Circadian rhythm disruption and Alzheimer’s disease: The dynamics of a vicious cycle

All mammalian cells exhibit circadian rhythm in cellular metabolism and energetics. Autonomous cellular clocks are modulated by various pathways that are essential for robust time keeping. In addition to the canonical transcriptional translational feedback loop, several new pathways of circadian timekeeping - non-transcriptional oscillations, post-translational modifications, epigenetics and cellular signaling in the circadian clock - have been identified. The physiology of circadian rhythm is expansive, and its link to the neurodegeneration is multifactorial. Circadian rhythm disruption is prevelant in contamporary society where light-noise, shift-work, and transmeridian travel are commonplace, and is also reported from the early stages of Alzheimer's disease (AD). Circadian alignment by bright light therapy in conjunction with chronobiotics is beneficial for treating sundowning syndrome and other cognitive symptoms in advanced AD patients. We performed a comprehensive analysis of the clinical and translational reports to review the physiology of the circadian clock, delineate its dysfunction in AD, and unravel the dynamics of the vicious cycle between two pathologies. The review delineates the role of putative targets like clock proteins PER, CLOCK, BMAL1, ROR, and clock-controlled proteins like AVP, SIRT1, FOXO, and PK2 towards future approaches for management of AD. Furthermore, the role of circadian rhythm disruption in aging is delineated

Bacterial Persister Cells and Development of Antibiotic Resistance in Chronic Infections: An Update

The global issue of antimicrobial resistance poses significant challenges to public health. The World Health Organization (WHO) has highlighted it as a major global health threat, causing an estimated 700,000 deaths worldwide. Understanding the multifaceted nature of antibiotic resistance is crucial for developing effective strategies. Several physiological and biochemical mechanisms are involved in the development of antibiotic resistance. Bacterial cells may escape the bactericidal actions of the drugs by entering a physiologically dormant state known as bacterial persistence. Recent findings in this field suggest that bacterial persistence can be one of the main sources of chronic infections. The antibiotic tolerance developed by the persister cells could tolerate high levels of antibiotics and may give rise to persister offspring. These persister offspring could be attributed to antibiotic resistance mechanisms, especially in chronic infections. This review attempts to shed light on persister-induced antibiotic resistance and the current therapeutic strategies

Optimizing gefitinib nanoliposomes by Box-Behnken design and coating with chitosan: A sequential approach for enhanced drug delivery

This study aimed to improve the stability and prolonged gefitinib release from the nanoliposomes. Nanoliposomes were prepared by reverse-phase evaporation and optimized using Box-Behnken design to investigate the influence of sonication time (X1), tween 80 / soya phosphatidylcholine ratio (X2), and cholesterol / soya phosphatidylcholine ratio (X3) on nanoliposomes. Optimized nanoliposomes were quasi-spherical shaped, with a mean dimension of 93.2 nm and an encapsulation efficiency of 87.56±0.17 %. Surface decoration of the optimized batch was done using different concentrations of chitosan. The optimal chitosan concentration required to adorn the surface of nanoliposomes was 0.01 %. In comparison to unadorned nanoliposomes (82.16±0.65 %), adorned nanoliposomes (78.04±0.35 %) released the drug consistently over 24 h via Fickian diffusion. The IC50 values for surface-adorned nanoliposomes in A549 and H1299 cells were 6.53±0.75 and 4.73±0.46 µM, respectively. Cytotoxicity of the surface-decorated nanoliposomes may be due to their higher zeta potential and prolonged drug release. At 4°C, adorned and unadorned nanoliposomes are most stable. In conclusion, the developed nanoliposomes may offer a new path for melanoma clinics

Pharmacological Evaluation of Antidepressant-Like Effect of Genistein and Its Combination with Amitriptyline: An Acute and Chronic Study

The present study was designed to evaluate the acute and chronic antidepressant effect of genistein in combination with amitriptyline in mice. Animals were divided into six groups (n=6) for treatment with water, genistein, or amitriptyline, either alone or in combination for ten days. Animals were subjected to locomotor activity testing; tail suspension test (TST); and forced swim test (FST) and immobility time was recorded on day one and day ten. Acute treatment of all treatment groups did not significantly reduce the immobility time (p>0.05). Chronic treatment of combination of genistein (10 mg/kg) and amitriptyline (5 mg/kg and 10 mg/kg) significantly reduced the immobility time as compared to control group (p<0.001) and was comparable to amitriptyline alone (10 mg/kg). However, no changes in anti-immobility activity in combination of subeffective doses of genistein (5 mg/kg) and amitriptyline (5 mg/kg) were observed. Genistein at its standard dose (10 mg/kg) rendered synergistic effects in combination with subeffective dose of amitriptyline (5 mg/kg) and additive effects in combination with therapeutic dose of amitriptyline (10 mg/kg)

Emerging trends in clinical implications of bio-conjugated silver nanoparticles in drug delivery

© 2020 Elsevier B.V. From nanopharmaceutics to renewable energy, silver nanoparticles (AgNPs) present innumerable applications in the contemporary era. However, the associated toxicity to the biosystems limits their application. Effective utilization of AgNPs, therefore, requires their surface conjugation with biologically benevolent moieties that enhance the bio-acceptability of silver-based nanosystems, and supplementary functionalities for further extension of their unique applications. The clinical importance of AgNPs was established long ago, but their clinical utilization has been explored only recently with the phenomenon of bio-conjugation. The biomolecule-conjugated AgNPs present operable solutions for tedious clinical complications of the present era, such as multidrug resistance, designing of pharmaceuticals with improved bioavailability, superior drug delivery vehicles and in situ bio imaging of important metabolites that utilize the biomolecule-anchored surface engineered AgNPs. This review epigrammatically discusses some interesting clinical applications of surface conjugated AgNPs with biomolecules such as peptides, nucleic acids, amino acids and antibodies in the current nanopharmaceutical paradigm

Alzheimer's disease-like perturbations in HIV-mediated neuronal dysfunctions: understanding mechanisms and developing therapeutic strategies

Excessive exposure to toxic substances or chemicals in the environment and various pathogens, including viruses and bacteria, is associated with the onset of numerous brain abnormalities. Among them, pathogens, specifically viruses, elicit persistent inflammation that plays a major role in Alzheimer's disease (AD) as well as dementia. AD is the most common brain disorder that affects thought, speech, memory and ability to execute daily routines. It is also manifested by progressive synaptic impairment and neurodegeneration, which eventually leads to dementia following the accumulation of Aβ and hyperphosphorylated Tau. Numerous factors contribute to the pathogenesis of AD, including neuroinflammation associated with pathogens, and specifically viruses. The human immunodeficiency virus (HIV) is often linked with HIV-associated neurocognitive disorders (HAND) following permeation through the blood-brain barrier (BBB) and induction of persistent neuroinflammation. Further, HIV infections also exhibited the ability to modulate numerous AD-associated factors such as BBB regulators, members of stress-related pathways as well as the amyloid and Tau pathways that lead to the formation of amyloid plaques or neurofibrillary tangles accumulation. Studies regarding the role of HIV in HAND and AD are still in infancy, and potential link or mechanism between both is not yet established. Thus, in the present article, we attempt to discuss various molecular mechanisms that contribute to the basic understanding of the role of HIV-associated neuroinflammation in AD and HAND. Further, using numerous growth factors and drugs, we also present possible therapeutic strategies to curb the neuroinflammatory changes and its associated sequels.Peer reviewe

Combinational effect of angiotensin receptor blocker and folic acid therapy on uric acid and creatinine level in hyperhomocysteinemia-associated hypertension

© 2019 International Union of Biochemistry and Molecular Biology, Inc. Homocysteine [HSCH2CH2CH(NH2)COOH] (Hcy) is a sulfur-containing amino acid of 135.18 Da of molecular weight, generated during conversion of methionine to cysteine. If there is a higher accumulation of Hcy in the blood, that is usually above 15 µmol/L, it leads to a condition referred to as hyperhomocysteinemia. A meta-analysis of observational study suggested an elevated concentration of Hcy in blood, which is termed as the risk factors leading to ischemic heart disease and stroke. Further experimental studies stated that Hcy can lead to an increase in the proliferation of vascular smooth muscle cells and functional impairment of endothelial cells. The analyses confirmed some of the predictors for Hcy presence, such as serum uric acid (UA), systolic blood pressure, and hematocrit. However, angiotensin-converting enzyme inhibitors angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) alone are inadequate for controlling UA and creatinine level, although the addition of folic acid may be beneficial in hypertensive patients who are known to have a high prevalence of elevated Hcy. We hypothesized that combination therapy with an ARB (olmesartan) and folic acid is a promising treatment for lowering the UA and creatinine level in hyperhomocysteinemia-associated hypertension

Pharmacological Evaluation of Antidepressant-Like Effect of Genistein and Its Combination with Amitriptyline: An Acute and Chronic Study

The present study was designed to evaluate the acute and chronic antidepressant effect of genistein in combination with amitriptyline in mice. Animals were divided into six groups ( = 6) for treatment with water, genistein, or amitriptyline, either alone or in combination for ten days. Animals were subjected to locomotor activity testing; tail suspension test (TST); and forced swim test (FST) and immobility time was recorded on day one and day ten. Acute treatment of all treatment groups did not significantly reduce the immobility time ( &gt; 0.05). Chronic treatment of combination of genistein (10 mg/kg) and amitriptyline (5 mg/kg and 10 mg/kg) significantly reduced the immobility time as compared to control group ( &lt; 0.001) and was comparable to amitriptyline alone (10 mg/kg). However, no changes in anti-immobility activity in combination of subeffective doses of genistein (5 mg/kg) and amitriptyline (5 mg/kg) were observed. Genistein at its standard dose (10 mg/kg) rendered synergistic effects in combination with subeffective dose of amitriptyline (5 mg/kg) and additive effects in combination with therapeutic dose of amitriptyline (10 mg/kg)