NOTCH Signaling Pathway: Occurrence, Mechanism, and NOTCH-Directed Therapy for the Management of Cancer.

It is now well understood that many signaling pathways are vital in carrying out and controlling essential pro-survival and pro-growth cellular functions. The NOTCH signaling pathway, a highly conserved evolutionary signaling pathway, has been thoroughly studied since the discovery of NOTCH phenotypes about 100 years ago in Drosophila melanogaster. Abnormal NOTCH signaling has been linked to the pathophysiology of several diseases, notably cancer. In tumorigenesis, NOTCH plays the role of a "double-edged sword," that is, it may act as an oncogene or as a tumor suppressor gene depending on the nature of the context. However, its involvement in several cancers and inhibition of the same provides targeted therapy for the management of cancer. The use of gamma (γ)-secretase inhibitors and monoclonal antibodies for cancer treatment involved NOTCH receptors inhibition, leading to the possibility of a targeted approach for cancer treatment. Likewise, several natural compounds, including curcumin, resveratrol, diallyl sulfide, and genistein, also play a dynamic role in the management of cancer by inhibition of NOTCH receptors. This review outlines the functions and structure of NOTCH receptors and their associated ligands with the mechanism of the signaling pathway. In addition, it also emphasizes the role of NOTCH-targeted nanomedicine in various cancer treatment strategies.

Understanding the role of hyperglycemia and the molecular mechanism associated with diabetic neuropathy and possible therapeutic strategies.

Diabetic neuropathy is a neuro-degenerative disorder that encompasses numerous factors that impact peripheral nerves in the context of diabetes mellitus (DM). Diabetic peripheral neuropathy (DPN) is very prevalent and impacts 50% of diabetic patients. DPN is a length-dependent peripheral nerve lesion that primarily causes distal sensory loss, discomfort, and foot ulceration that may lead to amputation. The pathophysiology is yet to be fully understood, but current literature on the pathophysiology of DPN revolves around understanding various signaling cascades involving the polyol, hexosamine, protein-kinase C, AGE, oxidative stress, and poly (ADP ribose) polymerase pathways. The results of research have suggested that hyperglycemia target Schwann cells and in severe cases, demyelination resulting in central and peripheral sensitization is evident in diabetic patients. Various diagnostic approaches are available, but detection at an early stage remains a challenge. Traditional analgesics and opioids that can be used "as required" have not been the mainstay of treatment thus far. Instead, anticonvulsants and antidepressants that must be taken routinely over time have been the most common treatments. For now, prolonging life and preserving the quality of life are the ultimate goals of diabetes treatment. Furthermore, the rising prevalence of DPN has substantial consequences for occupational therapy because such therapy is necessary for supporting wellness, warding off other chronic-diseases, and avoiding the development of a disability; this is accomplished by engaging in fulfilling activities like yoga, meditation, and physical exercise. Therefore, occupational therapy, along with palliative therapy, may prove to be crucial in halting the onset of neuropathic-symptoms and in lessening those symptoms once they have occurred.

Impact of armed conflict on health professionals' education and training in Syria: a systematic review.

OBJECTIVES: To provide an overview of the holistic impact of the armed conflict on medical education and health professionals' training (MEHPT) in Syria. SETTING: Syria is a country which underwent an armed conflict for 10 years and suffered from the weaponisation of health. METHODS: A mixed-methods systematic review including quantitative, qualitative, mixed-methods and textual literature between 2011 and 2021 including papers on the Syrian MEHPT undergraduate and postgraduate education and training personnel (including medicine, dentistry, pharmacy, nursing, midwifery and allied health professionals). The electronic search was conducted in October 2018 in Embase, Global Health, Medline, PsycINFO, Web of Science, PubMed, Scopus, CINAHL and grey literature. And an update to the search was conducted in August 2021 in PubMed, Google Scholar and Trip database. OUTCOMES: The impact of conflict on the MEHPT system, personnel, experiences, challenges and channels of support. RESULTS: Of the 5710 citations screened, 70 met the inclusion criteria (34 quantitative, 3 qualitative, 1 mixed-method, and 32 reports and opinion papers). The two major cross-cutting themes were attacks on MEHPT and innovations (present in 41% and 44% of the papers, respectively), followed by challenges facing the MEHPT sector and attitudes and knowledge of trainees and students, and lastly health system and policy issues, and narrating experiences. CONCLUSION: Conflict in Syria has politicised all aspects of MEHPT. Influenced by political control, the MEHPT system has been divided into two distinguished geopolitical contexts; government-controlled areas (GCAs) and non-GCAs (NGCAs), each having its characteristics and level of war impact. International and regional academic institutes collaboration and coordination efforts are needed to formulate educational platforms using innovative approaches (such as online/blended/store-and-forward/peer-training/online tutoring) to strengthen and build the capacity of the health workforce in conflict-affected areas.

Biotic elicitor-induced changes in growth, antioxidative defense, and metabolites in an improved prickleless Solanum viarum.

Solanum viarum serves as a raw material for the steroidal drug industry due to its alkaloid and glycoalkaloid content. Elicitation is well-known for measuring the increase in the yield of bioactive compounds in in vitro cultures. The current study was performed for the accumulation of metabolites viz. solasodine, solanidine, and α-solanine in S. viarum culture using microbial-based elicitors added in 1%, 3%, 5%, and 7% on 25th and 35th day of culture period and harvested on 45th and 50th days of culture cycle. The treatment of 3% Trichoderma reesei and Bacillus tequilensis culture filtrate (CF) significantly increased biomass, alkaloids/glycoalkaloid content, and yield in S. viarum. T. reesei was found to be the best treatment for enhanced growth (GI = 11.65) and glycoalkaloid yield (2.54 mg DW plant-1) after the 50th day of the culture cycle when added on the 25th day. The abundance of gene transcripts involved in the biosynthesis of alkaloids/glycoalkaloids, revealed by quantitative real-time PCR expression analysis correlates with the accumulation of their respective metabolites in elicited plants. Biochemical analysis shows that elicited plants inhibited oxidative damage caused by reactive oxygen species by activating enzymes (superoxide dismutase and ascorbate peroxidase) as well as non-enzymatic antioxidant mechanisms (alkaloids, total phenols, total flavonoids, carotenoids, and proline). The findings of this study clearly demonstrate that the application of T. reesei and B. tequilensis CF at a specific dose and time significantly improve biomass as well as upregulates the metabolite biosynthetic pathway in an important medicinal plant- S. viarum. KEY POINTS: • Biotic elicitors stimulated the alkaloids/glycoalkaloid content in S. viarum plant cultures. • T. reesei was found to be most efficient for enhancing the growth and alkaloids content. • Elicited plants activate ROS based-defense mechanism to overcome oxidative damage.

Growth and alkaloid production along with expression profiles of biosynthetic pathway genes in two contrasting morphotypes of prickly and prickleless Solanum viarum Dunal.

Growth and production kinetics of three important glycoalkaloids viz. α-solanine, solanidine, and solasodine in two contrasting prickly and prickleless plants of Solanum viarum Dunal were evaluated under in vitro conditions. The prickleless plants showed improved accumulation of total glycoalkaloid content [7.11 and 6.85 mg g-1 dry weight (DW)] and growth (GI = 11.08 and 19.26) after 45 and 50 days of culture cycle, respectively. For higher biomass (91.18 g l-1) as well as glycoalkaloid (52.56 mg l-1) recovery, the prickleless plants served as highly profitable platform. All the three studied glycoalkaloids were identified and quantified by mass spectrometry and HPLC. All the three studied glycoalkaloids accumulated in age-dependent manner. The presence of two constituents, i.e., solasodine and solanidine mainly contributed for higher accumulation of total glycoalkaloid content in the prickleless plants. However, the synthesis of α-solanine was highly age specific and could be detected after 4 to 5 weeks of culture cycle in both prickle containing as well as prickleless plants of S. viarum. The higher accumulation of glycoalkaloids in prickleless plants was also supported with the expression analysis of six key pathway enzymes viz. mevalonate kinase (MVK), 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMGR), farnesyl diphosphate synthase (FPS), UDP-galactose/solanidine galactosyltransferase (SGT1), UDP-glucose/solanidine glucosyltransferase (SGT2), and cytochrome P450 monooxygenase (CYP). The results indicated that the plants harvested after 45 and 50 days of culture cycle accumulated maximum bioactive in-demand glycoalkaloids in the prickly and prickleless plants of S. viarum Dunal, respectively.