Protein Phosphatase 2A as a Therapeutic Target in Pulmonary Diseases.

New disease targets and medicinal chemistry approaches are urgently needed to develop novel therapeutic strategies for treating pulmonary diseases. Emerging evidence suggests that reduced activity of protein phosphatase 2A (PP2A), a complex heterotrimeric enzyme that regulates dephosphorylation of serine and threonine residues from many proteins, is observed in multiple pulmonary diseases, including lung cancer, smoke-induced chronic obstructive pulmonary disease, alpha-1 antitrypsin deficiency, asthma, and idiopathic pulmonary fibrosis. Loss of PP2A responses is linked to many mechanisms associated with disease progressions, such as senescence, proliferation, inflammation, corticosteroid resistance, enhanced protease responses, and mRNA stability. Therefore, chemical restoration of PP2A may represent a novel treatment for these diseases. This review outlines the potential impact of reduced PP2A activity in pulmonary diseases, endogenous and exogenous inhibitors of PP2A, details the possible PP2A-dependent mechanisms observed in these conditions, and outlines potential therapeutic strategies for treatment. Substantial medicinal chemistry efforts are underway to develop therapeutics targeting PP2A activity. The development of specific activators of PP2A that selectively target PP2A holoenzymes could improve our understanding of the function of PP2A in pulmonary diseases. This may lead to the development of therapeutics for restoring normal PP2A responses within the lung.

Adopting the Rumsfeld approach to understanding the action of levodopa and apomorphine in Parkinson's disease.

Dopaminergic therapies dominate the treatment of the motor and non-motor symptoms of Parkinson's disease (PD) but there have been no major advances in therapy in many decades. Two of the oldest drugs used appear more effective than others-levodopa and apomorphine-but the reasons for this are seldom discussed and this may be one cause for a lack of progress. This short review questions current thinking on drug action and looks at whether adopting the philosophy of ex-US Secretary of State Donald Rumsfeld reveals 'unknown' aspects of the actions of levodopa and apomorphine that provide clues for a way forward. It appears that both levodopa and apomorphine have a more complex pharmacology than classical views would suggest. In addition, there are unexpected facets to the mechanisms through which levodopa acts that are either forgotten as 'known unknowns' or ignored as 'unknown unknowns'. The conclusion reached is that we may not know as much as we think about drug action in PD and there is a case for looking beyond the obvious.

[Alzheimer's disease-Which substances are at present in phase III studies?] / Alzheimer-Erkrankung ­ welche Substanzen befinden sich derzeit in Phase-III-Studien?

BACKGROUND: The recent approval of aduhelm/aducanumab by the US Food and Drug Administration (FDA) in June 2021 raised hopes that further substances against Alzheimer's disease might be approved in the near future. OBJECTIVE: The current status of phase III studies for Alzheimer's disease was evaluated. MATERIAL AND METHODS: The American database www. CLINICALTRIALS: gov was searched on 7 August 2021 for phase III studies which target the cognitive functions affected by Alzheimer's disease. The mode of action of the different substances was classified according to the Common Alzheimer's Disease Research Ontology (CADRO). RESULTS: With the applied search criteria 53 studies were found, 32 studies with 25 substances dealt with cognition, which was demonstrated by a cognition test as one of the primary outcome measures, 20 of the studies are recruiting, 4 are not yet recruiting and 8 studies are active but not recruiting. Of the studies seven target amyloid beta-peptide as well as tau protein. For 20 substances a disease modifying action is assumed. In 2022 and 2023 a total of 8 studies each are planned to be terminated. CONCLUSION: The mode of action of the substances, which are currently in studies, seems broad and for their action a modification of the disease is mostly assumed. Therefore, there is hope that in the next 2 years further drugs against Alzheimer's disease might be approved.

Nanotheranostics: A powerful next-generation solution to tackle hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is an epidemic burden and remains highly prevalent worldwide. The significant mortality rates of HCC are largely due to the tendency of late diagnosis and the multifaceted, complex nature of treatment. Meanwhile, current therapeutic modalities such as liver resection and transplantation are only effective for resolving early-stage HCC. Hence, alternative approaches are required to improve detection and enhance the efficacy of current treatment options. Nanotheranostic platforms, which utilize biocompatible nanoparticles to perform both diagnostics and targeted delivery, has been considered a potential approach for cancer management in the past few decades. Advancement of nanomaterials and biomedical engineering techniques has led to rapid expansion of the nanotheranostics field, allowing for more sensitive and specific diagnosis, real-time monitoring of drug delivery, and enhanced treatment efficacies across various malignancies. The focus of this review is on the applications of nanotheranostics for HCC. The review first explores the current epidemiology and the commonly encountered obstacles in HCC diagnosis and treatment. It then presents the current technological and functional advancements in nanotheranostic technology for cancer in general, and then specifically explores the use of nanotheranostic modalities as a promising option to address the key challenges present in HCC management.

Lipidome is lipids regulator in gastrointestinal tract and it is a life collar in COVID-19: A review.

The term lipidome is mentioned to the total amount of the lipids inside the biological cells. The lipid enters the human gastrointestinal tract through external source and internal source. The absorption pathway of lipids in the gastrointestinal tract has many ways; the 1st way, the lipid molecules are digested in the lumen before go through the enterocytes, digested products are re-esterified into complex lipid molecules. The 2nd way, the intracellular lipids are accumulated into lipoproteins (chylomicrons) which transport lipids throughout the whole body. The lipids are re-synthesis again inside the human body where the gastrointestinal lipids are: (1) Transferred into the endoplasmic reticulum; (2) Collected as lipoproteins such as chylomicrons; or (3) Stored as lipid droplets in the cytosol. The lipids play an important role in many stages of the viral replication cycle. The specific lipid change occurs during viral infection in advanced viral replication cycle. There are 47 lipids within 11 lipid classes were significantly disturbed after viral infection. The virus connects with blood-borne lipoproteins and apolipoprotein E to change viral infectivity. The viral interest is cholesterol- and lipid raft-dependent molecules. In conclusion, lipidome is important in gastrointestinal fat absorption and coronavirus disease 2019 (COVID-19) infection so lipidome is basic in gut metabolism and in COVID-19 infection success.

Acne vulgaris: new evidence in pathogenesis and future modalities of treatment.

Acne vulgaris, a common and chronic disorder of the pilosebaceous unit, affects up to 85% of adolescent and young adults. While a lot is already known about acne and its treatment, still the gaps in our understanding of acne remains. This article will review the emerging evidence in the complex pathogenesis of acne and provide an overview of the potential future therapy in management of acne vulgaris.Key pointsWhat is known? Propionibacterium acnes targeted therapy has been the mainstay in the management of acne till now.What is new? Sebocyte activity is controlled via a range of cellular pathways and hormones in addition to androgens. This has opened an array of therapeutic options to be available for treating acne in the near future.

A medical mystery of complex regional pain syndrome.

Complex regional pain syndrome (CRPS) is a condition of neuropathic pain, which is characterized by significant autonomic and inflammatory features. CRPS occurs in patients who have limb surgery, limb fractures, or trauma. Many patients may have pain resolve within twelve months of the inciting incident; however, a small subset progresses to the chronic form. This transitional process often happens by changing from warm CRPS with dominant inflammatory phase to cold CRPS, in which autonomic characteristics or manifestations dominate. Several peripheral and central mechanisms are involved, which might vary among individuals over a period of time. Other contributors include peripheral and central sensitization, autonomic alterations, inflammatory and immune changes, neurochemical changes, and psychological and genetic factors. Although effective management of the chronic CRPS form is often challenging, there are a few high quality randomized controlled trials that support the efficacy of the most commonly used therapeutic approaches.

Animal models of synucleinopathies and how they could impact future drug discovery and delivery efforts.

Introduction: Ample efforts have been carried out to develop efficient disease-modifying drugs of Parkinson's disease and related synucleinopathies. At present, the available animal models appropriate for drug development and delivery for these hitherto incurable disorders are limited. Areas covered: The author, herein, provides their perspectives on classical toxin-based animal models, which have provided some insight into their clinical picture and complex pathogenesis. They also discuss generic and virus-induced models and more recent αSyn transmitter models that reproduce essential clinical and morphological aspects but do not fully replicate the whole spectrum of the human diseases. Yet, these models have, however, provided new insights into the pathogenesis of these disorders. Expert opinion: The recent development of transgenic viral vector-induced αSyn inoculation models and those using induced pluripotent stem cells (iPSCs) in rodents, non-human primates and (rare) primates, reproducing many but not all aspects of the human synucleinopathies and their complex pathogenesis opened the door for the development of successful drugs. Despite these limits, a remarkable amount of work has already been done. However, further attention should be focused on the development of new models to enable better insight into the pathology of these proteinopathies as the basis for the future development of real disease-modifying or even preventive modalities.

Novel treatments for osteoarthritis: an update.

Osteoarthritis is the most prevalent chronic joint condition worldwide. The principles of osteoarthritis treatment are to alleviate pain and stiffness as well as maintain function, with current consensus guidelines recommending the use of a combination of conservative measures including physical therapy, analgesia, and surgical interventions such as arthroplasty. In recent years, several pharmacological therapies have emerged as potential alternatives. Although a disease-modifying osteoarthritis drug has yet to be identified, promising results have been reported in recent trials especially with serotonin-norepinephrine reuptake inhibitors, IL-1 antagonists, and antibodies to nerve growth factor. The present review aims to summarize and discuss the latest results of novel treatments for osteoarthritis and potential targets for future research.

Aptamer: A potential oligonucleotide nanomedicine in the diagnosis and treatment of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common cancers with a high mortality rate. Late diagnosis and poor prognosis are still a major drawback since curative therapies such as liver resection and liver transplantation are effective only for an early stage HCC. Development of novel molecular targeting therapies against HCC may provide new options that will improve the efficiency of the diagnosis and the success of the therapy, thus ameliorating the life expectancy of the patients. The aptamer is an oligonucleotide nanomedicine that has high binding affinity and specificity to small and large target molecules in the intracellular and extracellular environment with agonist or antagonist function. Currently, several aptamers for diagnostic and therapeutic purposes are under development to recognize different molecules of HCC. In in vitro models, the aptamer has been shown to be able to reduce the growth of HCC cells and increase the sensitivity to conventional chemotherapies. In in vivo mouse models, aptamer could induce cell apoptosis with antitumor activity. Overall data had shown that aptamer has limited toxicity and might be safe in clinical application. This review summarizes recent information of aptamer as a potential oligonucleotide nanomedicine tool, in diagnostics, targeted therapy, and as drug delivery nano-vehicles.

Is Platelet-Rich Plasma a Future Therapy in Pain Management?

Platelet-rich plasma (PRP) has the potential to regenerate tissues and decrease pain through the effects of bioactive molecules and growth factors present in alpha granules. Several PRP preparation systems are available with varying end products, doses of growth factors, and bioactive molecules. This article presents the biology of PRP, the preparation of PRP, and the effects PRP-related growth factors have on tissue healing and repair. Based on available evidence-based literature, the success of PRP therapy depends on the method of preparation and composition of PRP, the patient's medical condition, anatomic location of the injection, and the type of tissue injected.