Vivek Kumar Pandey

Background: Hereditary spastic paraplegia (HSP) is a rare genetic neurodegenerative disorder characterized by progressive lower-extremity spasticity, weakness, and gait impairment resulting from corticospinal tract degeneration. With no disease-modifying therapies available, novel strategies to improve motor function are needed. Transcutaneous spinal cord stimulation (tSCS) is a non-invasive neuromodulation approach that may improve motor function but has not been prospectively evaluated in HSP. This study will assess the safety, feasibility, and preliminary efficacy of repeated tSCS in adults with HSP. Methods and analysis: This prospective, open-label, single-arm pilot trial will enroll 15 adults with HSP. Participants will receive 16 tSCS sessions over 8 weeks targeting the lower thoracic and upper lumbar vertebral levels, followed by an 8-week follow-up. Outcomes will assess gait performance, spasticity, disease severity, mobility, walking endurance, muscle strength, 3D gait biomechanics, electromyography, and HSP-specific patient-reported measures. Exploratory blood-based neurodegenerative biomarkers and metabolomic and lipidomic profiles will investigate potential biological correlates of treatment response. Assessments will occur at baseline and weeks 4, 8, and 16. Feasibility and safety will be evaluated through recruitment, retention, adherence, and adverse events.

The current issue of the Journal of Cellular Signaling brings together a diverse set of studies that collectively broaden our understanding of cellular communication, from canonical biochemical pathways to emergent bioelectric and metabolic signaling systems. This editorial review synthesizes the major findings and conceptual advances presented in Volume 6 Issue 3, highlighting the converging trends that redefine how we view signaling as an integrative, dynamic, and multi-dimensional process. The featured articles span cancer biology, virology, neural differentiation, and cellular homeostasis, each illustrating how signaling mechanisms adapt, evolve, and cross disciplinary boundaries.

Aims/hypothesis Women with prior gestational diabetes mellitus (GDM) have higher incidence of age-associated diseases, including type 2 diabetes, CVD and cognitive impairment. Human studies cannot readily determine whether GDM causes these conditions or the underlying mechanisms. Here we used a well-validated rat model of GDM to address these questions. Methods Rats with beta cell-specific expression of human amylin, a pancreatic hormone, were used as a GDM model. Five-month-old female rats were randomly assigned to no-pregnancy, one-pregnancy and two-pregnancies experimental groups. GTTs and transthoracic echocardiography were performed at baseline and during the postpartum period. At 18 months of age, the novel object recognition test was administered, followed by euthanasia and organ collection. Results All female rats developed glucose intolerance and showed cardiac remodelling and impaired left ventricular relaxation with ageing. Glucose intolerance was exacerbated in rats with prior GDM pregnancies compared with nulliparous rats, with significant differences starting at 9 months of age. However, blood glucose levels were comparable in the three groups during the course of the study. Rats with two GDM-complicated pregnancies had increased left ventricular mass compared with the other groups following the second pregnancy and until the end of the study. At 18 months of age, rats with prior GDM pregnancies presented aggravated demyelination, particularly in the hippocampus and mid-brain region, oxidative stress and neuroinflammation, and had a lower recognition index in the novel object recognition test compared with nulliparous rats. Higher parity exacerbated these effects. Shorter telomeres and reduced mitochondrial DNA content, two hallmarks of biological ageing, were found in the brain, heart and pancreas of rats with prior GDM. Conclusions/interpretation These findings support the concept that GDM is a sex-specific risk factor for ageing-related diseases, and point to accelerated cellular ageing as a contributing mechanism. Data availability Cardiac echocardiography and GTT data are available at Dataverse under the identifier https://doi.org/10.7910/DVN/R2HITG Graphical Abstract

Population-based studies identified an association between a prior pregnancy complicated by gestational diabetes mellitus (GDM) and cardiac hypertrophy and dysfunction later in life. It is however unclear whether GDM initiates this phenotype and what are the underlying mechanisms. We addressed these questions by using female rats that express human amylin (HIP rats) as a GDM model and their wild-type (WT) littermates as the normal pregnancy model. Pregnant and two months postpartum HIP females had increased left-ventricular mass and wall thickness compared to non-pregnant HIP females, which indicates the presence of concentric hypertrophy. These parameters were unchanged in WT females during both pregnancy and postpartum periods. Hypertrophic Ca²⁺-dependent calcineurin/NFAT signaling was stimulated two months after giving birth in HIP females but not in the WT. In contrast, the CaMKII/HDAC hypertrophy pathway was active immediately after giving birth and returned to the baseline by two months postpartum in both WT and HIP females. Myocytes from two months postpartum HIP females exhibited slower Ca²⁺ transient relaxation and higher diastolic Ca²⁺ levels, which may explain calcineurin activation. No such effects occurred in the WT. These results suggest that a GDM-complicated pregnancy accelerates the development of pathological cardiac remodeling likely through activation of calcineurin/NFAT signaling.

Endoplasmic reticulum (ER) dysfunction plays a prominent role in the pathophysiology of diabetic nephropathy (DN). This study aimed to investigate the novel role of Naringenin (a flavanone mainly found in citrus fruits) in modulating ER stress in hyperglycemic NRK 52E cells and STZ/nicotinamide induced diabetes in Wistar rats. The results demonstrated that Naringenin supplementation downregulated the expression of ER stress marker proteins, including p-PERK, p-eIF2α, XBP1s, ATF4 and CHOP during hyperglycemic renal toxicity in vitro and in vivo. Naringenin abrogated hyperglycemia-induced ultrastructural changes in ER, evidencing its anti-ER stress effects. Interestingly, treatment of Naringenin prevented nuclear translocation of ATF4 and CHOP in hyperglycemic renal cells and diabetic kidneys. Naringenin prevented apoptosis in hyperglycemic renal cells and diabetic kidney tissues by downregulating expression of apoptotic marker proteins. Further, photomicrographs of TEM confirmed anti-apoptotic potential of Naringenin as it prevented membrane blebbing and formation of apoptotic bodies in hyperglycemic renal cells. Naringenin improved glucose tolerance, restored serum insulin level and reduced serum glucose level in diabetic rats evidencing its anti-hyperglycemic effects. Histopathological examination of kidney tissues also confirmed prevention of damage after 28 days of Naringenin treatment in diabetic rats. Additionally, Naringenin diminished oxidative stress and improved antioxidant defense response during hyperglycemic renal toxicity. Taken together, our study revealed a novel role of Naringenin in ameliorating ER stress during hyperglycemic renal toxicity along with prevention of apoptosis, cellular and tissue damage. The findings suggest that prevention of ER stress can be exploited as a novel approach for the management of hyperglycemic nephrotoxicity.

Impaired PI3K/Akt signaling (insulin resistance) and poor glycemic control (hyperglycemia) are the major risk factors involved in the progression of diabetic nephropathy (DN). This study was designed to identify factors influencing cell survival during DN. We found that high glucose exposure in renal proximal tubular cells (NRK52E) upregulated PHLPP1, an Akt phosphatase (Ser473), causing suppression in Akt and IGF1β phosphorylation leading to inhibition in insulin signaling pathway. Results demonstrate that sustained activation of PHLPP1 promoted nuclear retention of FoxO1 by preventing its ubiquitination via Mdm2, an Akt/ Nrf2-dependent E3 ligase. Thus, enhanced FoxO1 nuclear stability caused aberration in renal gluconeogenesis and activated apoptotic cascade. Conversely, gene silencing of PHLPP1-enhanced Nrf2 expression and attenuated FoxO1 regulated apoptosis compared to hyperglycemic cells. Mechanistic aspects of PHLPP1–Nrf2/FoxO1 signaling were further validated in STZ-nicotinamide-induced type 2 diabetic Wistar rats. Importantly, we observed via immunoblotting and dual immunocytochemical studies that treatment of Morin (2′,3,4′,5,7-Pentahydroxyflavone) during diabetes significantly augmented FoxO1 nuclear exclusion, resulting in its ubiquitination via Akt–Nrf2/Mdm2 pathway. Furthermore, lowering of PHLPP1 expression by Morin also prevented FoxO1/Mst1-mediated apoptotic signaling in vitro and in vivo. Morin treatment under the experimental conditions, effectively decreased blood glucose levels, ameliorated insulin resistance, alleviated oxidative stress and attenuated renal apoptosis in diabetic rats comparable to metformin thereby exhibiting tremendous potential against renal complications of diabetes. These novel results further acclaim that inhibition of PHLPP1/FoxO1–Mdm2 axis is critical in the pathogenesis of diabetic nephropathy.