPM7 (Dooku1 and NS8593, respectively) had no discernible impact. Moreover, Piezo2 in differentiated SCs appeared to participate in regulatory volume decreases (RVD) after cell swelling induced by hypotonic stimulation. A Piezo2 deficiency correlated with reduced RVD and prolonged cell swelling, leading to heightened release of the neurotrophic factor BDNF by upregulating the function of endogenously expressed Ca2+-permeable TRPV4. CONCLUSION: Our study unveils the mechanosensitivity of SCs and implicates Piezo2 channels in the release of neurotrophic factors from SCs. These results suggest that Piezo2 may contribute to RVD, thereby maintaining cellular homeostasis, and may also serve as a negative regulator of neurotrophic factor release. These findings underscore the need for further investigation into the role of Piezo2 in SC function and neurotrophic regulation.

Two-year administration of sodium-glucose co-transporter 2 inhibitor brought about marked reduction of body fat independent of skeletal muscle amount or glycemic improvement in Japanese patients with type 2 diabetes.

AIM: To investigate long-term effects of sodium-glucose co-transporter 2 inhibitor (SGLT2i) on anthropometric and metabolic factors in Japanese patients with type 2 diabetes (T2DM). PATIENTS AND METHODS: This is a retrospective observation study. Forty-six outpatients with T2DM (32 men and 14 women, 51 ± 13 years old, BMI 27.9 ± 4.8, means ± S.D.) who had been treated by SGLT2i for 2 years were selected and their metabolic and anthropometric data were retrieved from medical records retrospectively. Regular instruction for diet and exercise had been performed throughout the administration of SGLT2i in outpatient clinic basis. RESULTS: By the administration of SGLT2i for 2 years, body weight and body fat amount were significantly reduced (P < 0.0001) in spite of no change in skeletal muscle mass. HbA1c (P < 0.0001), liver function and lipid profile (P < 0.01) were ameliorated and eGFR was reduced significantly (P < 0.0001). It is of note that the reduction of body weight was strongly correlated to that of body fat (r = 0.951, P < 0.0001) with no correlation to the change of skeletal muscle mass. The reduction of HbA1c was strongly correlated to the baseline HbA1c (r = - 0.922, P < 0.0001) and modestly correlated to the baseline eGFR (r = - 0.449, P < 0.01). Multivariate analysis revealed a weak relationship between the amelioration of HbA1c and the reduction of body weight. CONCLUSION: SGLT2i can effectively reduce body weight and body fat mass independent of the blood glucose improvement or the renal function. Under the periodical instruction for nutrition and exercise this oral hypoglycemic agent can be safely administered for a long term without a risk for sarcopenia.

Thyroid-related ophthalmopathy development in concurrence with growth hormone administration.

BACKGROUND: Thyroid stimulating hormone (TSH) receptor and local infiltrate lymphocytes have been considered as major pathological factors for developing thyroid-related ophthalmopathy. Overexpression of insulin-like growth factor-I (IGF-I) receptor has emerged as a promising therapeutic target for refractory patients. However, the relationship between activation of growth hormone (GH)/IGF-I receptor signaling and development or exacerbation of thyroid ophthalmopathy has not been elucidated. Herein we describe a case that provides further clarification into the association between thyroid-related ophthalmopathy and GH/IGF-I receptor signaling. CASE PRESENTATION: A 62-year-old Japanese female diagnosed with thyroid-related ophthalmopathy was admitted to Kurume University Hospital. She had received daily administration of GH subcutaneously for severe GH deficiency; however, serum IGF-I levels were greater than + 2 standard deviation based on her age and sex. She exhibited mild thyrotoxicosis and elevation in levels of TSH-stimulating antibody. Discontinuation of GH administration attenuated the clinical activity scores of her thyroid-related ophthalmopathy. Additionally, concomitant use of glucocorticoid and radiation therapies resulted in further improvement of thyroid-related ophthalmopathy. The glucocorticoid administration was reduced sequentially, followed by successful termination. Thereafter, the patient did not undergo recurrence of thyroid-related ophthalmopathy and maintained serum IGF-I levels within normal physiological levels. CONCLUSIONS: We describe here a case in which development of thyroid-related ophthalmopathy occurred upon initiation of GH administration. GH/IGF-I signaling was highlighted as a risk factor of developing thyroid-related ophthalmopathy. Additionally, aberrant TSH receptor expression was suggested to be a primary pathophysiological mechanism within the development of thyroid-related ophthalmopathy. Physicians should be aware of the risks incurred via GH administration, especially for patients of advanced age, for induction of thyroid-related ophthalmopathy.

Pasireotide-induced hyperglycemia in a patient with Cushing's disease: Potential use of sodium-glucose cotransporter 2 inhibitor and glucagon-like peptide-1 receptor agonist for treatment.

Pasireotide improves hypercortisolemia and induces hyperglycemia via somatostatin receptor type-5 stimulation. GLP-1RA and SGLT2 inhibitor potentially help regulate hyperglycemia in patients with Cushing's disease, especially after pasireotide administration.

Accelerative effects of carbazole-type alkaloids from Murraya koenigii on neurite outgrowth and their derivative's in vivo study for spatial memory.

Murraya koenigii is a medicinal plant that contains several carbazole-type alkaloids as its characteristic constituents. Blood-brain barrier permeable constituents of M. koenigii accelerated neurite outgrowth in PC-12 cells. Nine compounds were isolated from M. koenigii and their effects on neurite outgrowth were examined. Murrayamine-E (8) at 10 µM showed significant effect. Focusing on the carbazole skeleton, we synthesized derivatives to attenuate cytotoxicity. 9-Benzyl-9H-carbazol-4-ol (15) exhibited strong neurite outgrowth accelerative effect. In addition, the novel object recognition test and the Morris water maze test were performed to evaluate memory improvement of 15 in APdE9 mice. Compound 15 tended to improve spatial memory in the Morris water maze test. These results suggest that carbazole derivative 15 would be a seed compound for Alzheimer's disease drug.

BBB-permeable aporphine-type alkaloids in Nelumbo nucifera flowers with accelerative effects on neurite outgrowth in PC-12 cells.

Blood-brain barrier (BBB)-permeable components in the methanolic extract of Nelumbo nucifera flowers showed accelerative effects on neurite outgrowth in PC-12 cells. Among the constituents isolated from N. nucifera flowers in our previous study, aporphine-type alkaloids, lirinidine, asimilobine, N-methylasimilobine, and pronuciferine, showed accelerative effects. Lirinidine, N-methylasimilobine, and an alkaloid-rich diethyl ether fraction at low concentrations increased the expression of mRNAs coding for TrkA, Vav3, and Rac1. In addition, good permeability of asimilobine and N-methylasimilobine was confirmed using an in vitro BBB model. Asimilobine and N-methylasimilobine are considered to be suitable as seed compounds of drugs for Alzheimer's disease, because of their activity and BBB permeability.

Comparison of lawsone contents among Lawsonia inermis plant parts and neurite outgrowth accelerators from branches.

Lawsonia inermis L. (Lythraceae) is cultivated in many countries, including Japan, China, India and Egypt. Its leaves are well known as hair dye and exhibit antibacterial, anticancer, antifungal and anticonvulsant activities. However, there are few reports on its branches. 2-Hydroxy-1,4-naphthoquinone (lawsone) is a characteristic compound in its leaves. However, it remains to be clarified whether lawsone is present in other plant parts or not. In this study, we measured lawsone contents in the extracts of L. inermis flowers, leaves and branches by HPLC with tandem mass spectrometry. The extracts of L. inermis flowers, leaves and branches contained 116.9, 486.2 and 5.4 µg/g lawsone, respectively. Lawsone content was much lower in branches than the other plant parts. Next, in order to identify the biological constituents in the branches, we isolated nine known compounds and examined their effects on neurite outgrowth in PC12 cells. Among the constituents isolated, 2-[4-(3-hydroxypropyl)-2-methoxyphenoxy]-propane-1,3-diol (1) and quercetin 7-O-ß-D-glucopyranoside (8) showed accelerative effects on neurite outgrowth in PC12 cells.

New potent accelerator of neurite outgrowth from Lawsonia inermis flower under non-fasting condition.

The methanolic extract of Lawsonia inermis L. (henna) showed accelerative effects on nerve growth factor-induced neurite outgrowth in PC12 cells under non-fasting conditions. To elucidate the active constituents responsible for the neuronal differentiation, we conducted a search of the constituents and examined their accelerative effects on neurite outgrowth in PC12 cells. We isolated a new acetophenone glycoside, inermioside A, which exerted a significant accelerative effect on neurite outgrowth. We also confirmed the activities of nine known compounds, including quercetin and lalioside. In addition, we found that quercetin, one of the active constituents, increased Vav3 mRNA expression.

Chemical structures of constituents from the whole plant of Bacopa monniera.

Two new dammarane-type triterpene oligoglycosides, bacomosaponins A and B, and three new phenylethanoid glycosides, bacomosides A, B1, and B2, were isolated from the whole plant of Bacopa monniera Wettst. The chemical structures of the new constituents were characterized on the basis of chemical and physicochemical evidence. In the present study, bacomosaponins A and B with acyl groups were obtained from the whole plant of B. monniera. This is the first report of acylated dammarane-type triterpene oligoglycosides isolated from B. monniera. In addition, dammarane-type triterpene saponins significantly inhibited the aggregation of 42-mer amyloid ß-protein.

γ-Lactam alkaloids from the flower buds of daylily.

Four new alkaloids, hemerocallisamines IV-VII, were isolated from the methanol extract of flower buds of daylily. The chemical structures of the new compounds were elucidated on the basis of chemical and physicochemical evidence. The absolute stereochemistry of the hemerocallisamines IV-VI was elucidated by the application of the modified Mosher's method, HPLC analysis, and optical rotation. In the present study, the isolated alkaloids significantly inhibited the aggregation of Aß42 in vitro. This is the first report about bioactive alkaloids with a γ-lactam ring from daylily. In addition, isolated nucleosides showed accelerative effects on neurite outgrowth under the non-fasting condition.