Biology subjects

Kesharwani, A.

Publications and source records attributed to Kesharwani, A..

3 recordsLinked to original sources

bioRxiv2026

Dehydrozingerone mitigates energy deficits and cognitive impairments induced by cranial irradiation

Radiotherapy is widely used in the management of brain tumors; however, it is often associated with delayed adverse effects, including cognitive decline and depression-like behavior. These effects are thought to arise, in part, from suppressed hippocampal neurogenesis, altered neuronal architecture, and microglial dysfunction. Despite this, the precise mechanisms underlying irradiation-induced cognitive deficits, as well as effective therapeutic interventions, remain poorly understood. In the present study, six-month-old male mice were subjected to a single 9 Gy dose of cranial irradiation, followed by behavioral assessments several weeks post-exposure. We observed that cranial irradiation significantly impaired hippocampal-, prefrontal cortex-, and cortical-dependent memory functions. Notably, treatment with dehydrozingerone (DH), a curcumin analog (50 mg/kg, oral administration for two weeks), markedly prevented these cognitive deficits. At the molecular level, irradiation disrupted the activity of key enzymes involved in the tricarboxylic acid (TCA) cycle and the glutamate-glutamine/GABA cycle, both of which were restored following DH treatment. Furthermore, irradiation induced dysregulation of genes and proteins associated with glycolysis (Atp2b1, mt-Nd2, mt-Atp6), mitochondrial energetics (mt-Atp8, mt-Cytb), glucose transport (Slc4a5), insulin resistance (Etnppl), lipid metabolism (Pla2g3, Plin4), and inflammation (Ighg2c), all of which were significantly normalized by DH. Importantly, DH also prevented irradiation-induced loss of cell-type-specific glucose transporter expression, including GLUT3 in neurons and GLUT5 in microglia. In conclusion, our findings suggest that DH is a promising therapeutic candidate for mitigating irradiation-induced energy deficits and cognitive impairments, likely through modulation of metabolic and mitochondrial pathways.

neuroscience↗

bioRxiv2026

Cannabidiol rescues age-associated cognitive decline in mouse model

This study addresses key gaps in our understanding of the cognitive changes associated with normal brain aging and their underlying structural and functional correlates. Declining levels of brain endocannabinoids (eCB), particularly 2-arachidonoylglycerol (2-AG), are thought to contribute to age-related cognitive impairment, but the mechanisms involved remain poorly understood. Here, we show that levels of 2-AG and its synthesizing enzyme, diacylglycerol lipase- (DAGL-), are significantly reduced in the medial prefrontal cortex (mPFC) of aged mice. This decline is associated with impairments in mood and memory, as demonstrated by behavioral analyses. Immunofluorescence studies further revealed reduced expression of cannabinoid receptors CB1 and CB2 on microglia in aged brains, suggesting that diminished eCB signaling may contribute to enhanced neuroinflammation. Consistent with this idea, microglia from aged mice exhibited increased HMGB1-TLR4-NF-{kappa}B signaling, indicative of a pro-inflammatory state. LC-HR-MS analysis also showed elevated glutamate levels and reduced glutamine and GABA levels in the mPFC, linking impaired eCB signaling to excitotoxic imbalance during aging. Importantly, intraperitoneal administration of cannabidiol (CBD) to aged mice reversed mood and memory deficits, restored CB1 and CB2 receptor expression, attenuated HMGB1-TLR4-NF-{kappa}B signaling, and normalized the glutamate-glutamine/GABA balance in the mPFC. Collectively, these findings identify eCB signaling as a critical regulator of age-associated cognitive decline and support CBD as a potential therapeutic strategy to promote healthy brain aging. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=188 SRC="FIGDIR/small/711942v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@e9c9ddorg.highwire.dtl.DTLVardef@c3fbd2org.highwire.dtl.DTLVardef@c9d5eforg.highwire.dtl.DTLVardef@fc4371_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIReduction of 2-AG in the brains medial prefrontal cortex (mPFC) over time is a hallmark of cognitive decline. C_LIO_LIPro-inflammatory signalling such as HMGB1 (High Mobility Group Box 1)-TLR4 (Toll-like receptor 4)-NF-kB (Nuclear Factor kappa B) signalling are elevated in aged brain. C_LIO_LIAltered glutamine-glutamate/GABA cycle associated with reduced 2-AG levels. C_LIO_LICBD administration mitigates cognitive decline associated with aging and diminishes neuroinflammation. C_LI

neuroscience↗

bioRxiv2024

Modeling of vascular interactions in endochondral ossification using human embryonic stem cells-derived organoid on a microfluidic chip

Vascular interactions play a crucial role in embryogenesis, including skeletal development. During endochondral ossification, vascular networks are formed as mesenchymal cells condense and later invade skeletal elements to form the bone marrow. We and other groups developed a model of endochondral ossification by implanting human embryonic stem cell (hESC)-derived sclerotome into immunodeficient mice. However, in vitro models of endochondral ossification, particularly vascular interaction with mesenchymal cells at its initial stage, are yet to be established. Therefore, we developed a method to model the initial stage of endochondral ossification using a microfluidic chip-based platform, with a particular focus on the vascular interaction. On the chip, we found that the fibrin gel helped align mCherry-expressing human umbilical vein endothelial cells (HUVECs) better than the collagen-I gel, suggesting that the fibrin gel is more suitable for the formation of a vascular-like network. The perfusability of the vascular-like networks was partially confirmed using fluorescein isothiocyanate (FITC)-dextran and fluorescent microbeads. We then mixed hESC-derived sclerotome with enhanced green fluorescent protein (EGFP)-expressing HUVECs and applied this mixture on the chip. We named this mixture of cells SH organoids. The SH organoids showed superior abilities to maintain the vascular-like network, which was formed by the mCherry-expressing HUVECs, compared with the sclerotome spheroids on the chip. The EGFP-expressing HUVECs migrated from the SH organoid, formed a vascular-like networks, and partially interacted with the mCherry-expressing vascular-like networks on the chip. Histological analysis showed that SRY-box transcription factor 9 (SOX9) and type I collagen were expressed mutually exclusively in the condensed mesenchymal cells and perichondrial-like cells, respectively. This study demonstrates that our SH organoid-on-a-chip method reproduces vascular networks that are formed at the initial stage of endochondral ossification. This model may provide insights into human endochondral ossification and has potential applications in bone disease modeling and drug screening.

bioengineering↗