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Ashwani Sharma,1 Tarun Virmani,1 Anjali Sharma,2 Vaishnavi Chhabra,1 Girish Kumar,1 Kamla Pathak,3 Abdulsalam Alhalmi4 1School of Pharmaceutical Sciences, MVN University, Palwal, Haryana, 121105, India; 2Freelancer, Pharmacovigilance Expert, Uttar Pradesh, India; 3Faculty of Pharmacy, Uttar Pradesh University of Medical Sciences, Uttar Pradesh, 206130, India; 4Department of Pharmaceutical Science, College of Pharmacy, Aden University, Aden, YemenCorrespondence: Abdulsalam Alhalmi, Department of Pharmaceutical Science, College of Pharmacy, Aden University, Aden, Yemen, Email aa.abdulla@pharm.adenuniv.comAbstract: Dipeptidyl-peptidase-4 (DPP-4) is an enzyme having various properties and physiological roles in lipid accumulation, resistance to anticancer agents, and immune stimulation. DPP-4 includes membrane-bound peptidases and is a kind of enzyme that cleaves alanine or proline-containing peptides such as incretins, chemokines, and appetite-suppressing hormones (neuropeptide) at their N-terminal dipeptides. DPP-4 plays a role in the final breakdown of peptides produced by other endo and exo-peptidases from nutritious proteins and their absorption in these tissues. DPP-4 enzyme activity has different modes of action on glucose metabolism, hunger regulation, gastrointestinal motility, immune system function, inflammation, and pain regulation. According to the literature survey, as DPP-4 levels increase in individuals with liver conditions, up-regulation of hepatic DPP-4 expression is likely to be the cause of glucose intolerance or insulin resistance. This review majorly focuses on the cleavage of alanine or proline-containing peptides such as incretins by the DPP-4 and its resulting conditions like glucose intolerance and cause of DPP-4 level elevation due to some liver conditions. Thus, we have discussed the various effects of DPP-4 on the liver diseases like hepatitis C, non-alcoholic fatty liver, hepatic regeneration and stem cell, hepatocellular carcinoma, and the impact of elevated DPP-4 levels in association with liver diseases as a cause of glucose intolerance and their treatment drug of choices. In addition, the effect of DPP-4 inhibitors on obesity and their negative aspects are also discussed in brief.Keywords: DPP-4, insulin, incretins, glucose intolerance, liver diseases, sitagliptin, DPP-4 inhibitors

The rising instances of drug resistance in Mycobacterium tuberculosis strains pose a significant global health challenge. Conventional tuberculosis (TB) treatments, which typically involve multiple antibiotics, face hurdles like drug resistance, reduced effectiveness, and heightened toxicity. Consequently, there is a pressing need for innovative anti-TB agents with new modes of action. Decaprenyl-phosphoryl-β-d-ribose 2′-epimerase 1(DprE1), a crucial enzyme in Mycobacterium tuberculosis, plays a vital role in cell wall biosynthesis – a critical aspect for the bacterium’s survival. Building on the success of diarylquinolines like bedaquiline, targeting DprE1 presents a promising avenue for developing anti-TB drugs, especially against drug-resistant strains. Our research focused on discovering novel DprE1 inhibitors using a ligand-based drug design strategy, starting with the established non-covalent inhibitor Ty38c. We assembled a library of 16 molecules, modifying them based on factors like drug-like properties, chemical accessibility, and synthetic feasibility. Molecular docking analyses of this library identified three molecules with binding affinities comparable to Ty38c. Among these, KS_QD_05 and KS_QD_04 are promising candidates, which were further validated through molecular dynamics simulation studies where root-mean-square deviation (RMSD) values of all three complexes reached a plateau, measuring around 0.3 nm, indicating that the apoprotein and all complexes stabilized during the simulation. The ligands KS_QD_04 and KS_QD_05 displayed significantly stable deviation. KS_QD_05 reached about 0.1 nm equilibrium value. However, the ligand KS_QD_04 reached an RMSD value of 0.17 nm and showed distress at 70 nm. KS_QD_04 and KS_QD_05 showed an average value of 1-3 H-bond interaction and regarding the RMSF values, both the compounds showed fluctuations less than 0.5 nm in the case of Mtb. DprE1 enzyme. This indicates the potential of both compounds to become lead compounds in the pursuit of DprE1 inhibitors for TB treatment.

In this review, we discuss first an example of one of the symptoms of PD, freezing of gait (FOG), then we will turn to the use of deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN) to treat PD, and the original studies that led to identification of the PPN as one source of locomotor control and why stimulation frequency is critical, and then describe the intrinsic properties of PPN neurons that require beta/gamma stimulation in order to fully activate all types of PPN neurons. Finally, we will describe recent findings on the proteomic and molecular consequences of gamma band activity in PPN neurons, with emphasis on the potential neuroepigenetic sequelae. These considerations will provide essential information for the appropriate refining and testing of PPN DBS as a potential therapy for PD, as well as alternative options. [ABSTRACT FROM AUTHOR]

Introduction: Tandem gait performance reportedly predicts fall risk in people with Parkinson's disease (PwPD) and help distinguish PwPD from atypical parkinsonism. In a cross-sectional study, we previously showed that tandem gait step-width widens with increasing Hoehn and Yahr (H&Y) staging scores. In this longitudinal study, we aimed to determine if progression in tandem gait deficits is dependent on disease severity in PwPD., Methods: Participants underwent an instrumented tandem gait measurement every 6 months for at least 2 years. The mean and variability of 4 tandem gait parameters were calculated at each visit: step-width, step-length, step-time, and step-velocity. The change in these parameters over time for 3 H&Y groups (stage 1, 2 and 2.5+) compared to aging controls was determined using a random coefficients regression model. The annual percent change in tandem gait parameters was correlated with initial disease features using Kendall's τ B ., Results: 66 participants were analyzed (46 PD, 20 controls). Mean step-width increased over time in an H&Y stage-dependent manner, with H&Y 2 and H&Y 2.5+ experiencing increases of 6% and 10% per year (p = 0.001 and 0.024 respectively). Annual percent-change in step-width was correlated with initial motor Unified Parkinson's Disease Rating Scale (UPDRS) scores (Kendall's τ B  = 0.229), total UPDRS scores (τ B  = 0.249), H&Y scores (τ B  = 0.266) and inversely correlated with Montreal Cognitive Assessment (MoCA) scores (τ B  = -0.209; ps ≤ 0.019)., Conclusion: Tandem gait step-width widens over time more rapidly in more severely affected PD patients. These results suggest that tandem gait should be routinely clinically evaluated and considered in the management of imbalance in PwPD., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Tuhin Virmani reports financial support was provided by National Institute of General Medical Sciences. Tuhin Virmani reports financial support was provided by Parkinson's Foundation Inc. Tuhin Virmani reports financial support was provided by University of Arkansas for Medical Sciences. Reid D. Landes reports financial support was provided by National Center for Advancing Translational Sciences. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Mitochondria, traditionally known as cellular powerhouses, now emerge as critical signaling centers influencing cancer progression and drug resistance. The review highlights the role that apoptotic signaling, DNA mutations, mitochondrial dynamics and metabolism play in the development of resistance mechanisms and the advancement of cancer. Targeted approaches are discussed, with an emphasis on managing mitophagy, fusion, and fission of the mitochondria to make resistant cancer cells more susceptible to traditional treatments. Additionally, metabolic reprogramming can be used to effectively target metabolic enzymes such GLUT1, HKII, PDK, and PKM2 in order to avoid resistance mechanisms. Although there are potential possibilities for therapy, the complex structure of mitochondria and their subtle role in tumor development hamper clinical translation. Novel targeted medicines are put forth, providing fresh insights on combating drug resistance in cancer. The study also emphasizes the significance of glutamine metabolism, mitochondrial respiratory complexes, and apoptotic pathways as potential targets to improve treatment effectiveness against drug-resistant cancers. Combining complementary and nanoparticle-based techniques to target mitochondria has demonstrated encouraging results in the treatment of cancer, opening doors to reduce resistance and enable individualized treatment plans catered to the unique characteristics of each patient. Suggesting innovative approaches such as drug repositioning and mitochondrial drug delivery to enhance the efficacy of mitochondria-targeting therapies, presenting a pathway for advancements in cancer treatment. This thorough investigation is a major step forward in the treatment of cancer and has the potential to influence clinical practice and enhance patient outcomes., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Impaired motor and cognitive function can make travel cumbersome for People with Parkinson's disease (PwPD). Over 50% of PwPD cared for at the University of Arkansas for Medical Sciences (UAMS) Movement Disorders Clinic reside over 30 miles from Little Rock. Improving access to clinical care for PwPD is needed., Objective: To explore the feasibility of remote clinic-to-clinic telehealth research visits for evaluation of multi-modal function in PwPD., Methods: PwPD residing within 30 miles of a UAMS Regional health center were enrolled and clinic-to-clinic telehealth visits were performed. Motor and non-motor disease assessments were administered and quantified. Results were compared to participants who performed at-home telehealth visits using the same protocols during the height of the COVID pandemic., Results: Compared to the at-home telehealth visit group ( n = 50), the participants from regional centers ( n = 13) had similar age and disease duration, but greater disease severity with higher total Unified Parkinson's disease rating scale scores ( Z = -2.218, p = 0.027) and lower Montreal Cognitive Assessment scores ( Z = -3.350, p < 0.001). Regional center participants had lower incomes (Pearson's chi = 21.3, p < 0.001), higher costs to attend visits (Pearson's chi = 16.1, p = 0.003), and lived in more socioeconomically disadvantaged neighborhoods ( Z = -3.120, p = 0.002). Prior research participation was lower in the regional center group (Pearson's chi = 4.5, p = 0.034) but both groups indicated interest in future research participation., Conclusions: Regional center research visits in PwPD in medically underserved areas are feasible and could help improve access to care and research participation in these traditionally underrepresented populations., Competing Interests: The authors have no conflicts of interest to disclose in relation to this work. Tuhin Virmani received grant support from the Parkinson’s Foundation (PF-JFA-1935), Translational Research Institute at the University of Arkansas for Medical Sciences (UAMS) through the National Center for Advancing Translational Sciences of the National Institutes of Health (Award number UL1TR003107) and the UAMS Clinician Scientist program, as well as salary support from the University of Arkansas for Medical Sciences. Mitesh Lotia received salary support from the University of Arkansas for Medical Sciences. Aliyah Glover received salary support from the above grants to TV. Lakshmi Pillai received salary support from the above grants to TV. Aaron Kemp received salary support from UAMS and the grants to TV and LLP and is a minority shareholder in NeuroComp Systems, Inc. Phillip Farmer received salary support from UAMS. Shorabuddin Syed received salary support from grants to FP. Horace J. Spencer received salary support from grants to TV, the National Institutes of Health, the Veterans Administration, and UAMS. Linda Larson-Prior received salary support from UAMS, the National Institutes of Health, and the Arkansas Children’s Nutrition Center (USDA-ARS) Fred Prior served as a member of the External Advisory Committees of the Arkansas Integrative Metabolic Research Center COBRE grant and the Imaging Data Commons contract from the National Cancer Institute to Harvard University. He received grant funding from the NCI, NSF, and PCORI grants. He also received contract funding through Leidos Biomedical Research for the NCI Cancer Imaging Archive. He served as core director for the NCATS CTSA award to UAMS and the Data Coordinating and Operations Center for the IDeA states Pediatric Clinical Trials Network. He also received salary support from UAMS., (© The Author(s) 2024.)

Competing Interests: Competing interests: JHG has received consultant fees from Abbott Medical, Saluda, and Stratus Medical. JHG receives research support from the Mainstay Medical and SPR Therapeutics. EP has received consultant fees from Abbott/St Jude Medical, Medtronic Neuromodulation, Nevro, Neuros Medical, Saluda, Vertos, and ReNeuron. EP receives research and education support from Nevro, Neuros Medical, ReNeuron, Saluda, and Medtronic Neuromodulation. EP has stock options in SynerFuse. LRT-M, CW, DJ, and GAB wish to declare no competing interests or financial disclosures.

Apigenin, a potent natural flavonoid, has emerged as a key therapeutic agent due to its multifaceted medicinal properties in combating various diseases. However, apigenin's clinical utility is greatly limited by its poor water solubility, low bioavailability and stability issues. To address these challenges, this review paper explores the innovative field of nanotechnology-based delivery systems, which have shown significant promise in improving the delivery and effectiveness of apigenin. This paper also explores the synergistic potential of co-delivering apigenin with conventional therapeutic agents. Despite the advantageous properties of these nanoformulations, critical challenges such as scalable production, regulatory approvals and comprehensive long-term safety assessments remain key hurdles in their clinical adoption which must be addressed for commercialization of apigenin-based formulations.

Upper-limb bradykinesia occurs early in Parkinson's disease (PD) and bradykinesia is required for diagnosis. Our goal was to develop, implement and validate a game "walking" a frog through a maze using bimanual, alternating finger-tapping movements to provide a salient, objective, and remotely monitorable method of tracking disease progression and response to therapy in PD. Twenty-five people with PD and 16 people without PD participated. Responses on 5 different mazes were quantified and compared to spatiotemporal gait parameters and standard disease metrics in these participants. Intertap interval (ITI) on maze 2 & 3, which included turns, was strongly inversely related to stride-length and stride-velocity and directly related to motor UPDRS scores. Levodopa decreased ITI, except in maze 4. PD participants with freezing of gait had longer ITI on all mazes. The responses quantified on maze 2 & 3 were related to disease severity and gait stride-length, were levodopa responsive, and were worse in people with freezing of gait, suggesting that these mazes could be used to quantify motor dysfunction in PD. Programming our frog-in-maze game onto a remotely distributable platform could provide a tool to monitor disease progression and therapeutic response in people with PD, including during clinical trials., (© 2023. The Author(s).)

Machine learning approaches have been used for the automatic detection of Parkinson's disease with voice recordings being the most used data type due to the simple and non-invasive nature of acquiring such data. Although voice recordings captured via telephone or mobile devices allow much easier and wider access for data collection, current conflicting performance results limit their clinical applicability. This study has two novel contributions. First, we show the reliability of personal telephone-collected voice recordings of the sustained vowel /a/ in natural settings by collecting samples from 50 people with specialist-diagnosed Parkinson's disease and 50 healthy controls and applying machine learning classification with voice features related to phonation. Second, we utilize a novel application of a pre-trained convolutional neural network (Inception V3) with transfer learning to analyze the spectrograms of the sustained vowel from these samples. This approach considers speech intensity estimates across time and frequency scales rather than collapsing measurements across time. We show the superiority of our deep learning model for the task of classifying people with Parkinson's disease as distinct from healthy controls., (© 2023. The Author(s).)

Cannabidiol (CBD), derived from Cannabis sativa, has gained remarkable attention for its potential therapeutic applications. This thorough analysis explores the increasing significance of CBD in treating neurological conditions including epilepsy, multiple sclerosis, Parkinson's disease, and Alzheimer's disease, which present major healthcare concerns on a worldwide scale. Despite the lack of available therapies, CBD has been shown to possess a variety of pharmacological effects in preclinical and clinical studies, making it an intriguing competitor. This review brings together the most recent findings on the endocannabinoid and neurotransmitter systems, as well as anti-inflammatory pathways, that underlie CBD's modes of action. Synthesized efficacy and safety assessments for a range of neurological illnesses are included, covering human trials, in vitro studies, and animal models. The investigation includes how CBD could protect neurons, control neuroinflammation, fend off oxidative stress, and manage neuronal excitability. This study emphasizes existing clinical studies and future possibilities in CBD research, addressing research issues such as regulatory complications and contradicting results, and advocates for further investigation of therapeutic efficacy and ideal dose methodologies. By emphasizing CBD's potential to improve patient well-being, this investigation presents a revised viewpoint on its suitability as a therapeutic intervention for neurological illnesses., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2023 Kuldeep Singh et al.)

The World Health Organization identifies tuberculosis (TB), caused by Mycobacterium tuberculosis , as a leading infectious killer. Although conventional treatments for TB exist, they come with challenges such as a heavy pill regimen, prolonged treatment duration, and a strict schedule, leading to multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains. The rise of MDR strains endangers future TB control. Despite these concerns, the hunt for an efficient treatment continues. One breakthrough has been the use of nanotechnology in medicines, presenting a novel approach for TB treatment. Nanocarriers, such as lipid nanoparticles, nanosuspensions, liposomes, and polymeric micelles, facilitate targeted delivery of anti-TB drugs. The benefits of nanocarriers include reduced drug doses, fewer side effects, improved drug solubility, better bioavailability, and improved patient compliance, speeding up recovery. Additionally, nanocarriers can be made even more targeted by linking them with ligands such as mannose or hyaluronic acid. This review explores these innovative TB treatments, including studies on nanocarriers containing anti-TB drugs and related patents.

In the past, curcumin was the go-to medication for diabetes, but recent studies have shown that tetrahydrocurcumin is more effective. The problem is that it's not very soluble in water or very bioavailable. So, our research aims to increase the bioavailability and anti-diabetic efficacy of tetrahydrocurcumin in streptozotocin-induced diabetic rats by synthesizing tetrahydrocurcumin-loaded solid lipid nanoparticles. Box Behnken Design was employed for the optimization of tetrahydrocurcumin-loaded solid lipid nanoparticles (THC-SLNs). The optimal formulation was determined by doing an ANOVA to examine the relationship between the independent variables (drug-to-lipid ratio, surfactant concentration, and co-surfactant concentration) and the dependent variables (particle size, percent entrapment efficiency, and PDI). Particle size, PDI, and entrapment efficiency all showed statistical significance based on F-values and p-values. The optimized batch was prepared using a drug-to-lipid ratio (1:4.16), 1.21% concentration of surfactant, and 0.4775% co-surfactant (observed with a particle size of 147.1 nm, 83.58 ± 0.838 % entrapment efficiency, and 0.265 PDI, and the values were found very close with the predicted ones. As the THC peak vanishes from the DSC thermogram of the improved formulation, this indicates that the drug has been transformed from its crystalline form into its amorphous state. TEM analysis of optimized formulation demonstrated mono-dispersed particles with an average particle size of 145 nm which are closely related to zetasizer's results. In-vitro release study of optimized formulation demonstrated burst release followed by sustained release up to 71.04% throughout 24 hrs. Increased bioavailability of the adjusted THC-SLN was found in an in vivo pharmacokinetics research with 9.47 folds higher AUC (0-t) compared to plain THC-suspension. Additionally, pharmacodynamic experiments of optimized formulation demonstrated a marked decrease in blood glucose level to 63.7% and increased body weight from 195.8 ± 7.223 to 231.2 ± 7.653 on the 28th day of the study and showed a better anti-diabetic effect than plain drug suspension. Results of stability studies revealed that formulation can be stored for longer periods at room temperature. Tetrahydrocurcumin can be effectively administered by SLN for the treatment of diabetes., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Traditional otic drug delivery methods lack controlled release capabilities, making reverse gelatination gels a promising alternative. Reverse gelatination gels are colloidal systems that transition from a sol to a gel phase at the target site, providing controlled drug release over an extended period. Thermosensitive norfloxacin reverse gelatination gels were developed using a Quality by Design (QbD)-based optimization approach. The formulations were evaluated for their in vitro release profile, rheological behavior, visual appearance, pH, gelling time, and sol-gel transition temperature. The results show that the gelation temperatures of the formulations ranged from 33 to 37 °C, with gelling durations between 35 and 90 s. The drug content in the formulations was uniform, with entrapment efficiency ranging from 55% to 95%. Among the formulations, F10 exhibited the most favorable properties and was selected for a stability study lasting 60 days. Ex-vivo release data demonstrate that the F10 formulation achieved 95.6percentage of drug release at 360 min. This study successfully developed thermosensitive norfloxacin reverse gelatination gels using a QbD-based optimization approach. The selected formulation, F10, exhibited desirable properties in terms of gelling temperature, drug content, and release profile. These gels hold potential for the controlled delivery of norfloxacin in the treatment of ear infections.

Exclusive physicochemical and biological properties of carbon allotrope graphene have attracted the peer attention of researchers for the synthesis and development of newer topical remedies including films, scaffolds, microspheres, and hydrogels. Here, graphene nanoplatelets (GN) were embedded into a different ratio of polymeric ERL100/ERS100 solution and fabricated in the form of a scaffold through the electrospinning process. FTIR spectra displayed characteristic similar peaks present both in GN and GN-loaded scaffold owing to the compatibility of GN and polymeric mixture. XRD curve revealed a distinct GN peak at nearly 26° whereas from DSC/TGA thermal stability was observed between polymers and graphene nanoplatelets. FESEM images showed ultrathin architecture of GN-loaded scaffold in a range of 280 ± 90 nm. The fabricated scaffold exhibited hydrophilicity (contact angle 48.8 ± 2.8°) and desirable swelling index (646% in skin pH media) which were desired criteria for the scaffold for topical application. In vitro, antifungal activity was conducted through the broth microdilution method against different virulent dermatophytes i.e., Microsporum gypseum , M. canis , M. fulvum , and Trychophyton rubrum . For in vivo evaluation, T. rubrum inoculum was applied on the dorsal surface of each group of Swiss albino mice, and the degree and intensity of mycelial growth or erythema on skin surfaces was visually investigated. The study depicted complete signs of cure after 14 days of application of G3-loaded scaffold on the infected dorsal site. Hence graphene-loaded scaffold represented a possible alternative for the treatment of topical fungal infections caused by dermatophytes., Competing Interests: The authors declare no conflict of interest.

Resistance to isoniazid (INH) is common and increases the possibility of acquiring multidrug-resistant tuberculosis. For this study, isoniazid-loaded nanostructured lipid carriers (INH-NLCs) were developed and effectively functionalized with mannose (Man) to enhance the residence time of the drug within the lungs via specific delivery and increase the therapeutic efficacy of the formulation. The mannose-functionalized isoniazid-loaded nanostructured lipid carrier (Man-INH-NLC) formulation was evaluated with respect to various formulation parameters, namely, encapsulation efficiency (EE), drug loading (DL), average particle size (PS), zeta potential (ZP), polydispersity index (PDI), in vitro drug release (DR), and release kinetics. The in vitro inhalation behavior of the developed formulation after nebulization was investigated using an Andersen cascade impactor via the estimation of the mass median aerosolized diameter (MMAD) and geometric aerodynamic diameter (GAD) and subsequently found to be suitable for effective lung delivery. An in vivo pharmacokinetic study was carried out in a guinea pig animal model, and it was demonstrated that Man-INH-NLC has a longer residence time in the lungs with improved pharmacokinetics when compared with unfunctionalized INH-NLC, indicating the enhanced therapeutic efficacy of the Man-INH-NLC formulation. Histopathological analysis led us to determine that the extent of tissue damage was more severe in the case of the pure drug solution of isoniazid compared to the Man-INH-NLC formulation after nebulization. Thus, the nebulization of Man-INH-NLC was found to be safe, forming a sound basis for enhancing the therapeutic efficacy of the drug for improved management in the treatment of pulmonary tuberculosis.

The limitations associated with the conventional treatment of cancer have necessitated the design and development of novel drug delivery systems based mainly on nanotechnology. These novel drug delivery systems include various kinds of nanoparticles, such as polymeric nanoparticles, solid lipid nanoparticles, nanostructured lipid carriers, hydrogels, and polymeric micelles. Among the various kinds of novel drug delivery systems, chitosan-based nanoparticles have attracted the attention of researchers to treat cancer. Chitosan is a polycationic polymer generated from chitin with various characteristics such as biocompatibility, biodegradability, non-toxicity, and mucoadhesiveness, making it an ideal polymer to fabricate drug delivery systems. However, chitosan is poorly soluble in water and soluble in acidic aqueous solutions. Furthermore, owing to the presence of reactive amino groups, chitosan can be chemically modified to improve its physiochemical properties. Chitosan and its modified derivatives can be employed to fabricate nanoparticles, which are used most frequently in the pharmaceutical sector due to their possession of various characteristics such as nanosize, appropriate pharmacokinetic and pharmacodynamic properties, non-immunogenicity, improved stability, and improved drug loading capacity. Furthermore, it is capable of delivering nucleic acids, chemotherapeutic medicines, and bioactives using modified chitosan. Chitosan and its modified derivative-based nanoparticles can be targeted to specific cancer sites via active and passive mechanisms. Based on chitosan drug delivery systems, many anticancer drugs now have better effectiveness, potency, cytotoxicity, or biocompatibility. The characteristics of chitosan and its chemically tailored derivatives, as well as their use in cancer therapy, will be examined in this review.

Uterine fibroids (UF), most prevalent gynecological disorder, require surgery when symptomatic. It is estimated that between 25 and 35 percent of women wait until the symptoms have worsened like extended heavy menstrual bleeding and severe pelvic pain. These UF may be reduced in size through various methods such as medical or surgical intervention. Progesterone (prog) is a crucial hormone that restores the endometrium and controls uterine function. In the current study, 28 plant-based molecules are identified from previous literature and docked onto the prog receptors with 1E3K and 2OVH. Tanshinone-I has shown the best docking score against both proteins. The synthetic prog inhibitor Norethindrone Acetate is used as a standard to evaluate the docking outcomes. The best compound, tanshinone-I, was analyzed using molecular modeling and DFT. The RMSD for the 1E3K protein-ligand complex ranged from 0.10 to 0.42 Å, with an average of 0.21 Å and a standard deviation (SD) of 0.06, while the RMSD for the 2OVH protein-ligand complex ranged from 0.08 to 0.42 Å, with an average of 0.20 Å and a SD of 0.06 showing stable interaction. In principal component analysis, the observed eigen values of HPR-Tanshinone-I fluctuate between -1.11 to 1.48 and -1.07 to 1.25 for PC1 and PC2, respectively (1E3K), and the prog-tanshinone-I complex shows eigen values of -38.88 to -31.32 and -31.32 to 35.87 for PC1 and PC2, respectively (2OVH), which shows Tanshinone-I forms a stable protein-ligand complex with 1E3K in comparison to 2OVH. The Free Energy Landscape (FEL) analysis shows the Gibbs free energy in the range of 0 to 8 kJ/mol for Tanshinone-I with 1E3K and 0 to 14 kJ/mol for Tanshinone-I with the 2OVH complex. The DFT calculation reveals ΔE value of 2.8070 eV shows tanshinone-I as a stable compound. 1E3K modulates the prog pathway, it may have either an agonistic or antagonistic effect on hPRs. Tanshinone-I can cause ROS, apoptosis, autophagy (p62 accumulation), up-regulation of inositol requiring protein-1, enhancer-binding protein homologous protein, p-c-Jun N-terminal kinase (p-JNK), and suppression of MMPs. Bcl-2 expression can change LC3I to LC3II and cause apoptosis through Beclin-1 expression., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Background: Postural instability can occur in the later-stages of Parkinson's disease (PD). The clinical pull-test is scored on a 0-4 scale on the Unified Parkinson's disease rating scale (UPDRS), with postural instability scored 2 or higher. This ordinal scale does not adequately track progression in early-PD or predict development of postural instability., Research Question: To develop a test that quantifiably measured the backward stepping response on the pull-test in early-PD., Methods: Participants (35 controls and 79 PD participants) were prospectively enrolled in this study. Participants stepped backwards with each shoulder pull at four strengths on an instrumented gait mat. Four spatiotemporal parameters (reaction-time, step-back-time, step-back-distance, step-back-velocity) were quantified using Protokinetics Movement Analysis Software. Spatiotemporal pull-test parameters were compared to standard PD measures using linear regression and correlation coefficients. Repeated measures analysis was used to determine group differences in pull-test parameters. In a subset of participants repeated testing was performed and Bland-Altman plots were used to determine reproducibility of the pull-test parameters., Result: Step-back-distance and step-back-velocity were inversely related to motor UPDRS and freezing of gait questionnaire scores. PD participants had shorter step-back-distance than controls adjusted for age and sex. Repeat assessments in 16 participants, on average 0.7 years apart, showed good agreement on most of the quantified parameters., Significance: The backward stepping response in PD participants was quantifiable, reproducible, and related to disease severity and could be used to quantify progression towards postural instability in early-PD., Competing Interests: Declaration of Competing Interest The authors declare that there are no financial disclosures or conflicts of interest relevant to this work., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: In people with Parkinson's disease (PwPD), Freezing of Gait (FOG) episodes can be levodopa responsive (OFF-FOG) or levodopa unresponsive (ONOFF-FOG). Steady-state gait abnormalities, outside of the freezing episodes themselves also exist and the response to levodopa in these different groups has not been previously documented., Objectives: To define the levodopa responsiveness in steady-state gait in OFF-FOG and ONOFF-FOG individuals., Methods: Steady-state gait was collected in both the effective levodopa OFF-state (doses withheld > 8 h) and ON-state (1 h after levodopa dosing) in 32 PwPD; 10 with OFF-FOG and 22 with ONOFF-FOG. Levodopa response was compared between the two groups in the mean and variability (CV) of 8 spatiotemporal gait parameters., Results: Both OFF-FOG and ONOFF-FOG participants showed improvement in mean stride-length and stride-velocity with levodopa. Improvement was seen in the OFF-FOG but not the ONOFF-FOG groups in mean stride-width and CV Integrated pressure with levodopa., Discussion: In this study we show that steady-state gait deficits improve with levodopa in PwPD with OFF-FOG and ONOFF-FOG, even though episodes of FOG did not resolve in the ONOFF-FOG group. Lowering levodopa in people with ONOFF-FOG, or levodopa-unresponsive freezing of gait, should be undertake with caution and objective gait titration at different levodopa doses may be beneficial. Further work is needed to elucidate the pathophysiologic mechanisms of these differences., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Virmani received salary support from the University of Arkansas for Medical Sciences (UAMS), salary from the UAMS clinician scientist program (UAMS CSP), salary from a grant from the Parkinson’s Foundation (PF-JFA-1935) and a pilot NIGMS award (GM110702). Ms. Glover and Ms. Pillai, received salary support from the UAMS CSP, PF and NIGMS pilot awards (to TV). Dr. Landes received salary support from NIH/NCATS and the PF grant. None of the authors have any financial disclosures or conflicts of interest related to the research covered in this manuscript., (© 2023 The Author(s).)

The accumulation of body fat due to an imbalance between calorie intake and energy expenditure is called obesity. Metabolic syndrome increases the risk of heart disease, type 2 diabetes, and stroke. The purpose of this study was to determine the effect of Jatropha tanjorensis (J.T.) and Fraxinus micrantha (F.M.) leaf extracts on high-fat diet-induced obesity in rats. Normal control, high-fat diet (HFD) control, orlistat standard, and test groups were created using male Albino Wistar rats (n = 6 per group) weighing 190 ± 15 g. Except for the control group, all regimens were administered orally and continued for 6 weeks while on HFD. Evaluation criteria included body weight, food intake, blood glucose, lipid profile, oxidative stress, and liver histology. High-Performance Thin Layer Chromatography (HPTLC) analysis was performed using a solvent system (7:3 hexane: ethyl acetate for sitosterol solution and Jatropha tanjorensis extracts and 6:4 hexane: ethyl acetate: 1 drop of acetic acid for esculetin and Fraxinus micrantha extracts). There were no deaths during the 14 days before the acute toxicity test, indicating that aqueous and ethanolic extracts of both J.T. and F.M. did not produce acute toxicity at any dose (5, 50, 300, and 2000 mg/kg). The ethanolic and aqueous extracts of J.T. and F.M. leaves at 200 and 400 mg/kg/orally showed a reduction in weight gain, feed intake, and significant decreases in serum glucose and lipid profile. As compared to inducer HFD animals, co-treatment of aqueous and ethanolic extract of both J.T. and F.M. and orlistat increased the levels of antioxidant enzymes and decreased lipid peroxidation. The liver's histological findings showed that the sample had some degree of protection. These results indicate that ethanolic samples of J.T. have antidiabetic potential in diabetic rats fed an HFD. The strong antioxidant potential and restoration of serum lipid levels may be related to this. Co-treatment of samples JTE, JTAQ, FME, FMAQ and orlistat resulted in an increase in antioxidant enzymes and reduction in lipid peroxidation as compared to inducer HFD animals. We report, for the first time, on using these leaves to combat obesity.

Objective: Epilepsy is one of the most prevalent neurological illnesses defined by periodic seizures with or without loss of consciousness caused by aberrant neural activity. There are many allopathic medications available for the treatment of epilepsy such as phenytoin (PHY), but the side effects are a major concern. Therefore, the present study involved the evaluation of the pharmacological significance of Amaranthus viridis L. extract (EAV) in the management of strychnine (STR)-induced epilepsy., Method: STR (3.5 mg/kg, i.p.) was injected into male rats 30 minutes after the pre-treatment of a standard drug (PHY: 20 mg/kg) and the two doses of EAV (EAV-200 and EAV-400 mg/kg, p.o.) to the respective groups to cause the convulsions. The anti-convulsant effect of EAV-200 and EAV-400 against STR-induced convulsion in rats was investigated in terms of convulsion onset, duration of convulsions, number of convulsions, and convulsion score. Furthermore, the mitochondrial function and integrity in the brain's prefrontal cortex (PFC) were also estimated., Results: EAV-400 significantly increased the onset of convulsion from 61.67 ± 3.051 to 119.2 ± 2.738 and reduced the STR-induced duration of convulsions from 144.8 ± 3.582 to 69.17 ± 3.736, number of convulsions from 4.000 ± 0.1592 to 1.533 ± 0.1542, and convulsion score from 5.000 ± 0.3651 to 2.833 ± 0.3073 in rats. EAV-400 significantly attenuated the STR-induced decrease in the mitochondrial function and integrity of the rat PFC. In rats, EAV-400 significantly accelerated the onset of convulsions while decreasing the STR-induced duration, frequency, and score., Conclusion: Based on investigational findings, EAV-400 could be inferred to be a possible anti-epileptic option for the treatment of epilepsy of this plan in preclinical research., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2023 Aashish Bharadwaj et al.)

Anticancer drugs in monotherapy are ineffective to treat various kinds of cancer due to the heterogeneous nature of cancer. Moreover, available anticancer drugs possessed various hurdles, such as drug resistance, insensitivity of cancer cells to drugs, adverse effects and patient inconveniences. Hence, plant-based phytochemicals could be a better substitute for conventional chemotherapy for treatment of cancer due to various properties: lesser adverse effects, action via multiple pathways, economical, etc. Various preclinical studies have demonstrated that a combination of phytochemicals with conventional anticancer drugs is more efficacious than phytochemicals individually to treat cancer because plant-derived compounds have lower anticancer efficacy than conventional anticancer drugs. Moreover, phytochemicals suffer from poor aqueous solubility and reduced bioavailability, which must be resolved for efficacious treatment of cancer. Therefore, nanotechnology-based novel carriers are employed for codelivery of phytochemicals and conventional anticancer drugs for better treatment of cancer. These novel carriers include nanoemulsion, nanosuspension, nanostructured lipid carriers, solid lipid nanoparticles, polymeric nanoparticles, polymeric micelles, dendrimers, metallic nanoparticles, carbon nanotubes that provide various benefits of improved solubility, reduced adverse effects, higher efficacy, reduced dose, improved dosing frequency, reduced drug resistance, improved bioavailability and higher patient compliance. This review summarizes various phytochemicals employed in treatment of cancer, combination therapy of phytochemicals with anticancer drugs and various nanotechnology-based carriers to deliver the combination therapy in treatment of cancer.

Background: Freezing of gait (FOG) is a debilitating, variably expressed motor symptom in people with Parkinson's disease (PwPD) with limited treatments., Objective: To determine if the rate of progression in spatiotemporal gait parameters in people converting from a noFOG to a FOG phenotype (FOGConv) was faster than non-convertors, and determine if gait parameters can help predict this conversion., Methods: PwPD were objectively monitored longitudinally, approximately every 6 months. Non-motor assessments were performed at the initial visit. Steady-state gait in the levodopa ON-state was collected using a gait mat (Protokinetics) at each visit. The rate of progression in 8 spatiotemporal gait parameters was calculated. FOG convertors (FOGConv) were classified if they did not have FOG at initial visit and developed FOG at a subsequent visit., Results: Thirty freezers (FOG) and 30 non-freezers were monitored an average of 3.5 years, with 10 non-freezers developing FOG (FOGConv). FOGConv and FOG had faster decline in mean stride-length, swing-phase-percent, and increase in mean total-double-support percent, coefficient of variability (CV) foot-strike-length and CV swing-phase-percent than the remaining non-freezers (noFOG). On univariate modeling, progression rates of mean stride-length, stride-velocity, swing-phase-percent, total-double-support-percent and of CV swing-phase-percent had high discriminative power (AUC > 0.83) for classification of the FOGConv and noFOG groups., Conclusion: FOGConv had a faster temporal decline in objectively quantified gait than noFOG, and progression rates of spatiotemporal gait parameters were more predictive of FOG phenotype conversion than initial (static) parameters Objectively monitoring gait in disease prediction models may help define FOG prone groups for testing putative treatments.

Background: Depression is a psychiatric disorder leading to anhedonia and lack of interest and motivation. Depressive symptoms are triggered by stressful life events, and patients with major depression are at significantly increased risk of attempting suicide. The crucial concern in depression treatment with antidepressant medications is that few weeks are required to show the therapeutic effect along with moderate side effects. The use of herbal medications is a new strategy for the treatment of depression which is often based on medicinal plants. Aegle marmelos (L.) Corr. (family: Rutaceae) is reported to have several actions on the central nervous system producing beneficial effects in anxiety, Alzheimer's disease, Parkinson's disease, epilepsy, and convulsion. Thus, the current investigation designed to assess the antidepressant activity of the standardized hydroethanolic extract of Aegle marmelos (EAM) leaves in male rats exposed to the chronic unpredictable mild stress (CUMS) paradigm., Methods: Rats were divided in 5 groups. The control group was not subjected to experimental CUMS paradigm, while 4 other groups were subjected to CUMS paradigm to induce depression-like behaviour from day 1 to day 28. Following the CUMS paradigm, 4 groups were divided as CUMS disease control, CUMS+EAM (150 mg/kg, p.o.), CUMS+EAM (300 mg/kg, p.o.), and CUMS+imipramine (15 mg/kg, p.o.), and treatment was given for seven consecutive days to the respective groups (day 29 to day 35). Behavioural parameters such as open field test, forced swim test, sucrose feeding test, and tail suspension test on day 1, day 28, and day 35 were measured, and biochemical parameters such as plasma corticosterone level, serotonergic system (5-HT, 5-HIAA, and 5-HT/5-HIAA), mitochondrial function, and proinflammatory mediators (TNF- α , IL-1 β , and IL-6) were estimated in hippocampus (HIP) and prefrontal cortex (PFC) regions of the brain on day 35, after the behavioural observations. On the other hand, phytochemical profile of Aegle marmelos was done., Results: On day 35, EAM (300 mg/kg) significantly reduced the immobility time during the tail suspension test from 208.66 ± 4.72 s to 108.83 ± 4.81 s and forced swim test from 200.16 ± 4.12 s to 148.5 ± 4.58 s. It also enhanced the behavioural parameters in the open field test such as ambulation from 26.5 ± 2.14 to 56.5 ± 1.80, rearing from 8.33 ± 0.71 to 19 ± 0.57, time spent in centre from 9.16 ± 0.9 to 17.16 ± 0.79 s, total distance travelled from 2.36 ± 0.12 to 4.68 ± 0.10 m, and anhedonia in the sucrose feeding test from 109.33 ± 1.08 to 135.83 ± 3.91 mL. The stimulation of the HPA axis resulting elevated corticosterone level caused by CUMS was reduced by EAM (300 mg/kg) from 80.12 ± 2.020 to 48.25 ± 2.407  μ g/dL. Furthermore, EAM (300 mg/kg) increase CUMS-induced changes in serotonin (5-HT) level in HIP and PFC from 3.132 ± 0.09586 to 4.518 ± 0.1812 and 4.308 ± 0.1593 to 5.262 ± 0.1014 ng/mg protein, respectively. EAM (300 mg/kg) significantly attenuated the CUMS-induced changes in proinflammatory cytokine production and mitochondrial function in HIP and PFC. One group used to determine the acute toxicity as per OECD-23 standard protocol which resulted that 300 mg/kg EAM has no significant acute toxicity. Total phenolic content and total flavonoid content of standardized hydroalcoholic extract of AM was found 95.024 ± 2.431 and 36.820 ± 3.41, respectively, and additional identification tests showed the presence of alkaloids, tannins, saponins, cardiac glycosides, flavonoids, and terpenoids., Conclusion: On the basis of findings, EAM can be inferred as a potential antidepressant-like effect of this plan in preclinical research., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Ashwani Sharma et al.)

The present research attempted to design and develop a nanoemulsion formulation of azilsartan medoxomil to improve its aqueous solubility and intestinal permeability. Based on the solubility profile, ethyl oleate, tween 80, and Transcutol P were selected as the oil phase, surfactant, and co-surfactant, respectively. Central composite design (CCD) suggested an optimized azilsartan medoxomil- nanoemulsion formulation (optimized AZL-NE formulation) with 1.25% oil, 15.73% Smix, and 90 s ultrasonication time; it was found to have the droplet size, percentage transmittance, and % cumulative drug release (%CDR) of 71.5 nm, 93.46 ± 1.13%, and 90.14 ± 0.94%, respectively. Furthermore, it exhibited a 0.141 polydispersity index, 34.05 mV zeta potential, a 1.413 ± 0.03 refractive index, 6.68 ± 0.22 pH, 28.17 ± 0.52 cps viscosity, and a 96.98 ± 0.94% percentage drug content. Transmission electron microscopy (TEM) assessed the nano-sized spherical shape, and a differential scanning calorimeter (DSC) assessed the solubilization of the drug in the optimized formulation. The %CDR was 1.71 times higher and the % cumulative drug permeation was 2.1 times higher for the optimized AZL-NE formulation than for the drug suspension through an intestinal segment of a rat, which was also supported by confocal laser scanning microscopy (CLSM) studies. Thus, the nanoemulsion formulation of azilsartan medoxomil ensured the enhancement of the drug availability in the body.

Abnormalities in airway mucus lead to chronic disorders in the pulmonary system such as asthma, fibrosis and chronic obstructive pulmonary disease (COPD). Among these, COPD is more prominent worldwide. Various conventional approaches are available in the market for the treatment of COPD, but the delivery of drugs to the target site remains a challenge with conventional approaches. Nanocarrier-based approaches are considered the best due to their sustained release properties to the target site, smaller size, high surface-to-volume ratio, patient compliance, overcoming airway defenses and improved pharmacotherapy. This article provides updated information about the treatment of COPD along with nanocarrier-based approaches as well as the potential of gene therapy and stem cell therapy to combat the COPD.

Introduction: Gait, balance, and cognitive impairment make travel cumbersome for People with Parkinson's disease (PwPD). About 75% of PwPD cared for at the University of Arkansas for Medical Sciences' Movement Disorders Clinic reside in medically underserved areas (MUAs). Validated remote evaluations could help improve their access to care. Our goal was to explore the feasibility of telemedicine research visits for the evaluation of multi-modal function in PwPD in a rural state., Methods: In-home telemedicine research visits were performed in PwPD. Motor and non-motor disease features were evaluated and quantified by trained personnel, digital survey instruments for self-assessments, digital voice recordings, and scanned and digitized Archimedes spiral drawings. Participant's MUA residence was determined after evaluations were completed., Results: Twenty of the fifty PwPD enrolled resided in MUAs. The groups were well matched for disease duration, modified motor UPDRS, and Montreal Cognitive assessment scores but MUA participants were younger. Ninety-two percent were satisfied with their visit, and 61% were more likely to participate in future telemedicine research. MUA participants traveled longer distances, with higher travel costs, lower income, and education level. While 50% of MUA participants reported self-reliance for in-person visits, 85% reported self-reliance for the telemedicine visit. We rated audio-video quality highly in approximately 60% of visits in both groups. There was good correlation with prior in-person research assessments in a subset of participants., Conclusions: In-home research visits for PwPD in MUAs are feasible and could help improve access to care and research participation in these traditionally underrepresented populations., (© The Author(s) 2022.)

Since ancient times, Chrysopogon zizanioides has been utilized as a traditional medicinal plant for the treatment of numerous ailments, but neither its plant extract form nor its phytoconstituents have been fully explored. With this in mind, the present research was designed to isolate and structurally characterize one of its chemical constituents and evaluate its cytotoxic potential. Therefore, an ethanolic extract of roots was prepared and subjected to column chromatography using solvents of varying polarities. The obtained pure compound was characterized using various chromatographic and spectroscopic techniques such as high-performance liquid chromatography (HPLC), carbon and proton nuclear magnetic resonance (NMR), and liquid chromatography-mass spectroscopy (LC-MS) and identified as longifolene. This compound was evaluated for its cytotoxic potential using an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay on the prostate (DU-145), oral (SCC-29B) cancer cell line and normal kidney cell line (Vero cells), taking doxorubicin as a standard drug. The obtained outcomes revealed that longifolene possesses cytotoxic potential against both prostate (IC 50 = 78.64 µg/mL) as well as oral (IC 50 = 88.92 µg/mL) cancer cell lines with the least toxicity in healthy Vero cells (IC 50 = 246.3 µg/mL) when compared to doxorubicin. Hence, this primary exploratory study of longifolene exhibited its cytotoxic potency along with wide safety margins in healthy cell lines, giving an idea that the compounds possess some ability to differentiate between cancerous cells and healthy cells.

Background: Mutations that alter splicing of X-linked ATP6AP2 cause a spectrum of neurodevelopmental and neurodegenerative pathologies including parkinsonism in affected males. All previously reported splicing mutations increase the level of a minor isoform with skipped exon 4 (Δe4) that encodes a functionally deficient protein., Objectives: We investigated the pathogenic mechanism of a novel c.168+6T>A variant reported in a family with X-linked intellectual disability, epilepsy, and parkinsonism. We also analyzed ATP6AP2 splicing defects in brains of carriers of a c.345C>T variant associated with X-linked spasticity and parkinsonism., Methods: We generated induced pluripotent stem cells from patients with c.168+6T>A, reprogrammed them to neural progenitor cells and analyzed them by RNA-Seq and qRT-PCR. We also quantified ATP6AP2 isoforms in the brains of c.345C>T carriers by Nanostring nCounter., Results: The c.168+6T>A increased skipping of ATP6AP2 exon 2 and usage of cryptic intronic donor splice sites. This results in out-of-frame splicing products and a reciprocal 50% reduction in functional full-length ATP6AP2 transcripts. Neural progenitors of patients with c.168+6T>A exhibited downregulated neural development gene networks. Analysis of blood transcriptomes of c.168+6T>A carriers identified potential biomarkers of ATP6AP2 deficiency in non-neural tissues. The c.345C>T variant increased exon 4 skipping with concomitant decrease of full length ATP6AP2 in brains of carriers., Conclusion: A common pathogenic consequence of splicing mutations affecting inclusion of different ATP6AP2 exons is reduction of the functional full-length transcript. The exacerbated ATP6AP2 splicing defect in brains of c.345C>T carriers is consistent with their CNS-restricted clinical presentations., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The global COVID-19 (coronavirus disease 2019) pandemic, which was caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in a significant loss of human life around the world. The SARS-CoV-2 has caused significant problems to medical systems and healthcare facilities due to its unexpected global expansion. Despite all of the efforts, developing effective treatments, diagnostic techniques, and vaccinations for this unique virus is a top priority and takes a long time. However, the foremost step in vaccine development is to identify possible antigens for a vaccine. The traditional method was time taking, but after the breakthrough technology of reverse vaccinology (RV) was introduced in 2000, it drastically lowers the time needed to detect antigens ranging from 5-15 years to 1-2 years. The different RV tools work based on machine learning (ML) and artificial intelligence (AI). Models based on AI and ML have shown promising solutions in accelerating the discovery and optimization of new antivirals or effective vaccine candidates. In the present scenario, AI has been extensively used for drug and vaccine research against SARS-COV-2 therapy discovery. This is more useful for the identification of potential existing drugs with inhibitory human coronavirus by using different datasets. The AI tools and computational approaches have led to speedy research and the development of a vaccine to fight against the coronavirus. Therefore, this paper suggests the role of artificial intelligence in the field of clinical trials of vaccines and clinical practices using different tools., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Ashwani Sharma et al.)

Background: Freezing in the levodopa-medicated-state (ON-state) is a debilitating feature of Parkinson's disease without treatment options. Studies detailing the distinguishing features between people with freezing of gait that improves with levodopa and those whose freezing continues even on levodopa are lacking., Objective: To characterize the gross motor, gait, and non-motor features of this phenotype., Methods: Instrumented continuous gait was collected in the levodopa-medicated-state in 105 patients: 43 non-freezers (no-FOG), 36 with freezing only OFF-levodopa (OFF-FOG) and 26 with freezing both ON- and OFF-levodopa (ONOFF-FOG). Evaluation of motor and non-motor disease features was undertaken using validated scales. A linear mixed model with age, sex, disease duration, and motor UPDRS scores as covariates was used to determine differences in spatiotemporal gait and non-motor disease features among the groups., Results: Compared to OFF-FOG, the ONOFF-FOG group had greater disease severity (on the Unified Parkinson's disease Rating Scale) and worse cognition (on the Montreal Cognitive Assessment, Frontal Assessment Battery and Scales for Outcome in Parkinson's disease-Cognition scales) and quality of life (on the PDQ-39), but similar mood (on the Hamilton depression and anxiety scales) and sleep quality (on Epworth sleepiness scale and RBD questionnaire). For several gait features, differences between the ONOFF-OFF groups were at least as large and in the opposite direction as differences between OFF-no groups, controlling for disease severity. Variability in ONOFF-FOG was greater than in other groups. Using results from our study and others, a power analysis for a potential future study reveals sample sizes of at least 80 ONOFF and 80 OFF-FOG patients would be needed to detect clinically meaningful differences., Conclusions: Intra-patient variability in spatiotemporal gait features was much greater in ONOFF-FOG than in the other two groups. Our results suggest that multifactorial deficits may lead to ONOFF-FOG development., Competing Interests: The authors have declared that no competing interests exist.

The objective of the study is to explore whether people with Parkinson's disease (PwPD) display a preferential turn bias dependent upon disease asymmetry, and whether specific disease features predict turn bias. PwPD and age-matched controls were instructed to walk on an instrumented gait mat making "normal" turns. Trials were analyzed using Proto Kinetics Movement Analysis Software (PKMAS) and time-locked video recordings to obtain turn directionality and spatiotemporal turn measures. Turn bias was estimated using previously defined formulas. Seventy-two PwPD and 28 controls were included. One hundred percent of controls and 85% of PwPD had left turn bias. Turn bias was not significantly associated with age, gender, handedness, disease asymmetry, cognition, or disease severity. The Freezing of Gait Questionnaire (FOGQ) questions 5 and 6 showed linear-by-linear association with turn bias. In binary logistic and ordinal regression models, FOGQ question 6 (average duration of turn freezing) and turn width were predictive of turn bias. Rightward turns had greater frequency of freezing episodes. Turn bias in our PwPD cohort does not appear related to disease asymmetry or other disease features, except gait freezing. Whether freezing severity on turning leads to non-left turn bias or vice versa requires more focused studies. Physical therapy interventions targeting turning direction in PwPD could reduce freezing severity., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Hypertension is one of the most important causes of mortality, affecting the health status of the patient. At the same time, hypertension causes a huge health and economic burden on the whole world. The incidence and prevalence of hypertension are rising even among young people in both urban as well as rural communities. Although various conventional therapeutic moieties are available for the management of hypertension, they have serious flaws such as hepatic metabolism, reduced dose frequency, poor aqueous solubility, reduced bioavailability, and increased adverse effects, making the drug therapy ineffective. Therefore, it is required to design a novel drug delivery system having the capability to solve the constraints associated with conventional treatment of hypertension. Nanotechnology is a new way of using and manipulating the matter at the molecular level, whose functional organization is measured in nanometers. The applications of nanotechnology in the field of medicine provide an alternative and novel direction for the treatment of cardiovascular diseases and show excellent performance in the field of targeted drug therapy. Various nanotechnologies based drug delivery systems, such as solid lipid nanoparticles, nanosuspension, nanoemulsion, liposome, self-emulsifying systems, and polymeric nanoparticles, are available. Among them, nanoemulsion has provided a niche to supplement currently available therapeutic choices due to numerous benefits like stability, ease of preparation, enhanced drug absorption, reduced hepatic metabolism, increased dose frequency, enhanced bioavailability, and encapsulation of hydrophilic as well as hydrophobic drugs. This present review provides an in-depth idea about progression in treatment of hypertension, constraints for antihypertensive drug therapy, need of nanoemulsions to overcome these constraints, comparative analysis of nanoemulsions over other nanostructure drug delivery systems, pharmacodynamics studies of nanoemulsions for treatment of hypertension, recent patents for drug-loaded nanoemulsions meant for hypertension, and marketed formulations of nanoemulsions for hypertension., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Girish Kumar et al.)

Movement amplitude setting is affected early in Parkinson's disease (PD), clinically manifesting as bradykinesia. Our objective was to determine if amplitude setting of upper limb bimanual movements and bipedal gait are similarly modulated in PD. 27 PD and 24 control participants were enrolled. Participants performed a bimanual anti-phase finger tapping task wearing gloves with joint angular sensors, and an instrumented gait assessment. Participants performed normal and fast paced assessments to vary motor load. PD participants were evaluated OFF (PD-OFF) and ON (PD-ON) levodopa. PD-OFF participants had smaller tap amplitude, and greater tap amplitude variability than controls in the more affected hands (all p < 0.05). Tap amplitude and stride length (p = 0.030) were correlated in PD-OFF. Tap amplitude was also correlated with motor UPDRS (p < 0.005) and bradykinesia motor (p < 0.05) and ADL (p < 0.005) UPDRS subscores. The relative amount of improvement in tap amplitude and stride length with levodopa was correlated. In PD, upper limb and gait amplitude setting are similarly scaled with motor demand and dopamine supplementation. This suggests these automated motor functions are subserved by common functional networks., (© 2022. The Author(s).)