Potent anti-inflammatory and anti-apoptotic activities of electrostatically complexed C-peptide nanospheres ameliorate diabetic nephropathy.

In the present era of "Diabetic Pandemic", peptide-based therapies have generated immense interest however, are facing odds due to inevitable limitations like stability, delivery complications and off-target effects. One such promising molecule is C-peptide (CPep, 31 amino acid polypeptide with t1/2 30 min); it is a cleaved subunit of pro-insulin, well known to suppress microvascular complications in kidney but has not been able to undergo translation to the clinic till date. Herein, a polymeric CPep nano-complexes (NPX) was prepared by leveraging electrostatic interaction between in-house synthesized cationic, polyethylene carbonate (PEC) based copolymer (Mol. wt. 44,767 Da) and negatively charged CPep (Mol. wt. 3299 Da) at pH 7.4 and further evaluated in vitro and in vivo. NPX exhibited a spherical morphology with a particle size of 167 nm and zeta potential equivalent to +10.3, with 85.70 % of CPep complexation efficiency. The cellular uptake of FITC-tagged CPep NPX was 95.61 % in normal rat kidney cells, NRK-52E. Additionally, the hemocompatible NPX showed prominent cell-proliferative, anti-oxidative (1.8 folds increased GSH; 2.8 folds reduced nitrite concentration) and anti-inflammatory activity in metabolic stress induced NRK-52E cells as well. The observation was further confirmed by upregulation of anti-apoptotic protein BCl2 by 3.5 folds, and proliferative markers (ß1-integrin and EGFR) by 3.5 and 2.3 folds, respectively, compared to the high glucose treated control group. Pharmacokinetic study of NPX in Wistar rats revealed a 6.34 folds greater half-life than free CPep. In in-vivo efficacy study in STZ-induced diabetic nephropathy animal model, NPX reduced blood glucose levels and IL-6 levels significantly by 1.3 and 2.5 folds, respectively, as compared to the disease control group. The above findings suggested that NPX has tremendous potential to impart sustained release of CPep, resulting in enhanced efficacy to treat diabetes-induced nephropathy and significantly improved renal pathology.

The Rarity of Maxillary Osteomyelitis: Insights From a Unique Case Report.

Maxillary osteomyelitis is a rare bone infection and is rarer to come across with the advent of advanced antibiotic therapies. It is often linked to immunocompromised conditions, namely diabetes mellitus, cancer, and chronic alcoholism, as they increase the chances of developing osteomyelitis. We present a rare case of maxillary osteomyelitis along with an infraorbital abscess in a 32-year-old male patient with uncontrolled diabetes. The patient complained of dental pain, facial swelling, and visual disturbances. The patient was managed with sequestrectomy along with curettage, incision, and drainage of orbital abscess. The patient responded well to surgery and had no complications post-surgery. As radiographic signs may present late, the authors aim to highlight the significance of thorough clinical examination and good patient history. Prompt radical treatment is necessary to avoid any severe consequences.

Immunological Nuances and Complications of Pediatric Organ Transplant: A Narrative Review.

Organ transplantation is considered an exaggerated immune state in which the body reacts in an elaborate cascade of reactions against the lifesaving graft transplanted. Unrepairable organ damage is the main indication for a pediatric patient to undergo a transplant. The host and the donor must fulfill the criteria for a successful transplant to have as few side effects as possible. There has been much-needed research in the domain of surgery of organ transplantation, thereby extending into the pediatric age group. This article elaborates on the post-transplant management, the immuno-biochemistry aspect, and its post-surgery treatment. The post-surgery period requires great emphasis as morbidity and mortality are highest. There is much to understand about managing transplant patients to avoid complications such as infections, hypertension, or side effects of immunosuppressive drugs. The treating clinician faces the challenges of managing the dose and frequency of immuno-suppressive medicines to prevent complications in the patients. If the dose is inadequate, there are chances of graft rejection. If the immuno-suppression is prolonged, there may be chances of infections in the patient. This article aims to summarize the mechanism of graft rejection and put forth the need for further research about creating a universal protocol for managing a patient's immune system post-transplant. The authors hope this protocol will help the clinician better understand the patient's current state and help in appropriately using immuno-suppressive drugs. It calls upon the need for a reliable and easily repeatable battery of investigations that will help solve this dilemma.

Resistance to Resilience: Understanding Post-surgical Hormone Therapy in Breast Cancer Care.

Breast cancer is one of the most common types of cancer affecting women worldwide. Over the years, breast cancer has become a major public health concern, and its incidence is rising globally. The treatment of breast cancer does not stop with surgical intervention, but adjuvant therapies are administered to improve patient outcomes post-surgery based on the type of breast cancer diagnosed. This review focuses on the value of hormone therapy (HT) in improving the prognosis of breast cancer patients and why adhering to adjuvant treatment post-surgery is difficult for patients. HT aims to reduce the chances of breast cancer recurrence after surgical treatment. Even though HT is life-saving, patients tend to not adhere to the therapy due to various factors such as side effects, age-related issues, and socioeconomic status. Most patients stop adhering to the therapy as the duration can be as long as 5-10 years, and the quality of life is greatly impacted due to the side effects of the treatment. This review examines the possible factors leading to non-adherence to HT and tries to propose possible interventions that might improve patient compliance with the treatment. This article not only focuses on the impact of side effects of HT on patients' quality of life but also tries to understand the problems faced by breast cancer patients in adhering to HT.

Belinostat loaded lipid-polymer hybrid nanoparticulate delivery system for breast cancer: improved pharmacokinetics and biodistribution in a tumor model.

Despite various treatment modalities for breast cancer, it still persists as one of the most diagnosed types of cancer in females. The recent investigations in the epigenetics of breast cancer reveal several aberrations in the expression levels of various HDAC enzymes. Henceforth, the present work entails the formulation and characterization of a lipid polymer-based hybrid nanoparticulate (LPN) system for delivery of an epigenetic modulator drug, Belinostat, for its clinical application in breast cancer. The size of Belinostat nanoparticles prepared using a modified hot homogenization method was found to be 166.6 ± 19.95 nm with an encapsulation efficiency of 94.5 ± 5.1%. In vitro characterization for cytotoxicity, cellular uptake, and protein expression in two different breast cancer cells, 4T1 and MCF 7, revealed the superiority of the formulation in comparison with the free drug in MCF 7 cells. Subsequently, the behaviour of the formulation in in vivo settings of healthy and breast cancer xenograft bearing animals was analyzed using pharmacokinetic and biodistribution studies. The results revealed that the formulation demonstrated multi-fold improvement in the pharmacokinetic parameters in tumor bearing animals when compared with the free drug while no difference in pharmacokinetic behaviour was observed in healthy animals indicating the altered biodistribution and specificity of the formulation in breast tumor. This was confirmed by the biodistribution studies exhibiting 20-fold improved uptake and retention of the nanoparticulate formulation in tumor tissues of the animal model at the end of 4 h. Thus, the developed LPN system holds potential to act as a novel drug delivery system for Belinostat with several advantages over the free drug.

The Application of Deep Learning to Electroencephalograms, Magnetic Resonance Imaging, and Implants for the Detection of Epileptic Seizures: A Narrative Review.

Epilepsy is a neurological disorder characterized by recurrent seizures affecting millions worldwide. Medically intractable seizures in epilepsy patients are not only detrimental to the quality of life but also pose a significant threat to their safety. Outcomes of epilepsy therapy can be improved by early detection and intervention during the interictal window period. Electroencephalography is the primary diagnostic tool for epilepsy, but accurate interpretation of seizure activity is challenging and highly time-consuming. Machine learning (ML) and deep learning (DL) algorithms enable us to analyze complex EEG data, which can not only help us diagnose but also locate epileptogenic zones and predict medical and surgical treatment outcomes. DL models such as convolutional neural networks (CNNs), inspired by visual processing, can be used to classify EEG activity. By applying preprocessing techniques, signal quality can be enhanced by denoising and artifact removal. DL can also be incorporated into the analysis of magnetic resonance imaging (MRI) data, which can help in the localization of epileptogenic zones in the brain. Proper detection of these zones can help in good neurosurgical outcomes. Recent advancements in DL have facilitated the implementation of these systems in neural implants and wearable devices, allowing for real-time seizure detection. This has the potential to transform the management of drug-refractory epilepsy. This review explores the application of ML and DL techniques to Electroencephalograms (EEGs), MRI, and wearable devices for epileptic seizure detection. This review briefly explains the fundamentals of both artificial intelligence (AI) and DL, highlighting these systems' potential advantages and undeniable limitations.

Scientific Evolution of Artificial Heart Valves: A Narrative Review.

Cardiovascular disorders have always been the top contributors to the number of mortality occurring worldwide. But the last few decades have seen a drop in those numbers as the lives of millions of people have been saved due to ground-breaking advances in both therapeutic and surgical treatment modalities. Achieving this level of scientific glory in cardiology was a challenging feat. The credit goes to the scientists and physicians of the previous century who, despite their time's technological limitations, made discoveries and laid a solid foundation for modern medicine. Valvular complications are a major part of the global burden of cardiac diseases. The ongoing development of heart valve replacements remains a fascinating subject, as it continues to progress. Valve replacements comprise either mechanical heart valves or bioprosthetic heart valves. Both types of valves have their merits and demerits; their usage depends mostly on individual patient requirements. This article aims to review the evolution of the implantation of heart valves, and it is the objective of this article to give credit to scientists and physicians for their contributions. The article highlights the research gaps in finding more durable materials and the scope of further research in creating a heart valve that can be universally used for better patient outcomes.

Calcaneal Spurs: A Potentially Debilitating Disorder.

Feet are often the most neglected part of the body, all the while being the highly dependent part of daily work and mobility. The lack of attention to them can lead to painful conditions such as calcaneal spurs and associated conditions. Calcaneal spurs are bony projections that form around the calcaneal bone, the strongest, most significant, and posterior-most bone in the feet. The classic symptom of the calcaneal spur is talalgia, commonly known as heel pain. There are many causes of heel pain, which are usually associated with calcaneal spurs. Hence it becomes imperative to diagnose and treat them effectively. The development of calcaneal spur is shrouded in mystery, and why a few individuals are more prone to developing the condition than others depends on their gender, age, occupation, and lifestyle. Calcaneal spurs are seen in association with many diseases. It is also regarded as the etiological factor in plantar fasciitis and increasing body weight and as a complication in arthropathies, Gout, pes cavus, and pes planus. This review article aims to highlight a relationship between those factors while also summarizing the treatment modalities present today. Hence, it promotes the usage of a model for administering treatment based on a tier-wise follow-up procedure, where the response to a particular treatment is recorded. If it does not resolve the spur, the treatment progresses to the next tier. This review article hopes to shed light on the understanding and treatment of calcaneal spurs.

The Actions of Lithium on Glaucoma and Other Senile Neurodegenerative Diseases Through GSK-3 Inhibition: A Narrative Review.

Glaucoma can be described as a set of progressive optic neuropathies. They cause a gradual, irreversible loss of the field of view, which concludes in complete blindness. Evidence suggests that patients who have glaucoma face a greater risk of suffering from senile dementia. Dementia is a group of conditions that occur in old age individuals. Neurodegeneration is a characteristic pathological feature of dementia, the progression of which causes a decline in cognition, which may be accompanied by memory loss. Severe dementia in old individuals usually presents as Alzheimer's disease, which significantly contributes to a load of dementia in India. Parkinsonism is another common neurodegenerative disease that is known to occur in the elderly. The WNT (Wingless-related integration site)/ß-catenin pathway is a multistep process that is responsible for the regulation of various cellular functions. Lithium can up-regulate this pathway by disrupting Glycogen synthase kinase-3ß (GSK-3ß). This action of Lithium can effectively counteract neuroinflammation and neurodegeneration. The current use of Lithium remains majorly confined to its use for episodes of mania in bipolar disorder (BD). However, recent literature gives insight into how Lithium can improve the visual field in glaucomatous eyes. Symptomatic improvement after lithium administration is seen as it has neuroprotective actions on the retinal ganglion cells (RGCs). Prolonged lithium use improves axonal regeneration and neuronal survival. Lithium also improves the worsening of symptoms in other dementia-related neurodegenerative diseases like Alzheimer's and Parkinsonism. The physiological actions of Lithium can be utilized in providing effective, holistic therapy options in pathologically related senile degenerative disorders. Significantly better results can be obtained if Lithium therapy is given in conjunction with the drugs used to manage these disorders.

National Hypertension Guidelines: A Review of the India Hypertension Control Initiative (IHCI) and Future Prospects.

Hypertension is a silent killer; however, the treatment of hypertension is simple, effective, readily available, and needs to be continued lifelong. It is a significant health problem that is included under the umbrella of non-communicable disease conditions and has a strong alliance with cardiovascular morbidity and mortality. The India Hypertension Control Initiative (IHCI) is an extensive program in India that involves the Indian Council of Medical Research, the Ministry of Health and Family Welfare (Government of India), the state governments of India, and World Health Organization Country Office for India (WHO-India). The IHCI is a multi-partner initiative carried forward systemically across various states. The states are categorized into Grade I and Grade II. There is the involvement of specialized teams of cardiovascular experts and health officials to insure precise execution and seamless healthcare service.  The implementation of the free and easy-to-use mobile application and software, Simple (Resolve to Save Lives, New York City, United States), in the analysis and storage of data, is a novel step taken to insure safe record keeping and follow-ups. Emphasis is on the adoption of demography-specific interventional methods and drugs, and proper acquisition and storage of these drugs is the key step. Treatment modalities involve the adoption of medicines and lifestyle modifications as a combined recipe. Advancements have been made in the area of drug development like gene therapies but they seem to show low success rates at the given moment. Adoption of lifestyle modifications along with medications is the gold standard treatment option. This review article aims to shed light on the current status of IHCI, its milestones, and the future of the initiative in India.

Role of Chain Length and Degree of Unsaturation of Fatty Acids in the Physicochemical and Pharmacological Behavior of Drug-Fatty Acid Conjugates in Diabetes.

Several drug-fatty acid (FA) prodrugs have been reported to exhibit desirable physicochemical and pharmacological profile; however, comparative beneficial effects rendered by different FAs have not been explored. In the present study, four different FAs (linoleic acid, oleic acid, palmitic acid, and α-lipoic acid) were selected based on their chain length and degree of unsaturation and conjugated to Lisofylline (LSF), an antidiabetic molecule to obtain different drug-FA prodrugs and characterized for molecular weight, hydrophobicity, purity, self-assembly, and efficacy in vitro and in vivo in type 1 diabetes model. Prodrugs demonstrated a 2- to 6-fold increase in the plasma half-life of LSF. Diabetic animals treated with prodrugs, once daily for 5 weeks, maintained a steady fasting blood glucose level with a significant increase in insulin level, considerable restoration of biochemical parameters, and preserved ß-cells integrity. Among the different LSF-FA prodrugs, LSF-OA and LSF-PA demonstrated the most favorable physicochemical, systemic pharmacokinetic, and pharmacodynamic profiles.

Nanoparticulate tablet dosage form of lisofylline-linoleic acid conjugate for type 1 diabetes: in situ single-pass intestinal perfusion (SPIP) studies and pharmacokinetics in rat.

Lisofylline (LSF) is an anti-inflammatory molecule with high aqueous solubility and rapid metabolic interconversion to its parent drug, pentoxifylline (PTX) resulting in very poor pharmacokinetic (PK) parameters, necessitating high dose and dosing frequency. In the present study, we resolved the physicochemical and pharmacokinetic limitations associated with LSF and designed its oral dosage form as a tablet for effective treatment in type 1 diabetes (T1D). Self-assembling polymeric micelles of LSF (lisofylline-linoleic acid polymeric micelles (LSF-LA PLM)) were optimized for scale-up (6 g batch size) and lyophilized followed by compression into tablets. Powder blend and tablets were evaluated as per USP. LSF-LA PLM tablet so formed was evaluated for in vitro release in simulated biological fluids (with enzymes) and for cell viability in MIN-6 cells. LSF-LA PLM in tablet formulation was further evaluated for intestinal permeability (in situ) along with LSF and LSF-LA self-assembled micelles (SM) as controls in a rat model using single-pass intestinal perfusion (SPIP) study. SPIP studies revealed 1.8-fold higher oral absorption of LSF-LA from LSF-LA PLM as compared to LSF-LA SM and ~5.9-fold higher than LSF (alone) solution. Pharmacokinetic studies of LSF-LA PLM tablet showed greater Cmax than LSF, LSF-LA, and LSF-LA PLM. Designed facile LSF-LA PLM tablet dosage form has potential for an immediate decrease in the postprandial glucose levels in patients of T1D.

Therapeutic agents for targeting desmoplasia: current status and emerging trends.

Desmoplasia is a major barrier to chemotherapy in several cancers, particularly pancreatic ductal adenocarcinoma and breast cancer. Tumors comprise of cellular and noncellular components and chemoresistant cancer stem cells (CSCs) with established signaling pathways. In this review, we discuss drugs, such as pentoxifylline, aspirin, and metformin, that have been repurposed and investigated for their antidesmoplastic activity in combination with antitumor drugs. We also highlight less explored new small-molecule drugs, and gene and peptide-based therapeutics for the treatment of desmoplasia and to target CSCs. Promising results from preclinical studies have encouraged several clinical trials to evaluate these antidesmoplastic agents as adjunct to chemotherapy.

Multi-component clobetasol-loaded monolithic lipid-polymer hybrid nanoparticles ameliorate imiquimod-induced psoriasis-like skin inflammation in Swiss albino mice.

Lipid-polymer hybrid nanoparticles (LPNs) exhibit several advantages over polymeric and non-polymeric systems in terms of improved drug loading, controlled release, stability, and cellular uptake. Herein we report a scalable and stable monolithic lipid-polymer hybrid nanoparticles (LPNs) consisting of a combination of lipids (solid and liquid) and an amphiphilic copolymer, mPEG-PLA. Clobetasol propionate, a topical corticosteroid, was encapsulated in the hydrophobic core of these LPNs that showed spherical shaped particles with a z-average size of 94.8 nm (PDI = 0.213) and encapsulation efficiency of 84.3%. These clobetasol loaded LPNs (CP/LPNs) were formulated into a topical hydrogel using carbopol 974P. CP/LPNs gel showed a sustained in vitro clobetasol release for 7 days with no burst release and 6 month stability at 2-8°C and room temperature. Further, CP/LPNs showed an improved cellular uptake with significant growth inhibition of HaCaT cells. In ex vivo studies, these LPNs penetrated into the viable epidermis and dermis region of the psoriatic skin with undetectable quantities leaching to the reservoir. Further, the topical application of CP/LPNs gel on Swiss albino mice with psoriasis-like inflammation showed negligible leaching of clobetasol into the systemic circulation. Efficacy assessment showed significantly improved PASI score, reduced skin damage and proliferation after treatment with CP/LPNs gel as compared to marketed product (Clobetamos™). Collectively, the enhanced cellular uptake, high skin penetration with increased skin retention, and improved efficacy demonstrate the potential of these LPNs for future clinical application.