Sanjib Bhattacharyya

Alzheimer's disease (AD) is characterized by a progressive loss of cognition and its distinct hyperphosphorylated Tau (p‐tau) pathology. Both insulin resistance(IRT) and p‐tau share a causal relationship in AD, whereas the connective mechanism between them remains largely unknown. Tau protein is considered the primary target to combat AD as loss of Tau function triggers neuronal loss in AD. In the prior report, it is observed that self‐therapeutic gold nanoparticles alleviate Tauopathy in models of AD. Gold nanoparticles (AuNPs)─polyethylene glycol 2000 (PEG₂₀₀₀)─transferrin (Tf) nanoconjugate is synthesized for passive targeting to pharmacologically regulate neuronal tau. It is observed that AuNPs─PEG₂₀₀₀─Tf decreases p‐tau while restores insulin receptor(IR) and activates protein kinase B (AKT) kinase in SHSY5Y cell overexpressing Tau. AuNPs─PEG₂₀₀₀─Tf downregulates transferrin receptor by inhibiting recombinant divalent metal transporter 1 protein, affecting Fe²⁺ accumulation. AuNPs─PEG₂₀₀₀─Tf improves learning ability of mice in okadaic‐acid‐induced, stereotaxic model in a dose‐dependent fashion compared to memantine and subsequently decreases both p‐tau and acetyl tau levels and upregulates the AKT signal. Changes in p‐tau/Tau index from mouse brain homogenate is diminished following AuNPs─PEG₂₀₀₀─Tf treatment as a desired therapeutic outcome. Given AuNPs─PEG₂₀₀₀─Tf treatment restricts pathogenic conversion of Tau (p‐tau, acetyl Tau), further investigation is warranted to bridge the connection between gold‐nanoparticle‐mediated alteration of IRT and AD progression.

Amyotrophic lateral sclerosis (ALS) is a lethal disease that involves the progressive annihilation of motor neurons. In a preclinical setting, sensitive functional testing is required to detect malfunctioning motor behavior in the SOD1^G93A transgenic mouse model of ALS. Earlier, we reported the restoration of motor processivity upon gold nano-chaperon treatment in vitro that was dampened upon the exogenous addition of proteotoxic A4V SOD1. In the present in vivo study, we evaluated the pharmacological potential of a synthesized Au-PEG nanoconjugate in transgenic SOD1^G93A mice. We found differences in the detection of the onset of symptoms and the progression of the disease upon Au-PEG treatment when assessed using behavioral tests, such as rotarod and walking tests. Additionally, the gastrocnemius muscle histopathology showed notable alteration upon Au-PEG administration. The therapeutic potential of the nanoconjugate was found to be notable, with additional survival for ∼1 week, a delayed mean age at onset, and improved rotarod performance. Furthermore, molecular docking studies reveal that the addition of the lethal A4V SOD1 mutant to the tubulin dimer has a negative impact on the binding of the kinesin motor to tubulin (K_d = 1.4 × 10⁻⁷ mol L⁻¹vs. K_d = 2.5 × 10⁻⁹ mol L⁻¹), whereas the exogenous addition of gold nanoparticles (Au NPs) to the protein complex of A4V SOD1–tubulin has a substantially positive effect on the binding affinity of kinesin to the tubulin dimer (K_d = 2.7 × 10⁻¹² mol L⁻¹), reinstating the dynamics as a result. Thus, the engineering of self-therapeutic gold nanoparticles for combinatorial therapy holds potential and, therefore, the role of Au NPs in modifying the state of ALS deserves further investigation, with the eventual aim of managing the complex disease ALS.

Neurodegenerative diseases (NDs) are characterised by progressive dysfunction of synapses, neurons, glial cells and their networks. Neurodegenerative diseases can be classified according to primary clinical features (e.g., dementia, parkinsonism, or motor neuron disease), anatomic distribution of neurodegeneration (e.g., frontotemporal degenerations, extrapyramidal disorders, or spinocerebellar degenerations), or principal molecular abnormalities. The most common neurodegenerative disorders are amyloidosis, tauopathies, a-synucleinopathy, and TAR DNA-binding protein 43 (TDP-43) proteopathy. The protein abnormalities in these disorders have abnormal conformational properties along with altered cellular mechanisms, and they exhibit motor deficit, mitochondrial malfunction, dysfunctions in autophagic–lysosomal pathways, synaptic toxicity, and more emerging mechanisms such as the roles of stress granule pathways and liquid-phase transitions. Finally, for each ND, microglial cells have been reported to be implicated in neurodegeneration, in particular, because the microglial responses can shift from neuroprotective to a deleterious role. Growing experimental evidence suggests that abnormal protein conformers act as seed material for oligomerization, spreading from cell to cell through anatomically connected neuronal pathways, which may in part explain the specific anatomical patterns observed in brain autopsy sample. In this review, we mention the human pathology of select neurodegenerative disorders, focusing on how neurodegenerative disorders (i.e., Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and multiple sclerosis) represent a great healthcare problem worldwide and are becoming prevalent because of the increasing aged population. Despite many studies have focused on their etiopathology, the exact cause of these diseases is still largely unknown and until now with the only available option of symptomatic treatments. In this review, we aim to report the systematic and clinically correlated potential biomarker candidates. Although future studies are necessary for their use in early detection and progression in humans affected by NDs, the promising results obtained by several groups leads us to this idea that biomarkers could be used to design a potential therapeutic approach and preclinical clinical trials for the treatments of NDs.

Physical stressors play a crucial role in the progression of irritable bowel syndrome (IBS). Here we report a heterogeneous physical stress induced IBS rat model which shows depression and subsequent modulation of IBS by oral treatment of thymol. Oral administration of Thymol reduces the stress induced IBS significantly altering the stress induced gastrointestinal hypermotility, prolonged the whole gut transit time, and increased abdominal withdrawal reflex suggesting gastrointestinal hypermotility and visceral discomfort caused the onset of depression. Immunohistochemical analysis in small intestine and colon of rats shows the decreased 5-HT_3AR expression level while thymol treatment normalized the 5-HT_3AR expression in the stressed rats. Molecular docking studies showed that thymol competes with endogenous serotonin and an antagonist, Tropisetron and all have similar binding energies to 5-HT_3AR. Molecular dynamics simulations revealed that thymol and tropisetron might have similar effects on 5-HT_3AR. Our study suggest that thymol improves IBS symptoms through 5-HT_3AR, could be useful for the treatment of IBS.

Objective: To determine the impact of smoking status in the prediction of stroke using CHADS₂ and CHA₂DS₂-VASc schemes. Methods: Five hundred twenty-eight consecutive patients with arrhythmic symptoms and without any documented arrhythmia from Queen Mary Hospital, Hong Kong, were followed up to determine the incidence of ischemic stroke, new-onset atrial fibrillation (AF), or all-cause mortality. Smoking status was classified into nonsmokers and smokers. The pairwise comparisons of C-statistics for outcomes were performed. Results: During a median follow-up period of 6.2 years, 65 (12.3%) individuals developed ischemic stroke. Smokers experienced higher annual incidence of stroke, a new-onset AF, and all-cause death compare to nonsmokers, with corresponding hazard ratio (HR) of stroke, AF, and all-cause death being 2.51 (95% confidence intervals, CI 1.36als, CIse death bein 1.15a3.24), and 1.95 (95% CI 1.161.95 (95% CIath being 2.51 (95% confidence corr₂ and CHA₂DS₂-VASc for stroke were 0.60 (95% CI 0.51 for stp = 0.09) and 0.59 (95% CI 0.50 (95%, p = 0.15) respectively, whereas the C-statistics of CHADS₂ and CHA₂DS₂-VASc were 0.66 (95% CI 0.61 were 0p = 0.005), 0.75 (95% CI 0.7 CI 0.7p < 0.0001), respectively among nonsmokers. After incorporating smoking, both the CHADS₂-smoking and CHA₂DS₂-VASc-smoking achieved better C-statistics for new-onset ischemic stroke prediction superior to baseline score systems in male groups. Conclusion: Cigarette smoking status has impact on stroke stratification using CHADS₂ and CHA₂DS₂-VASc scheme. The discrimination of the CHADS₂ and CHA₂DS₂-VASc scheme for stroke can be significantly improved if smoking status is additionally considered.

Tauopathy is a complex disorder associated at the junction of several other pathologies. Intrinsically disordered tau protein remains therapeutically challenging due to its undruggable nature and is a possible reason for monumental failure of several tau‐based therapies. Herein, nanogold remodeled tau is reported as a pseudo‐nanochaperon and shows therapeutic benefit by passive targeting in transgenic tau P301L mutant mice. Treatment with nanogold polyethylene glycol (Au‐PEG) conjugate moderately improves the learning ability of the tau P301L mice that corroborates with diminished phosphorylated tau burden. Circulating total tau level that acts in a prion fashion is significantly reduced upon Au‐PEG treatment. Similarly, a high level of tau is found in macaque monkey serum and Au‐PEG inhibits amyloidosis of Alzheimer's patients and primate's serum samples ex vivo. Addtionally, brain MRI of an old aged macaque monkey shows the decrease of grey matter, which correlates with mutual loss of grey matter upon progressive dementia as reported. Au‐PEG tunes tau and other circulating pro‐dementia factors that are present in human AD serum, by remodeling the protein and repairing aberrant proteostasis. Alteration of proteotoxic tau function by nanogold as a kinetic stablizer holds translational potential to combat socially challenging dementia.

Methicillin-resistant Staphylococcus aureus (MRSA) has been well-recognized as one of the most common multiresistant bacteria threatening human health. Broad-spectrum recognition of multiple MRSA strains can meet the urgent demands for efficient diagnosis and subsequent decision of relevant treatment of MRSA-induced infections. Here, recombinant cell-binding domain (CBD) and green fluorescent protein-fused CBD of MRSA bacteriophage were expressed in soluble form. Distinct from the strain-specific MRSA bacteriophage, both recombinant CBD proteins displayed broad-spectrum recognition capability toward all five staphylococcal cassette chromosome mec types of MRSA. Furthermore, they did not display any lytic activity toward the host bacteria, which facilitated the capture of whole MRSA cells with ideal flexibility for downstream manipulation and tracing. For demonstration of their application potential, a flow cytometry method employing the recombinant CBD proteins as the recognition agents was established to detect MRSA within a dynamic range of 1.5 × 10² to 1.5 × 10⁶ cfu mL^–1. The method can exclude potential interference from methicillin-sensitive Staphylococcus aureus strains and other bacterial species. The recombinant CBD proteins were also successfully employed in antibiotic susceptibility testing of MRSA with a microplate-based method. The obtained results were consistent with those by the standard broth microdilution method. The satisfying results demonstrated their great application potential in clinical diagnosis and treatment of MRSA-induced infections.