Recent Advances in Molecular Pathways and Therapeutic Implications Targeting Mitochondrial Dysfunction for Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder which leads to mental deterioration due to aberrant accretion of misfolded proteins in the brain. According to mitochondrial cascade hypothesis, mitochondrial dysfunction is majorly involved in the pathogenesis of AD. Many drugs targeting mitochondria to treat and prevent AD are in different phases of clinical trials for the evaluation of safety and efficacy as mitochondria are involved in various cellular and neuronal functions. Mitochondrial dynamics is regulated by fission and fusion processes mediated by dynamin-related protein (Drp1). Inner membrane fusion takes place by OPA1 and outer membrane fusion is facilitated by mitofusin1 and mitofusin2 (Mfn1/2). Excessive calcium release also impairs mitochondrial functions; to overcome this, calcium channel blockers like nilvadipine are used. Another process acting as a regulator of mitochondrial function is mitophagy which is involved in the removal of damaged and non-functional mitochondria however this process is also altered in AD due to mutations in Presenilin1 (PS1) and Amyloid Precursor Protein (APP) gene. Mitochondrial dynamics is altered in AD which led to the discovery of various fission protein (like Drp1) inhibitors and drugs that promote fusion. Modulations in AMPK, SIRT1 and Akt pathways can also come out to be better therapeutic strategies as these pathways regulate functions of mitochondria. Oxidative phosphorylation is major generator of Reactive Oxygen Species (ROS) leading to mitochondrial damage; therefore reduction in production of ROS by using antioxidants like MitoQ, Curcumin and Vitamin Eis quiteeffective.

Yogic Neti-Kriya Using Povidone Iodine: Can it have a Preventive Role Against SARS-CoV-2 Infection Gateway?

During this COVID-19 pandemic, except steroid, none of the therapeutic measures have showed any evidence of efficacy. Traditionally jala-neti using lukewarm salted water remains a yogic way of maintaining upper airway hygiene. Saline irrigation decreases the concentration of inflammatory mediators (e.g. histamine, leukotriene etc.) in nasal secretions, reduces the severity and frequency of sinusitis, reduce need of antibiotic therapy and restores competency of nasal mucosa. Jala-neti is an integral part of six cleansing techniques of yogic kriyas practised in India since thousands of years. Jala-neti can clean the upper airways, prevents colonization of infectious agents, removes foreign bodies, prevents stasis of mucous and subsequently enhances the drainage of paranasal sinuses and maintain health. Regular practice of Jala neti improves nasal symptoms and overall health status of patients with sinusitis. Jala-neti sample can even be used for COVID-19 diagnosis. Povidone iodine (PVP-I) has been utilized as a time tested antimicrobial agent with broad spectrum coverage against wide range of bacteria and viruses. Anti-SARS-CoV-2 action of PVP-I was seen at a concentration as low as 0.45%. PVP-I is generally well tolerated upto 5%, however nasal ciliotoxicity is reported at this concentration, however, this toxicity is not reported with lower concentrations(1.25% and 0.5%). So, theoretically, by using neti-kriya with povidone iodine (0.5-1%) as irrigation solution can combine and enhance the protection against COVID-19 and this can be an important armor in the fight against COVID-19. However, this hypothesis needs to be validated in real life clinical trial scenario before implementing.

Promising traditional Indian medicinal plants for the management of novel Coronavirus disease: A systematic review.

Traditional Indian medical practices (Ayurveda, Siddha, Unani, and homeopathy) are a vast reservoir of knowledge about medicinal plants. The promising pharmacological properties of these plants have paved the way for developing therapy against novel Coronavirus (CoV) infection. The current review will summarize published works of literature on the effects of traditional Indian medicinal plants against acute respiratory infection (COVID-19, SARS, Influenza, and Respiratory syncytial virus infection) and registered clinical trials of traditional Indian herbal medicines in COVID-19. The current study aims to comprehensively evaluate the data of traditional Indian medicinal plants to warrant their use in COVID-19 management. PubMed, Embase, and Cochrane databases were searched along with different clinical trial databases. A total of 22 relevant traditional Indian medicinal plants (35 relevant studies) were included in the current study having potential antiviral properties against virus-induced respiratory illness along with promising immunomodulatory and thrombolytic properties. Further, 36 randomized and nonrandomized registered clinical trials were also included that were aimed at evaluating the efficacy of herbal plants or their formulations in COVID-19 management. The antiviral, immunomodulatory, and thrombolytic activities of the traditional Indian medicinal plants laid down a strong rationale for their use in developing therapies against SARS-CoV-2 infection. The study identified some important potential traditional Indian medicinal herbs such as Ocimum tenuiflorum, Tinospora cordifolia, Achyranthes bidentata, Cinnamomum cassia, Cydonia oblonga, Embelin ribes, Justicia adhatoda, Momordica charantia, Withania somnifera, Zingiber officinale, Camphor, and Kabusura kudineer, which could be used in therapeutic strategies against SARS-CoV-2 infection.

Current status of in silico, preclinical and clinical study registries across the globe: A systematic review and meta-analysis.

INTRODUCTION: Registration of study protocols brings about transparency and traceability and the amount of publication bias can be estimated. In this study, we have collected and presented data regarding clinical study registries, preclinical, in vitro and in silico study registries across the globe. MATERIALS AND METHODS: We searched via Google Search Engine with appropriate keywords e.g. name of country (n = 198), name of continent (n = 7), registry, study registry, animal, in silico, virtual, simulation, preclinical, animal, clinical trial. The overall pooled prevalence of clinical study registries and WHO primary registries in per continent was calculated using Medcalc software. RESULTS: The overall pooled prevalence of clinical study registries were 13% in each continent. The prevalence of WHO primary study registries were 8.9% of the countries per continent. Overall, there are 17 primary registries associated with WHO ICTRP as primary registries, 2 partner registries and 6 registries are affiliated to ICMJE. However, the amount of preclinical animal study registry was quite less (n = 4). Regarding in vitro studies, only country specific in vitro fertilization registries were available, however, in other research domains, registries were absent. Only one simulation study registry was available. CONCLUSION: At priori study registration is essential to deal with selective reporting. Comparison between study protocol and final report allows us to know the protocol deviations and allows us to evaluate risk of bias and internal validity of the research findings. Although trialists are responsible for the completeness of records, yet the registries must have some measures for their periodic update and quality control of the data.

Efficacy of green tea, its polyphenols and nanoformulation in experimental colitis and the role of non-canonical and canonical nuclear factor kappa beta (NF-kB) pathway: a preclinical in-vivo and in-silico exploratory study.

NF-kB plays a major role in the aetiopathogenesis of inflammatory-colitis. In this study, we evaluated the efficacy of green tea and its polyphenols and their nanoformulation in Tri-Nitro Benzene Sulfonic acid (TNBS) induced colitis in in-vivo system (Rat) and the involvement of non-canonical and canonical NF-kB pathway in green tea mediated protection (in-silico platform). We used the Wister rat model of TNBS-induced colitis. Rats were grouped into eleven groups (six animals each) and administered vehicle (ethanol), TNBS, Epicatechin (EC), Epigallocatechin (EGC), Epicatechin-gallate (ECG), Epigallocatechin-gallate (EGCG), sulfasalazine, green tea, EGCG + sulfasalazine, nano-EGCG and nano-EGCG + sulfasalazine for 14 days after induction of colitis. Colonic tissue was evaluated for the level of malondialdehyde, myeloperoxidase activity, catalase, reduced glutathione, glutathione peroxidase, IL-6, TNF-α, IL-1ß, NF-κB and morphological and histopathological evidence of damage. In the in-silico part, molecular docking and dynamic simulation study of EGCG was done against different targets in NF-kB for detailed evaluation of the role of non-canonical and canonical NF-KB pathway. In our study, EGCG reduced colonic inflammation, markers of oxidative stress, TNF-α, NF-κB, IL-1ß and IL-6. Nano-EGCG + sulfasalazine was more efficacious when compared to EGCG + sulfasalazine. In molecular docking and molecular dynamic simulation studies, EGCG showed a good binding profile to the inhibitor binding sites of IKK-beta, IKK-alpha and NIK. Thus, it can be concluded that EGCG showed protective action in experimental colitis acting through both non-canonical and canonical NF-kB pathway. Nano-EGCG + sulfasalazine combination showed better protection than nano-EGCG alone. Communicated by Ramaswamy H. Sarma.

Virtual screening and molecular dynamics study of approved drugs as inhibitors of spike protein S1 domain and ACE2 interaction in SARS-CoV-2.

BACKGROUND: The receptor binding domain (RBD) of spike protein S1 domain SARS-CoV-2 plays a key role in the interaction with ACE2, which leads to subsequent S2 domain mediated membrane fusion and incorporation of viral RNA into host cells. In this study we tend to repurpose already approved drugs as inhibitors of the interaction between S1-RBD and the ACE2 receptor. METHODS: 2456 approved drugs were screened against the RBD of S1 protein of SARS-CoV-2 (target PDB ID: 6M17). As the interacting surface between S1-RBD and ACE2 comprises of bigger region, the interacting surface was divided into 3 sites on the basis of interactions (site 1, 2 and 3) and a total of 5 grids were generated (site 1, site 2, site 3, site 1+site 2 and site 2+site 3). A virtual screening was performed using GLIDE implementing HTVS, SP and XP screening. The top hits (on the basis of docking score) were further screened for MM-GBSA. All the top hits were further evaluated in molecular dynamics studies. Performance of the virtual screening protocol was evaluated using enrichment studies. RESULT: and discussion: We performed 5 virtual screening against 5 grids generated. A total of 42 compounds were identified after virtual screening. These drugs were further assessed for their interaction dynamics in molecular dynamics simulation. On the basis of molecular dynamics studies, we come up with 10 molecules with favourable interaction profile, which also interacted with physiologically important residues (residues taking part in the interaction between S1-RBD and ACE2. These are antidiabetic (acarbose), vitamins (riboflavin and levomefolic acid), anti-platelet agents (cangrelor), aminoglycoside antibiotics (Kanamycin, amikacin) bronchodilator (fenoterol), immunomodulator (lamivudine), and anti-neoplastic agents (mitoxantrone and vidarabine). However, while considering the relative side chain fluctuations when compared to the S1-RBD: ACE2 complex riboflavin, fenoterol, cangrelor and vidarabine emerged out as molecules with prolonged relative stability. CONCLUSION: We identified 4 already approved drugs (riboflavin, fenoterol, cangrelor and vidarabine) as possible agents for repurposing as inhibitors of S1:ACE2 interaction. In-vitro validation of these findings are necessary for identification of a safe and effective inhibitor of S1: ACE2 mediated entry of SARS-CoV-2 into the host cell.

Comparison of efficacy of diclofenac and tramadol in relieving pain in patients of acute pancreatitis: A randomized parallel group double blind active controlled pilot study.

BACKGROUND: Opioids and non steroidal anti inflammatory drugs (NSAIDs) are commonly used for pain relief in acute pancreatitis (AP). Opioids carry risk of sphincter of oddi constriction. Although diclofenac prevents post endoscopic retrograde cholangio-pancreatography (ERCP) pancreatitis, few reports of diclofenac associated AP are also present. Although, both tramadol and diclofenac are commonly used for pain relief in AP, no study has evaluated their comparative efficacy and safety. MATERIALS AND METHODS: Forty-six eligible participants were randomized to either diclofenac or tramadol. Primary objectives of our study were improvement in pain intensity on visual analogue scale (VAS pain score after 1 hr of drug administration) and number of patients requiring supplementary analgesia. The secondary objectives were total number of times of supplementary analgesia requirement, time to significant decrease (33%) in VAS pain score from baseline, number of painful days (VAS pain score >5), VAS pain score on 7th day, side effects, all cause death and complications of pancreatitis between the two groups. RESULTS: Although 46 patients were randomized, the final analysis included 41 participants. Five patients were withdrawn from the study (intubation = 3, altered sensorium = 2). No significant difference was seen in terms of VAS score after 1 hr of drug administration, number of patients requiring supplementary analgesic and number of painful days. However, time taken to significant reduction of pain was lower in the diclofenac group (p = .028). Both the agents were comparable in terms of safety. Although complications were less in the diclofenac group, the difference was not statistically significant. CONCLUSION: Both diclofenac and tramadol are equally effective in controlling pain in AP with similar safety profile. SIGNIFICANCE: There are no studies that have compared the safety and efficacy of two commonly used analgesics for pain relief in patients with AP. We found that both diclofenac and tramadol are equally effective in decreasing the pain associated with AP. There is also no significant difference in the incidence of side effects between both the groups. Hence both diclofenac and tramadol can be used safely and effectively for pain control in AP. TRIAL REGISTRATION: The trial was registered with clinical trials registry India (Number- CTRI/2018/05/014309).