A Profound Insight into the Structure-activity Relationship of Ubiquitous Scaffold Piperazine: An Explicative Review.

Despite extensive research in the field of drug discovery and development, still there is a need to develop novel molecular entities. Literature reveals a substantial heterocyclic nucleus named, piperazine, which shows an immense therapeutic voyage. For several decades, molecules having the piperazine nucleus have entered the market as a drug exhibiting biological potential. It was known to possess antipsychotic, antihistamine, antianginal, antidepressant, anticancer, antiviral, cardioprotective, and anti-inflammatory activity with a specific basis for structural activity relationship. Thus, it is regarded as a key structural feature in most of the already available therapeutic drugs in the market. Reports also suggest that the extensive utilization of these currently available drugs having a piperazine nucleus shows increasing tolerance significantly day by day. In addition to this, various other factors like solubility, low bioavailability, cost-effectiveness, and imbalance between pharmacokinetics and pharmacodynamics profile limit their utilization. Focusing on that issues, various structural modification studies were performed on the piperazine moiety to develop new derivatives/analogs to overcome the problems associated with available marketed drugs. Thus, this review article aims to gain insight into the number of structural modifications at the N-1 and N-4 positions of the piperazine scaffold. This SAR approach may prove to be the best way to overcome the above-discussed drawbacks and lead to the design of drug molecules with better efficacy and affinity. Hence, there is an urgent need to focus on the structural features of this scaffold which paves further work for deeper exploration and may help medicinal chemists as well as pharmaceutical industries.

Terpenoids in Diabetic Nephropathy: Advances and Therapeutic Opportunities.

Diabetic nephropathy (DN) is the foremost ailment resulting in end-stage renal damage. Chronic hyperglycaemia and hyperlipidaemia are the foremost reason for disease progression. The disease is characterized by the severity of albuminuria and cardiovascular disorders. Approximately 20 to 40% of the global prevalence of DN is mostly reported to occur in individuals with diabetes, and nearly 28% of DN occurs in individuals with other renal disorders. The pathological mechanism is very complex, involving innumerable targets and leading to multiple pharmacological effects. Thus, the scientific community is forced to work in search of safe and potent therapeutics that can tackle the complex pathology of DN effectively. The secondary plant metabolites categorized as terpenoids gained attention as potential therapeutics contrary to others for the management of diabetic nephropathy and other associated syndromes by their strong antioxidant activity and inhibition of advanced glycation and its associated products. This review focused on herbal therapeutics for the management of diabetic nephropathy. Moreover, different types of terpenoids, their biological sources, and proposed mechanisms of action are explored for the development of a novel pharmacophore for diabetic nephropathy.

Mixed-Anion Contact Ion-Pair Formation Enabling Improved Performance of Halide-Free Mg-Ion Electrolytes.

Discovery of stable and efficient electrolytes that are compatible with magnesium metal anodes and high-voltage cathodes is crucial to enabling energy storage technologies that can move beyond existing Li-ion systems. Many promising electrolytes for magnesium anodes have been proposed with chloride-based systems at the forefront; however, Cl-containing electrolytes lack the oxidative stability required by high-voltage cathodes. In this work, we report magnesium trifluoromethanesulfonate (triflate) as a viable coanion for Cl-free, mixed-anion magnesium electrolytes. The addition of triflate to electrolytes containing bis(trifluoromethane sulfonyl) imide (TFSI-) anions yields significantly improved Coulombic efficiency, up to a 100 mV decrease in the plating/stripping overpotential, improved tolerance to trace H2O, and improved oxidative stability (0.35 V improvement compared to that of hybrid TFSI-Cl electrolytes). Based on 19F nuclear magnetic resonance and Raman spectroscopy measurements, we propose that these improvements in performance are driven by the formation of mixed-anion contact ion pairs, where both triflate and TFSI- are coordinated to Mg2+ in the electrolyte bulk. The formation of this mixed-anion magnesium complex is further predicted by the density functional theory to be thermodynamically driven. Collectively, this work outlines the guiding principles for the improved design of next-generation electrolytes for magnesium batteries.

Active Learning Guided Computational Discovery of Plant-Based Redoxmers for Organic Nonaqueous Redox Flow Batteries.

Organic nonaqueous redox flow batteries (O-NRFBs) are promising energy storage devices due to their scalability and reliance on sourceable materials. However, finding suitable redox-active organic molecules (redoxmers) for these batteries remains a challenge. Using plant-based compounds as precursors for these redoxmers can decrease their costs and environmental toxicity. In this computational study, flavonoid molecules have been examined as potential redoxmers for O-NRFBs. Flavone and isoflavone derivatives were selected as catholyte (positive charge carrier) and anolyte (negative charge carrier) molecules, respectively. To drive their redox potentials to the opposite extremes, in silico derivatization was performed using a novel algorithm to generate a library of > 40000 candidate molecules that penalizes overly complex structures. A multiobjective Bayesian optimization based active learning algorithm was then used to identify best redoxmer candidates in these search spaces. Our study provides methodologies for molecular design and optimization of natural scaffolds and highlights the need of incorporating expert chemistry awareness of the natural products and the basic rules of synthetic chemistry in machine learning.

Lipids: A Major Culprit in Diabetic Nephropathy.

The pathophysiology of diabetic nephropathy (DN) is too complex and involves a variety of pathways and mediators. Hyperglycaemia and dyslipidemia are identified as major risk factors for diabetic nephropathy. Various studies revealed the fact that dyslipidemia is a major contributor to the process of diabetic nephropathy. Dyslipidemia refers to abnormal lipid levels. Lipids like LDL, free fatty acids, abnormal lipoproteins, ceramides, etc., are unsafe for kidneys. They target proximal tubular epithelial cells, podocytes, and tubulointerstitial tissues through biochemical changes, especially by enhancing the release of reactive oxygen species (ROS) and lipid peroxidation, endorsing tissue inflammation and mitochondrial damage, which give rise to nephropathy. Major lipid targets identified are SREBP1, LXR, FXR PPAR, CD-36, PKc, AGE/RAGE pathway, and ferroptosis. The drug acting on these targets has shown improvement in DN patients. Various preclinical and clinical studies support the fact that hyperlipidemic agents are promising targets for DN. Therefore, in conjunction with other standard therapies, drugs acting on dyslipidemia can be added as a part of the regimen in order to prevent the incidence of ESRD and CVD.

Quadricuspid aortic valve.

A 56-year-old man presented with typical angina for 1 day and a prior history of exertional dyspnea of 6 months duration. Clinically, he was diagnosed with severe aortic regurgitation (AR). Electrocardiogram showed left ventricular hypertrophy with volume overload.

Conventional rehabilitation post-TKA achieves better knee flexion with higher resource utilization compared to application-based rehabilitation - a systematic review and meta-analysis.

Background: Post-operative physiotherapy is a major component of the effectiveness of knee replacement. Adequate rehabilitation protocols are required for better functional outcomes. With the advent of smartphones and smartwatches, the use of telerehabilitation has increased recently. This study aims to compare tele rehabilitation using various mobile-based applications to conventional rehabilitation protocols. Methods: From Jan 2000 to Jun 2022, all the RCTs from SCOPUS, EMBASE and PUBMED comparing patient-related outcome measures between the smartphone-based app and conventional rehabilitation protocols were scanned and seven studies meeting the eligibility criteria were included in this systematic review and meta-analysis. The quantitative analysis compared outcomes using the knee injury and osteoarthritis outcome score (KOOS), the knee society function score (KSFS), the active range of motion (AROM), Euro-Qol-5D-5L, and MUA. The qualitative analysis compared VAS, NRS, and Time up and go (TUG). Results: The study shows statistically significant improvement in traditional rehabilitation over app based on KSFS score (M.D.: 6.05, p = 0.05) and AROM on long-term follow-up (12 months) (M.D.: 2.46, p = 0.02). AROM was insignificant on 3 months or less follow-up. NRS and VAS were found to be statistically better in app-based groups. No statistically significant results were seen on KOOS, Euro-Qol-5D-5L, MUA and TUG. 90 days of readmission and a number of physiotherapy visits were more in conventional groups. No difference was seen in single-leg stance and satisfaction rates. Conclusions: The present review highlights improved early pain scores and comparable patient-reported outcome analysis at a short-term follow-up period among patients receiving mobile app-based rehabilitation. However, knee range of motion and KSFS score achieved after surgery is analysed to be better with traditional rehabilitation at the one-year end follow-up period.

New Insights on the Uptake and Trafficking of Coenzyme Q.

Coenzyme Q (CoQ) is an essential lipid with many cellular functions, such as electron transport for cellular respiration, antioxidant protection, redox homeostasis, and ferroptosis suppression. Deficiencies in CoQ due to aging, genetic disease, or medication can be ameliorated by high-dose supplementation. As such, an understanding of the uptake and transport of CoQ may inform methods of clinical use and identify how to better treat deficiency. Here, we review what is known about the cellular uptake and intracellular distribution of CoQ from yeast, mammalian cell culture, and rodent models, as well as its absorption at the organism level. We discuss the use of these model organisms to probe the mechanisms of uptake and distribution. The literature indicates that CoQ uptake and distribution are multifaceted processes likely to have redundancies in its transport, utilizing the endomembrane system and newly identified proteins that function as lipid transporters. Impairment of the trafficking of either endogenous or exogenous CoQ exerts profound effects on metabolism and stress response. This review also highlights significant gaps in our knowledge of how CoQ is distributed within the cell and suggests future directions of research to better understand this process.

1,3-thiazole Derivatives: A Scaffold with Considerable Potential in the Treatment of Neurodegenerative Diseases.

1,3-thiazoles, which contain nitrogen and a sulfur atom is an unsaturated five-membered heterocyclic ring, have achieved a unique significant place in drug design and development because of their versatile structure and a variety of pharmacological activities, viz. anticancer, antiviral, antimicrobial, anticonvulsant, antioxidant, antidiabetic, etc. They have inspired researchers to design novel thiazole with different biological activities. The presence of the thiazole moiety has resulted in a large number of clinically useful drugs with a wide range of activities, such as Ritonavir (antiviral), Sulfathiazole (antimicrobial antibiotic), Abafungin, Ravuconazole (antifungal), Meloxicam (NSAID), etc., that further verify this statement. The prevalence of neurodegenerative diseases like Alzheimer's, Parkinson's, and Huntington's is increasing at a rapid pace but existing treatments mainly provide symptomatic relief and are associated with undesired effects. Consequently, designing novel compounds with more effectiveness and reduced toxicity are required. 1,3-thiazole derivatives have emerged as excellent candidate in this regard and have an important role for the treatment of neurodegenerative diseases. In the current review, we have gathered all the appropriate literature which demonstrate the remarkable role of 1,3-thiazole and its derivatives in these diseases that may help design new compounds with more desired characteristics. The literature was assessed through worldwide scientific databases like GOOGLE, SCOPUS, and PUBMED using different keywords, and only relevant information published in English was evaluated.

AmpC Inhibition: An Explicit Approach against Multi-Drug Resistance (MDR).

Multi-drug resistance and its transmission is a ubiquitous health issue worldwide. The beta-lactamase AmpC resistance is a major concern among all health settings like hospitals and child care centers, etc. The clinical pipeline of the new antibiotics remains dry due to the production of AmpC beta-lactamases by the bacteria to develop resistance against antibiotics. According to the global antimicrobial resistance and use surveillance system, the rate of resistance to ciprofloxacin an antibiotic commonly used to treat urinary tract infections, varied from 8.4% to 92.9% for Escherichia coli and from 4.1% to 79.4% for Klebsiellapneumoniae in different countries. The lack of comprehensiveness within the data makes a choice problematic for the selection of appropriate ß-lactam antibiotic for the treatment of resistant microorganisms. Most experts agree it is prudent to avoid expanded-spectrum (i.e. third-generation) cephalosporins for the treatment of organisms posing the greatest risk of AmpC induction. Nonetheless, the development of specific inhibitors for the AmpC enzyme, either naturally or synthetically, is only unfolding. To date, there is no single and clinically active drug available that inhibits the AmpC enzyme and combats multidrug resistance and its transmission in individuals. The deficit of the enzyme inhibitor focused the researchers to work in the area. This present review will emphasize on the chemistry, and structure of clinically important and potent inhibitors against AmpC enzymes.

Utility of clinicoradiological, microbiological, histopathological, and molecular methods in the diagnosis of spinal tuberculosis.

PURPOSE: The diagnosis of STB is mainly based on clinicoradiological observations substantiated by bacterial culture, staining, Gene Xpert, and histopathology. The purpose of the study was to correlate these methods to evaluate the effectiveness in the diagnosis of STB. METHODS: A total of 178 clinicoradiologically suspected cases of STB were included in the study. The specimens for diagnostic workup were collected either during surgery or by CT-guided biopsy. All these specimens were tested for tuberculosis through ZN staining, solid culture, histopathology, and PCR. The sensitivity, specificity, PPV, and NPV of each test were calculated using histopathology as a gold standard. RESULTS: Out of the 178 cases, a total of 15 cases were excluded from this study. Among the remaining 163 cases, TB was diagnosed in 143 [87.73%] on histopathology, 130 [79.75%] on Gene Xpert, 40 [24.53%] on culture, and 23 [14.11%] on ZN stain. The sensitivity, specificity, PPV, and NPV of Gene Xpert were 86.71, 70, 95.38, and 42.42%, respectively. The sensitivity, specificity, PPV, and NPV of AFB culture were 27.97, 100, 100, and 16.26%, respectively. The sensitivity, specificity, PPV, and NPV of AFB stain were 16.08, 100, 100, and 14.29%, respectively. Gene Xpert showed a moderate agreement [Ƙc = 0.4432] with histopathology. CONCLUSION: No single diagnostic modality can ascertain the diagnosis, and it is desirable to have a combination of diagnostic batteries for better results. A combination of Gene Xpert and histopathology aids in early and reliable diagnosis of STB.

Effect of an Antacid (Aluminum Hydroxide/Magnesium Hydroxide/Simethicone) or a Proton Pump Inhibitor (Omeprazole) on the Pharmacokinetics of Tebipenem Pivoxil Hydrobromide (TBP-PI-HBr) in Healthy Adult Subjects.

Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is a novel oral carbapenem prodrug being developed for the treatment of serious bacterial infections. This open-label, 3-period, fixed sequence study evaluated the effect of gastric acid-reducing agents, aluminum hydroxide/magnesium hydroxide/simethicone, and omeprazole on the pharmacokinetics (PK) of tebipenem (TBP), the active moiety, following coadministration with immediate release TBP-PI-HBr during fasting. In Period 1, subjects received a single oral dose of TBP-PI-HBr 600 mg (2 × 300 mg tablets). In Period 2, subjects received a single oral dose of aluminum hydroxide 800 mg/magnesium hydroxide 800 mg/simethicone 80 mg suspension co-administered with a single dose of TBP-PI-HBr 600 mg. In Period 3, subjects received a single oral dose of omeprazole 40 mg once daily over 5 days, followed by single dose administration of TBP-PI-HBr 600 mg on day 5. In each period, whole blood samples were obtained prior to, and up to 24 h, following TBP-PI-HBr dose administration in order to characterize TBP PK. A 7-day washout was required between periods. Twenty subjects were enrolled and completed the study. Following co-administration of TBP-PI-HBr with either aluminum hydroxide/magnesium hydroxide/simethicone or omeprazole, total TBP exposure (area under the curve [AUC]) was approximately 11% (geometric mean ratio 89.2, 90% confidence interval: 83,2, 95.7) lower, and Cmax was 22% (geometric mean ratio 78.4, 90% confidence interval: 67.9, 90.6) and 43% (geometric mean ratio 56.9, 90% confidence interval: 49.2, 65.8) lower, respectively, compared to administration of TBP-PI-HBr alone. Mean TBP elimination half-life (t1/2) was generally comparable across treatments (range: 1.0 to 1.5 h). Concomitant administration of TBP-PI-HBr with omeprazole or aluminum hydroxide/magnesium hydroxide/simethicone is not expected to impact the efficacy of TBP-PI-HBr, as there is minimal impact on TBP plasma AUC, which is the pharmacodynamic driver of efficacy. Co-administration was generally safe and well tolerated.

Bakuchiol: A Potential Anticancer Compound from Psoralea corylifolia Linn.

BACKGROUND: Bakuchiol is a monoterpene phenol isolated from the seeds of Psoralea corylifolia Linn. It is used traditionally in Indian and Chinese medicine and has been reported to possess extensive pharmacological potential against a variety of ailments. A recent study enumerates the anticancer potential of bakuchiol. OBJECTIVE: The objective of the present review study is to explore the anticancer potential of bakuchiol which provides insight into the design and develop novel molecular entities against various disorders. METHODS: Current prose and patents emphasizing the anticancer potential of bakuchiol have been identified and reviewed with particular emphasis on their scientific impact and novelty. An extensive literature survey was performed and compiled via the search engine, PubMed, Science Direct, and from many reputed foundations. RESULTS: The study's findings suggested and verified the anticancer potential that Psoralea and bakuchiol against a variety of cancer. Both Psoralea and bakuchiol also portrayed synergistic or potentiating effects when given in combination with other anticancer drugs or natural compounds. CONCLUSION: Altogether, the promising anticancer potential of bakuchiol may open new probes for therapeutic invention in various types of tumors. Thus, the present review gives the erudition of bakuchiol and Psoralea as anticancer which paves the way for further work in exploring their potential.

The Mechanistic Role of Different Mediators in the Pathophysiology of Nephropathy: A Review.

Nephropathy has become the most common reason for end-stage renal disease worldwide. The progression of end-stage renal disease occurs caused by decreased glomerular filtration rate, damage to capillaries in renal glomeruli or a higher risk of cardiovascular morbidity and mortality in diabetic patients. The involvement of mechanism in the development of nephropathy via generation of AGEs, the elevation of growth factors, altered hemodynamic and metabolic factors, inflammatory mediators, oxidative stress and dyslipidaemia. The prevalence of chronic kidney disease in India will rise from 3.7 million in 1990 to 7.63 million in 2020 becoming the main cause of mortality and morbidity. The pathogenesis of nephropathy mediates by various molecules that cause alterations in the structure and function of the kidney like growth factors, endothelins, transforming growth factor (TGF-ß), and Angiotensin-converting enzymes (ACE), fibronectin and proinflammatory cytokines, mast cells and dyslipidemia. Growth factors like VEGF, IGFs, PDGF, EGFR and TGF-ß contribute to excessive extracellular matrix accumulation, together with thickening of the glomerular and tubular basement membranes and an increase in the mesangial matrix, leading to glomerulosclerosis and tubulointerstitial fibrosis. Oxidative stress and inflammation factors like TNF-α, IL-1 and IL-6 are hypothesized to play a role in the development of pathological changes in nephropathy like renal hyperfiltration and hypertrophy, thickening of the glomerular basement membrane (GBM), glomerular lesion and tubulointerstitial fibrosis. Dyslipidemia is involved in the progression of nephropathy by impaired action of lipoprotein lipase, lecithincholesterol acyltransferase (LCAT) and cholesteryl ester transferase protein (CETP) resulting in the increased level of LDL-C, Triglyceride level and decrease HDL-C that enhance macrophage infiltration, excessive extracellular matrix production and accelerate inflammation with the development of proteinuria. Interruption in the RAS, oxidative stress and dyslipidemia have yielded much better results in terms of reno-protection and progression of nephropathy. In this review, we would focus on various factors that have been shown to contribute to renal injury in many experimental models of nephropathy.

Predicting and Understanding the Pathology of Single Nucleotide Variants in Human COQ Genes.

Coenzyme Q (CoQ) is a vital lipid that functions as an electron carrier in the mitochondrial electron transport chain and as a membrane-soluble antioxidant. Deficiencies in CoQ lead to metabolic diseases with a wide range of clinical manifestations. There are currently few treatments that can slow or stop disease progression. Primary CoQ10 deficiency can arise from mutations in any of the COQ genes responsible for CoQ biosynthesis. While many mutations in these genes have been identified, the clinical significance of most of them remains unclear. Here we analyzed the structural and functional impact of 429 human missense single nucleotide variants (SNVs) that give rise to amino acid substitutions in the conserved and functional regions of human genes encoding a high molecular weight complex known as the CoQ synthome (or Complex Q), consisting of the COQ3-COQ7 and COQ9 gene products. Using structures of COQ polypeptides, close homologs, and AlphaFold models, we identified 115 SNVs that are potentially pathogenic. Further biochemical characterizations in model organisms such as Saccharomyces cerevisiae are required to validate the pathogenicity of the identified SNVs. Collectively, our results will provide a resource for clinicians during patient diagnosis and guide therapeutic efforts toward combating primary CoQ10 deficiency.

Optoelectronics of Atomic Metal-Semiconductor Interfaces in Tin-Intercalated MoS2.

Metal-semiconductor interfaces are ubiquitous in modern electronics. These quantum-confined interfaces allow for the formation of atomically thin polarizable metals and feature rich optical and optoelectronic phenomena, including plasmon-induced hot-electron transfer from metal to semiconductors. Here, we report on the metal-semiconductor interface formed during the intercalation of zero-valent atomic layers of tin (Sn) between layers of MoS2, a van der Waals layered material. We demonstrate that Sn interaction leads to the emergence of gap states within the MoS2 band gap and to corresponding plasmonic features between 1 and 2 eV (0.6-1.2 µm). The observed stimulation of the photoconductivity, as well as the extension of the spectral response from the visible regime toward the mid-infrared suggests that hot-carrier generation and internal photoemission take place.

No added benefits of adipofascial flaps over fasciocutaneous flaps except for footwear ease and bulkiness: A systematic review and meta-analysis.

Purpose: The fasciocutaneous (FC) flap or the axial flap consists of skin, subcutaneous tissue, and deep fascia. In the literature today, there is no evidence suggesting that either surgery is superior to the other in terms of outcome and complications. Reviews in the literature currently compare the outcomes of skin closure after Orthopedic surgeries. The meta-analysis aims to compare the clinical outcomes, complication rates, need for re-surgery, and donor site morbidity between the AF flaps and FC flaps. A null hypothesis that stated inferior outcomes of FC flaps along with more complication rates over AF flaps was kept at the start of the study. Methods: Cochrane Library, PubMed, Embase were searched until December 2020. The review included all original studies which compared the outcomes or complications between FC and AF flaps. The quality of studies was assessed using the Minors score. Results: A total of 7 original studies with AF and FC flap procedures of which 136 underwent FC flap and 212 underwent AF flap. The pooled data meta-analysis and the subgroup analysis of these studies found no standardized protocol for reporting the outcomes or the cosmetic outcome of the flap surgery. The adipofascial group showed overall shorter operative time, less bulky flap and ability to wear footwear. Also the complications did not differ in both groups with respect to flap loss, complication following surgery, wound dehiscence, wound closure, donor site complications. Conclusion: The current meta-analysis reveals that there is no added benefit of using AF flaps over the FC flaps. The rates of partial or total flap necrosis along with donor site morbidities and successful wound closure and overall complication rates were similar between the two groups. However, there is evidence to support the superiority of AF flaps over the FC variety with respect to ease of wearing footwear and a less bulky flap. Level of evidence: Level 1 Systematic review and meta-analysis.

Evaluation of Tebipenem Hydrolysis by ß-Lactamases Prevalent in Complicated Urinary Tract Infections.

Tebipenem pivoxil is the first orally available carbapenem antibiotic and has been approved in Japan for treating ear, nose, and throat and respiratory infections in pediatric patients. Its active moiety, tebipenem, has shown potent antimicrobial activity in vitro against clinical isolates of Enterobacterales species from patients with urinary tract infections (UTIs), including those producing extended-spectrum ß-lactamases (ESBLs) and/or AmpC ß-lactamase. In the present study, tebipenem was tested for stability to hydrolysis by a set of clinically relevant ß-lactamases, including TEM-1, AmpC, CTX-M, OXA-48, KPC, and NDM-1 enzymes. In addition, hydrolysis rates of other carbapenems, including imipenem, meropenem, and ertapenem, were determined for comparison. It was found that, similar to other carbapenems, tebipenem was resistant to hydrolysis by TEM-1, CTX-M, and AmpC ß-lactamases but was susceptible to hydrolysis by KPC, OXA-48, and NDM-1 enzymes with catalytic efficiency values (kcat/Km) ranging from 0.1 to 2 × 106 M-1s-1. This supports the reported results of antimicrobial activity of tebipenem against ESBL- and AmpC-producing but not carbapenemase-producing Enterobacterales isolates. Considering that CTX-M and AmpC ß-lactamases represent the primary determinants of multidrug-resistant complicated UTIs (cUTIs), the stability of tebipenem to hydrolysis by these enzymes supports the utility of its prodrug tebipenem, tebipenem pivoxil hydrobromide (TBP-PI-HBr), as an oral therapy for adult cUTIs.